text:
"""
AutoFocus Tags Feed integration
"""
from typing import Dict, List, Optional

import urllib3

import demistomock as demisto  # noqa: F401
from CommonServerPython import *  # noqa: F401

# disable insecure warnings
urllib3.disable_warnings()

''' CONSTANTS '''

DATE_FORMAT = '%Y-%m-%dT%H:%M:%SZ'  # ISO8601 format with UTC, default in XSOAR

AF_TAGS_DATE_FORMAT = '%Y-%m-%d %H:%M:%S'

TAG_CLASS_TO_DEMISTO_TYPE = {
    'malware_family': ThreatIntel.ObjectsNames.MALWARE,
    'actor': ThreatIntel.ObjectsNames.THREAT_ACTOR,
    'campaign': ThreatIntel.ObjectsNames.CAMPAIGN,
    'malicious_behavior': ThreatIntel.ObjectsNames.ATTACK_PATTERN,
}

MAP_RELATIONSHIPS = {
    ThreatIntel.ObjectsNames.MALWARE:
        {
            ThreatIntel.ObjectsNames.MALWARE: 'related-to',
            ThreatIntel.ObjectsNames.THREAT_ACTOR: 'used-by',
            ThreatIntel.ObjectsNames.CAMPAIGN: 'used-by',
            ThreatIntel.ObjectsNames.ATTACK_PATTERN: 'used-by'
        },
    ThreatIntel.ObjectsNames.THREAT_ACTOR:
        {
            ThreatIntel.ObjectsNames.MALWARE: 'uses',
            ThreatIntel.ObjectsNames.THREAT_ACTOR: 'related-to',
            ThreatIntel.ObjectsNames.CAMPAIGN: 'attributed-by',
            ThreatIntel.ObjectsNames.ATTACK_PATTERN: 'uses'
        },
    ThreatIntel.ObjectsNames.CAMPAIGN:
        {
            ThreatIntel.ObjectsNames.MALWARE: 'uses',
            ThreatIntel.ObjectsNames.THREAT_ACTOR: 'attributed-to',
            ThreatIntel.ObjectsNames.CAMPAIGN: 'related-to',
            ThreatIntel.ObjectsNames.ATTACK_PATTERN: 'used-by'
        },
    ThreatIntel.ObjectsNames.ATTACK_PATTERN:
        {
            ThreatIntel.ObjectsNames.MALWARE: 'uses',
            ThreatIntel.ObjectsNames.THREAT_ACTOR: 'used-by',
            ThreatIntel.ObjectsNames.CAMPAIGN: 'uses',
            ThreatIntel.ObjectsNames.ATTACK_PATTERN: 'related-to'
        },

}

SCORES_MAP = {
    ThreatIntel.ObjectsNames.MALWARE: ThreatIntel.ObjectsScore.MALWARE,
    ThreatIntel.ObjectsNames.THREAT_ACTOR: ThreatIntel.ObjectsScore.THREAT_ACTOR,
    ThreatIntel.ObjectsNames.CAMPAIGN: ThreatIntel.ObjectsScore.CAMPAIGN,
    ThreatIntel.ObjectsNames.ATTACK_PATTERN: ThreatIntel.ObjectsScore.ATTACK_PATTERN,
}

# The page size in the AutoFocus response (can be 1-200)
PAGE_SIZE = 50

''' CLIENT CLASS '''

class Client(BaseClient):
    """
    Client class to interact with AutoFocus API
    Args:
        api_key: AutoFocus API Key.
    """

    def __init__(self, api_key, base_url, verify, proxy):
        super().__init__(base_url=base_url, verify=verify, proxy=proxy)
        self.headers = {
            'apiKey': api_key,
            'Content-Type': 'application/json'
        }

        add_sensitive_log_strs(api_key)

    def get_tags(self, data: Dict[str, Any]):
        res = self._http_request('POST',
                                 url_suffix='tags',
                                 headers=self.headers,
                                 json_data=data,
                                 timeout=90,
                                 )
        return res

    def get_tag_details(self, public_tag_name: str):
        res = self._http_request('POST',
                                 url_suffix=f'tag/{public_tag_name}',
                                 headers=self.headers,
                                 timeout=90,
                                 )
        return res

    def build_iterator(self, is_get_command: bool, limit: int = -1) -> list:
        """
        Retrieves all entries from the feed.
        This method implements the logic to get tags from the feed.
        Args:
            limit: max amount of results to return
            is_get_command: whether this method is called from the get-indicators-command
        Returns:
            A list of objects, containing the indicators.
        """

        results: list = []
        if is_get_command:
            # since get-indicators command is used mostly for debug,
            # getting the tags from the first page is sufficient
            page_num = 0
        else:
            integration_context = get_integration_context()
            # if so, than this is the first fetch
            if not integration_context:
                page_num = 0
                time_of_first_fetch = date_to_timestamp(datetime.now(), DATE_FORMAT)
                set_integration_context({'time_of_first_fetch': time_of_first_fetch})
            else:
                page_num = integration_context.get('page_num', 0)
        get_tags_response = self.get_tags({
            'pageNum': page_num,
            'pageSize': PAGE_SIZE,
            'sortBy': 'created_at'
        })
        tags = get_tags_response.get('tags', [])
        # when finishing the "first level fetch" (getting all the tags from the feed), the next call to the api
        # will be with a page num greater than the total pages, and the api should return an empty tags list.
        if not tags:
            # now the fetch will retrieve only tags that has been updated after the last fetch time
            return incremental_level_fetch(self)
        # this is the "first level fetch" logic. Every fetch returns at most PAGE_SIZE indicators from the feed.
        for tag in tags:
            if is_get_command and limit > 0:
                if len(results) >= limit:
                    return results
            public_tag_name = tag.get('public_tag_name', '')
            tag_details_response = self.get_tag_details(public_tag_name)
            results.append(tag_details_response)
        if not is_get_command:
            page_num += 1
            context = get_integration_context()
            context['page_num'] = page_num
            set_integration_context(context)
        return results

''' HELPER FUNCTIONS '''

def incremental_level_fetch(client: Client) -> list:
    """
    This method implements the incremental level of the feed. It checks if any updates
    have been made in the tags from the last fetch time, and returns the updated tags.
    Args:
        client: Client object
    Returns:
        A list of tag details represents the tags that have been updated.
    """

    results: list = []
    integration_context = get_integration_context()
    # This field saves tags that have been updated since the last fetch time and need to be updated in demisto
    list_of_all_updated_tags = argToList(integration_context.get('tags_need_to_be_fetched', ''))
    time_from_last_update = integration_context.get('time_of_first_fetch')
    index_to_delete = 0
    for tag in list_of_all_updated_tags:
        # if there are such tags, we first get all of them, so we wont miss any tags
        if len(results) < PAGE_SIZE:
            results.append(client.get_tag_details(tag.get('public_tag_name', '')))
            index_to_delete += 1
        else:
            context = get_integration_context()
            context['time_of_first_fetch'] = date_to_timestamp(datetime.now(), DATE_FORMAT)
            context['tags_need_to_be_fetched'] = list_of_all_updated_tags[index_to_delete:]
            set_integration_context(context)
            return results

    list_of_all_updated_tags = get_all_updated_tags_since_last_fetch(client,
                                                                     list_of_all_updated_tags,
                                                                     time_from_last_update)

    # add only PAGE_SIZE tag_details to results, so we wont make too many calls to the API
    index_to_delete = 0
    for tag in list_of_all_updated_tags:
        if len(results) < PAGE_SIZE:
            public_tag_name = tag.get('public_tag_name')
            response = client.get_tag_details(public_tag_name)
            results.append(response)
            index_to_delete += 1
        else:
            break
    # delete from the list all tags that will be returned this fetch
    list_of_all_updated_tags = list_of_all_updated_tags[index_to_delete:]
    # update integration context
    context = get_integration_context()
    context['tags_need_to_be_fetched'] = list_of_all_updated_tags
    context['time_of_first_fetch'] = date_to_timestamp(datetime.now(), DATE_FORMAT)
    set_integration_context(context)
    return results

def get_all_updated_tags_since_last_fetch(client: Client,
                                          list_of_all_updated_tags: list,
                                          time_from_last_update: int) -> list:
    """
    This method makes API calls to gat all the tags that has been updated since the last fetch time
    It filters the tags according to the update time (and gets another pages if needed),
    adds them to list_of_all_updated_tags and returns it.
    Args:
        client: Client object
        list_of_all_updated_tags:
        time_from_last_update:

    Returns:
        List of all tags that has been updated and need to be fetched.
    """

    page_num = 0
    has_updates = True
    while has_updates:
        response = client.get_tags({
            'pageNum': page_num,
            'pageSize': 200,
            'sortBy': 'updated_at',
            'order': 'desc'
        })
        tags = response.get('tags', [])
        for tag in tags:
            update_time = tag.get('updated_at')
            update_time = datetime.strptime(update_time, AF_TAGS_DATE_FORMAT).strftime(
                DATE_FORMAT) if update_time else None
            update_time = date_to_timestamp(update_time, DATE_FORMAT)
            if update_time >= time_from_last_update:
                # this means that the tag hase been updated, so it needs to be added to the list of updated tags
                list_of_all_updated_tags.append(
                    {'public_tag_name': tag.get('public_tag_name')})
            else:
                has_updates = False
                break
        page_num += 1
    # the list contained all tags that has been updated since the last fetch time
    return list_of_all_updated_tags

def get_tag_class(tag_class: Optional[str], source: Optional[str]) -> Optional[str]:
    """
    Returns the tag class as demisto indicator type.
    Args:
        tag_class: tag class name
        source: tag source
    Returns:
        The tag class as demisto indicator type, None if class is not specified.
    """

    # indicators from type Attack Pattern are only created if its source is unit42
    if not tag_class:
        return None
    if (tag_class != 'malicious_behavior') or (tag_class == 'malicious_behavior' and source == 'Unit 42'):
        return TAG_CLASS_TO_DEMISTO_TYPE.get(tag_class)
    return None

def get_tag_groups_names(tag_groups: list) -> list:
    """
    Returns the tag groups as a list of the groups names.
    Args:
        tag_groups: list of all groups
    Returns:
        The tag groups as a list of the groups names
    """

    # tag_groups is a list of dictionaries, each contains a tag group name and its description
    results = []
    if len(tag_groups) > 0:
        for group in tag_groups:
            tag_group_name = group.get('tag_group_name', '')
            if tag_group_name:
                results.append(tag_group_name)
    return results

def create_publications(refs: list) -> list:
    """
    Creates the publications list of the indicator
    Args:
        refs: a list of all publications
    Returns:
        A list of publications of the indicator
    """

    publications: list = []
    if len(refs) > 0:
        for ref in refs:
            url = ref.get('url', '')
            source = ref.get('source', '')
            time_stamp = ref.get('created', '')
            title = ref.get('title', '')
            publications.append({'link': url, 'title': title, 'source': source, 'timestamp': time_stamp})
    return publications

def create_indicators_fields(tag_details: Dict[str, Any]) -> Dict[str, Any]:
    """
    Returns the indicator fields
    Args:
        tag_details: a dictionary containing the tag details.
    Returns:
        A dictionary represents the indicator fields.
    """

    fields: Dict[str, Any] = {}
    tag = tag_details.get('tag', {})
    refs = json.loads(tag.get('refs', '[]'))
    fields['publications'] = create_publications(refs)
    fields['aliases'] = tag_details.get('aliases', [])
    fields['description'] = tag.get('description', '')
    last_hit = tag.get('lasthit', '')
    fields['lastseenbysource'] = datetime.strptime(last_hit, AF_TAGS_DATE_FORMAT).strftime(
        DATE_FORMAT) if last_hit else None
    updated_at = tag.get('updated_at', '')
    fields['updateddate'] = datetime.strptime(updated_at, AF_TAGS_DATE_FORMAT).strftime(
        DATE_FORMAT) if updated_at else None
    fields['reportedby'] = tag.get('source', '')
    remove_nulls_from_dictionary(fields)
    return fields

def update_integration_context_with_indicator_data(public_tag_name: str, tag_name: str, tag_type: str) -> None:
    """
    Updates the integration context with seen tags (to save some API calls)
    Args:
        tag_name: tag name
        public_tag_name: public tag name
        tag_type: tag type
    """

    integration_context = get_integration_context()
    seen_tags = integration_context.get('seen_tags', {})
    seen_tags[public_tag_name] = {'tag_name': tag_name, 'tag_type': tag_type}
    integration_context['seen_tags'] = seen_tags
    set_integration_context(integration_context)

def create_relationships_for_tag(client: Client, name: str, tag_type: str, related_tags: List[str]):
    """
    Creates all the relationships of an indicator.
    Args:
        client: Client class
        name: The indicator's name
        tag_type: The indicator's type
        related_tags: A list of all indicators related to the spesific indicator
    Returns:
        a list represents the relationships of an indicator.
    """

    relationships: list = []
    integration_context = get_integration_context()
    seen_tags = integration_context.get('seen_tags', {})
    for related_tag_public_name in related_tags:
        if related_tag_public_name in seen_tags.keys():
            related_tag_name = seen_tags.get(related_tag_public_name, {}).get('tag_name', '')
            related_tag_type = seen_tags.get(related_tag_public_name, {}).get('tag_type', '')
        else:
            try:
                related_tag_details = client.get_tag_details(related_tag_public_name)
            except DemistoException:
                demisto.debug(
                    f'AutoFocus Tags Feed: Could not create relationship for {name} with {related_tag_public_name}.')
                continue
            tag = related_tag_details.get('tag', {})
            related_tag_name = tag.get('tag_name', '')
            tag_class = tag.get('tag_class', '')
            source = tag.get('source', '')
            related_tag_type = get_tag_class(tag_class, source)
        if related_tag_type:
            relationships.append(
                create_relationship(name, tag_type, related_tag_name, related_tag_type).to_indicator())
            update_integration_context_with_indicator_data(related_tag_public_name,
                                                           related_tag_name,
                                                           related_tag_type)
    return relationships

def create_relationship(tag_name: str, tag_class: str, related_tag_name: str, related_tag_class: str):
    """
    Returns an EntityRelationship object for the tag
    Args:
        tag_name: the tag name
        tag_class: the tag type
        related_tag_name: the related tag name
        related_tag_class: the related tag type
    Returns:
        EntityRelationship object
    """

    return EntityRelationship(
        name=MAP_RELATIONSHIPS.get(tag_class, {}).get(related_tag_class),
        entity_a=tag_name,
        entity_a_type=tag_class,
        entity_b=related_tag_name,
        entity_b_type=related_tag_class,
        reverse_name=MAP_RELATIONSHIPS.get(related_tag_class, {}).get(tag_class),
    )

''' COMMAND FUNCTIONS '''

def test_module(client: Client) -> str:
    """
    Builds the iterator to check that the feed is accessible.
    Args:
        client: Client object.
    Returns:
        Returning 'ok' indicates that the integration works like it is supposed to.
        Connection to the service is successful.
        Raises exceptions if something goes wrong.
    """

    client.get_tags(data={'pageSize': 1})
    return 'ok'

def fetch_indicators(client: Client,
                     is_get_command: bool,
                     tlp_color: Optional[str] = None,
                     feed_tags: List = None,
                     limit: int = -1,
                     create_relationships: bool = True,
                     ) -> List[Dict]:
    """
    Retrieves indicators from the feed
    Args:
        create_relationships:whether to create indicators relationships
        is_get_command: whether this method is called from the get-indicators-command
        client (Client): Client object
        tlp_color (str): Traffic Light Protocol color
        feed_tags (list): tags to assign fetched indicators
        limit (int): max amount of results to return
    Returns:
        Indicators list.
    """

    iterator = client.build_iterator(is_get_command, limit)
    indicators = []
    for tag_details in iterator:
        tag_dict = tag_details.get('tag', {})
        public_tag_name = tag_dict.get('public_tag_name', '')
        tag_name = tag_dict.get('tag_name' '')
        tag_class = tag_dict.get('tag_class', '')
        source = tag_dict.get('source', '')
        tag_type = get_tag_class(tag_class, source)
        if not tag_type:
            continue
        raw_data = {
            'value': tag_name,
            'type': tag_type,
        }
        update_integration_context_with_indicator_data(public_tag_name, tag_name, tag_type)
        raw_data.update(tag_details)
        indicator_obj = {
            'value': tag_name,
            'type': tag_type,
            'service': 'AutoFocus',
            'fields': create_indicators_fields(tag_details),
            'rawJSON': raw_data,
            'score': SCORES_MAP.get(tag_type)
        }
        related_tags = tag_details.get('related_tags', [])
        if related_tags and create_relationships:
            relationships = (create_relationships_for_tag(client, tag_name, tag_type, related_tags))
            if relationships:
                indicator_obj['relationships'] = relationships
        tag_groups = get_tag_groups_names(tag_details.get('tag_groups', []))
        if feed_tags or tag_groups:
            if feed_tags:
                tag_groups.extend(feed_tags)
            indicator_obj['fields']['tags'] = tag_groups

        if tlp_color:
            indicator_obj['fields']['trafficlightprotocol'] = tlp_color
        indicators.append(indicator_obj)
    return indicators

def get_indicators_command(client: Client,
                           params: Dict[str, str],
                           args: Dict[str, str]
                           ) -> CommandResults:
    """
    Wrapper for retrieving indicators from the feed to the war-room.
    Args:
        client: Client object
        params: A dictionary containing the integration parameters
        args: A dictionary containing the command arguments
    Returns:
        CommandResults object containing a human readable output for war-room representation.
    """

    limit = arg_to_number(args.get('limit', '10')) or 10
    if limit > PAGE_SIZE:
        demisto.debug(f'AutoFocus Tags Feed: limit must be under {PAGE_SIZE}. Setting limit to {PAGE_SIZE}.')
        limit = PAGE_SIZE
    tlp_color = params.get('tlp_color')
    feed_tags = argToList(params.get('feedTags', ''))
    indicators = fetch_indicators(client=client,
                                  is_get_command=True,
                                  tlp_color=tlp_color,
                                  feed_tags=feed_tags,
                                  limit=limit,
                                  create_relationships=False)
    human_readable = tableToMarkdown('Indicators from AutoFocus Tags Feed:', indicators,
                                     headers=['value', 'type', 'fields'], headerTransform=string_to_table_header,
                                     removeNull=True)
    return CommandResults(
        readable_output=human_readable,
        outputs_prefix='',
        outputs_key_field='',
        raw_response=indicators,
        outputs={},
    )

def fetch_indicators_command(client: Client, params: Dict[str, Any]) -> List[Dict]:
    """
    Wrapper for fetching indicators from the feed to the Indicators tab.
    Args:
        client: Client object with request
        params: demisto.params()
    Returns:
        List of indicators from the feed.
    """

    feed_tags = argToList(params.get('feedTags', ''))
    tlp_color = params.get('tlp_color')
    create_relationships = params.get('create_relationships', True)
    indicators = fetch_indicators(client=client,
                                  is_get_command=False,
                                  tlp_color=tlp_color,
                                  feed_tags=feed_tags,
                                  create_relationships=create_relationships,
                                  )
    return indicators

''' MAIN FUNCTION '''

def main():
    """
    main function, parses params and runs command functions
    """

    params = demisto.params()

    insecure = not params.get('insecure', False)
    proxy = params.get('proxy', False)
    api_key = params.get('api_key', {}).get('password', '')
    base_url = params.get('url')
    if not api_key:
        if is_demisto_version_ge('6.5.0'):
            api_key = demisto.getLicenseCustomField('AutoFocusTagsFeed.api_key')
            if not api_key:
                raise DemistoException('Could not resolve the API key from the license nor the instance configuration.')
        else:
            raise DemistoException('An API key must be specified in order to use this integration')

    command = demisto.command()
    args = demisto.args()

    demisto.debug(f'Command being called is {command}')

    try:
        client = Client(
            api_key=api_key,
            base_url=base_url,
            verify=insecure,
            proxy=proxy,
        )

        if command == 'test-module':
            return_results(test_module(client))

        elif command == 'autofocus-tags-feed-get-indicators':
            return_results(get_indicators_command(client, params, args))

        elif command == 'fetch-indicators':
            # This is the command that initiates a request to the feed endpoint and create new indicators objects from
            # the data fetched. If the integration instance is configured to fetch indicators, then this is the command
            # that will be executed at the specified feed fetch interval.
            indicators = fetch_indicators_command(client, params)
            for iter_ in batch(indicators, batch_size=2000):
                demisto.createIndicators(iter_)
        else:
            raise NotImplementedError(f'Command {command} is not implemented.')

    except Exception as e:
        return_error(f'Failed to execute {command} command.\nError:\n{str(e)}')

if __name__ in ['__main__', 'builtin', 'builtins']:
    main()


text:
Belterra Village is coming, Nutty Brown Café is going
by Ann Fowler
CEDAR VALLEY – Soon, entertainment and dining choices may have Oak Hill residents heading west on Highway 290 West when Belterra Village opens in the fall of 2017. The development is being built by Crescent Communities and Endeavor Real Estate Group.
The 90-acre complex, at the southeast corner of Highway 290 West and Nutty Brown Road, will include a 14-screen movie theater, Sky Cinemas (above illustration), from the creators of Violet Crown Cinema.
The theater will serve food, and have a menu that will include fare such as salads, burgers and fries, plus beer on tap and wine by the glass. The full-leg reclining seats include attached tray tables, but wait service will not be available in the movie auditoriums. The theater also plans a dining area and outdoor beer garden.
"Sky Cinemas represents our effort to bring the highest quality cinema experience to growing suburban areas, and we're excited to launch the first Sky Cinemas in Dripping Springs to expand on its already family-friendly, fun, local culture," said Sky Cinemas founder Bill Banowsky.
"The theater conveys our reimagining of the traditional cinema business," added Banowsky. "We've taken from all of our experiences in cinema—both traditional and specialized—and are bringing the best of each to Sky Cinemas, including plush reclining seats and auditoriums designed with a more intimate scale, similar to what we've done in Violet Crown."
Phase 1 of the development, to start construction this fall, will include more than 200,000 square feet of retail and restaurant space, medical offices, a senior living community, plus a Hampton Inn.
Some of the eateries that have already leased space at Belterra Village include Zaxby's, Torchy's Tacos, Mama Fu's, Jersey Mike's, Baskin Robbins and Dunkin Donuts.
Other retailers moving in include Great Clips, Pet Supplies Plus, Spec's Wines, Spirits and Finer Foods and Breed & Co. Hardware.
"Opening our third Breed & Co in Belterra Village allows us to share our unique brand of upscale houseware specialty products and everyday hardware necessities with this fast growing corridor of Southwest Austin and Dripping Springs," said CEO and President of Breed & Company, Dave Barker. "Residents of Belterra and nearby areas will be able to take care of their home while planning a wedding through our amazing bridal registry or just hosting a get together with their neighbors. All you need is Breed."
Daniel Campbell, principal with Endeavor Real Estate Group, said, "This trade area has been historically underserved, and once we were able to demonstrate to the market a master plan for a site in the trade area that would create a significant node of retail and other uses, the project really came together. What we intend to create with Belterra Village is a community gathering spot where neighbors down the street and across town can come together for shared experiences."
"Those are the types of businesses we need closer to Oak Hill, plus several restaurants," said Granada Hills resident Rick Perkins. "Too bad the Westpark PUD was derailed here in Oak Hill."
"It's the right time to bring a development like this to the Hwy. 290 corridor to provide a destination with a mixture of uses to Southwest Austin residents," said Crescent Communities' Tommy Tucker. "In addition to shopping and entertainment offerings, we've carefully planned for more than 79 high-density residential offerings in Belterra Village to accommodate the growing housing demand in Belterra's master-planned community and its surrounding areas."
Nutty Brown Café heading north
While southwest Austin is gaining entertainment and eating choices with Belterra Village, it is losing an iconic restaurant and music venue when the Nutty Brown Café moves to Round Rock. The restaurant opened its doors 13 years ago on the northeast corner of U.S. 290 West and Nutty Brown Road. It is popular for its outdoor music venue.
Last year, H-E-B purchased 65 acres of land, including the 20-acre Nutty Brown site, but released a statement, "The Nutty Brown Cafe will continue with their operations and Texas country music concert series. We have no plans to develop the property at this time."
Although not feeling pressured to move, owner Mike Farr started looking at other locations, ultimately deciding on McNeil Park in Round Rock. The restaurant and music venue should be fully operational at its new 18.4-acre site by March of 2017.
Once the restaurant has moved, H-E-B will be free to build on that site. The Belterra Village site map shows "H-E-B coming soon" at the Nutty Brown Café location.
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Home Uncategorized Review: On Rusty Trails
Review: On Rusty Trails
Every now and then, along comes a title that just sucks you into its world. It's a fact: true gamers can't resist a combination of original storytelling, exciting gameplay, immersive design, and unique soundscapes. On Rusty Trails hits the spot every time.
From the makers of Tiny & Big and About Love, Hate and the other ones comes a heart-throbbing title with Black Pants Studio's signature style, but a whole new adventure.
You're Elvis, a conscious, metallic tetrahedron person whose house has been reduced to a pile of a rubble by a thunderstorm. It's a strange world, but you belong here. You're only option is to figure out how to find a new home. This is literally the simple, minimalistic basis from which a fast-paced, shapeshifting, and thought-provoking journey is about to start.
You guide Elvis through an illustrative platform world inhabited by creatures similar to him, and other [hairy] folk who are not so similar! We won't call them enemies here. You'll have to play the game to decide for yourself.
Controlling Elvis is fluid, whether you're playing with keyboard or joypad. Elvis' magnetic boots deliver a unique platform experience as you can walk on walls and ceilings. This drastically changes the perspective on puzzles and how you approach them. Advance a little further into the game, and you'll find the "Shifty Suit". Not only does it help you move incognito among the hairy folk, this suit alters how the entire environment reacts to you.
Overcoming challenges in On Rusty Trails depends highly upon how you transform yourself, with a moral lesson on not having biased judgment. What looks like straightforward gameplay, is actually disguised complexity. On Rusty Trails has a delicious secret around every corner.
On Rusty Trails feels a little bit like a comic book coming to life in your hands. It's got that scrapyard, almost post-apocalyptic feel to it. Everything would be so cute if it wasn't for the pain and hate that come across in its characters eyes.
It's also one of those games where you need to pay attention to the graphics. This is good because you'll want to. On Rusty Trails features signboards and pop-up emoticons to clue you in on gameplay as opposed to long text explanations. We suppose it's how the people in this miniature world prefer to communicate!
If you were born into a metallic body, with a metallic heart, in a metallic world, everything would sound the way it does in On Rusty Trails. On the one hand, the music is soft and tribal. It's the soundtrack to the ticking of your mind working out puzzles and your fingers flexing out dexterity. However, every click, clunk, and electronic wave lets you know. This is the sound of struggle and you're up for a challenge. Get a taste of the sound in the video below.
Replay Value
On Rusty Trails is a stack of numerous, short, diverse, and intense levels. You'll get several good hours playing through the entire game. Then you'll get several intense hours playing through the entire game to tick off the more hardcore of its 44 achievements. Then you'll get several awesome hours playing just to warm up for the sequel! Okay… False Alert. We don't know if there will be a sequel, but we definitely hope so!
Elvis has left the building and he's On Rusty Trails. Even if you're not a platform lover, this is one of those titles that you must experience. Find a surprisingly touching story brought to you through fun gameplay. And for the sake of common hospitality, help Elvis find a home.
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Q: phpMyAdmin export, half file compressed? Okay, I have to admit, that I derped up. I've exported a database from a to-be-reinstalled server and didn't check that file.
Now, that I try to import it, I've discovered something very strange, the file was supposed to be GZIP compressed, yet it cannot be compressed, so I open it up in Notepad++ and I see that it's not compressed. BUT when I try to import it as plain SQL i discover something more strange, somewhere in the middle of the file starts a byte stream.
Looks like phpmyadmin derped up the export somehow. Here you can see that file.
Has anyone exprienced something like this? Is there any way to recover such file?
It's not a very imporatant database, It could be recreated within couple of hours, plus I can restore it from off-site backup. BUT probably there will be someone who doesn't make regular data backups (you really should!), since I haven't seen anything like this on the Internet, I'm sharing it here, maybe somebody knows what could have caused it, how to fix it and how to recover such files.

A: I had the same issue last night and was able to solve it. You'll need the gzrt package to repair the gzip. Here's how to fix it:

*

*Copy the beginning plaintext portion of your database.sql.gz file to a new file called database.sql

*Run gzrecover database.sql.gz

*Append the contents of database.sql.recovered into database.sql

You might have to manually replace a couple of characters.
See this issue for more info on why it happened.

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Never cease to be amazed how the undeserving manage to get jobs way beyond their capabilities. My abiding memory of this chap is him making it into the record books by becoming the manager who was able to lose a cup final in extra time despite having a 2 man advantage. Should have been dismissed immediately but clung on due to having no doubt friends in high places. And no, I didn't forget the next match against Celtic which I, like the majority of the support, missed due to being severely irate. So, no welcome back from the frog.
Stubbs showed what he really thinks of Scottish football. Like Craig before him, he considered that reserves and lower/non league English players would be good enough to play in our top league. That in itself would be grounds for dismissal but for the directors to actually allow him to squander precious funds on untried players is akin to dereliction of duty. He goes with my good riddance although no doubt he will be permitted, just like that other ne`er do well Alex Rae, to pontificate to us mere mortals about that which is above our intelligence....football. I despair.
Will be giving this one a miss, season ticket or not. Anticipate a mauling.
Very glad to see him gone from Saints. Would love to see his ilk having to do what the rest of us have to.....find a proper job !!!
I think I am correct in saying that this is the biggest away win in the Scottish cup between two teams in the top division ever. We almost equalled the record of an away win last season in Edinburgh but just missed out.
To go from the highs of last season, even the second half of the preceding season and then losing our best player and best manager in living memory is a real blow just when theres been a great atmosphere among the fans and in the town. It seems many already have us as likely relegation candidates. I am not impressed with either the new manager or any of the signings - I know theres no basis for the pessimism yet but I have a bad feeling - and sincerely hope we are not going down the Craig route of lower league English players which is a huge risk playing against the likes of the old firm, Aberdeen and the capital clubs. Only time will tell, of course, and I wish the team well this coming season. Hope not to be watching from behind a sofa at some matches,lol.
Spineless jellyfish, well beaten but no fight whatsoever. The English guy who manages them should be booted out, he is hopeless.
The amphibian view on this appointment is one of disappointment, which would most likely have always been such after a great success like JR. One thing I always pick up on though is that English people always have an eye on returning home as soon as a decent opening arises ( see Davis signing for Grimsby as a perfect example). He couldn't get out of Hibs quickly enough to the second division down there and made rather a hash of things. I may well be proved wrong but having sang froid I weigh these things up impassionately. One thing I do ask of him is, please do not bring in Jules Verne league players, Craig tried it and it doesn't work !
Not looking very promising already after such a great 18 months. The wind has been taken firmly out of our sails having lost our manager and best player. My main hope is that the idiots who had selected the previous managers have now departed and sense may prevail. Fingers crossed. I do however think that either English managers or those who have been based in English football should be avoided like the plague, as the first sign of a job opportunity down there will see them leave in a cloud of dust.
The amount of hype from the English media printed about Salah, comparing him to Messi, Ronaldo et al, shows how completely out of touch and unrealistic they are. Because a player does well in their league automatically puts him in the "world class" department, lol. Didn't take Madrid long to snuff him out and show Liverpool a clean pair of heels. Unfortunately lots in this country are starstruck by our southern cousins, also taken in by the media hype.
Even I was able to watch a bit of it on Freesports. Pathetic display and result. The guy in charge - could hear him shouting from the touchline in an English accent - has a pretty poor record at this level and should be relieved of the position. some of Scotlands play was amateurish, could hardly string a pass together.
Oh yes, the old "they bring in lots of tourists and money" rubbish that's wheeled out every time those parasites require mugs like us to fund their lifestyles. I don't imagine places like Paisley or anywhere outside the Home Counties made much from this charade. Incidentally, if its meant to "unite the nation", then why are all those events held in the same area ? ( the wealthiest region in the uk just by chance). As an earlier poster mentioned, the Russians, Germans Italians etc got shot of their scroungers long ago and must be laughing at us still forking out to pay for millionaire ne`er do wells` housing and holidays. Probably serves us right for being so stupid and subservient when behind their backs they despise the great unwashed. Rant over, lol.
Ive never heard of James and hope he does well, but I have said before that players from England always have an eye on returning home at the first opportunity and rarely settle in this country. I hope to be proved wrong and that someone from lower league football can step up to our premiership.
The Pontiff is a keen football fan, apparently a season ticket holder at San Lorenzo in B.A.
I am never surprised when English people cite "family reasons" for their departure back home. In footballing terms I don't think Davis would have been good enough anyway for the step up so at least we have time to replace him. One thing I will predict is that he gets a club straight away near to wherever he comes from. We were more than reasonable in giving him the chance for first team football and he repaid that with some good performances last season, so he leaves with my good wishes.


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January 9, 2022 Zoe West
In response to these environmental changes, pancreatic -cells trigger the unfolded protein response (UPR) by activation of ER stress sensor proteins including the transcription factor CCAAT/enhancer binding protein C/EBP [43]. as secretion by various pathways that are regulated by reversible phosphorylation of proteins. Moreover, CK2 inhibition modulates pathways that are involved in the development of diabetes and prevents signal transduction, leading to late complications such as diabetic retinopathy. Hence, targeting CK2 may represent a novel therapeutic strategy for the treatment of diabetes. strong class="kwd-title" Keywords: CK2, diabetes, -cells, insulin 1. Introduction Protein kinase CK2 is a ubiquitously expressed, constitutively active serine/threonine- and tyrosine kinase. With more than 500 substrates, CK2 is estimated to be responsible for up to 10% of the whole human phosphoproteome [1,2]. The CK2 holoenzyme is a tetramer, comprised of two catalytic – or – and two non-catalytic -subunits [3]. The -subunits are encoded by two distinct homologous genes, CSNK2A1, which encodes CK2 [4], and CSNK2A2, which encodes CK2 [5]. The -subunit is encoded by CSNK2B [6]. CK2 is not only a simple onCoff regulator of S1PR2 the catalytic activity of CK2 but also regulates thermostability, substrate specificity, and the ability to attach and penetrate cell membranes [7,8,9,10]. CK2 and CK2 are also highly important for embryonic development. CK2?/? embryos die in mid-gestation with defects in the heart and neural tube [11]. CK2?/? mice die shortly after implantation with no signs of apoptosis, but reduced cell proliferation [12]. However, CK2?/? knock-out mice are viable, but male mice exhibit globozoospermia [13]. It is well known that CK2 activity is elevated in most cancer cells and more importantly, CK2 inhibition leads to the induction of apoptosis in these cells [14,15]. Several studies have reported that this kinase is involved in various oncogenic signaling pathways such as the phosphoinositide 3-kinase (PI3K) and Wnt signaling [16,17]. The latter is associated with the regulation of cell development and cell differentiation [18]. Defects in Wnt signaling are often associated with tumorigenesis [18]. For instance, loss-of-function mutations for adenomatous polyposis coli (APC) result in -catenin accumulation, and thus, promote the expression of a number of potential oncogenes [17]. CK2 phosphorylates -catenin, which results in increased protein stability [19]. On the basis of these results and further studies that showed that this kinase regulates important cancer signaling pathways, multiple attempts have been made to develop chemotherapeutic drugs based on CK2 inhibition. These inhibitors include T56-LIMKi 4,5,6,7-tetrabromobenzotriazole (TBB), (2E)-3-(2,3,4,5-Tetrabromophenyl)-2-propenoic acid (TBCA), tetrabromo-1H-benzimidazole (DMAT), and CX-4945, also known as Silmitasertib [20,21,22]. The latter is currently the most specific CK2 inhibitor that has entered phase II clinical trials ("type":"clinical-trial","attrs":"text":"NCT02128282″,"term_id":"NCT02128282″NCT02128282). Aside from the T56-LIMKi well-established role of CK2 in tumorgenesis, this kinase is also implicated in the regulation of other physiological processes including glucose homeostasis [23,24,25,26]. In the last few years, it has been reported that CK2 seems to play an important role in endocrine pancreatic functions because CK2 affects insulin expression at different cellular levels. Moreover, the kinase itself is T56-LIMKi regulated by glucose concentration in pancreatic -cells [27]. Based on these findings, the present review will summarize the current knowledge about the putative function of CK2 in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus T56-LIMKi (T2DM), the risk factors triggering T2DM as well as diabetes mellitus-associated complications. 1.1. CK2 Regulates Pancreatic -Cell Death T1DM results from an autoimmune destruction of insulin-producing -cells, leading to a complete lack or inadequate secretion of insulin [28]. In contrast, T2DM is characterized by insulin resistance, impaired insulin reaction of the target cells, and dysregulated insulin secretion [29]. Interestingly, it has also been shown that T2DM inflammation can contribute to the progression of the disease [30,31]. The inflammatory response is triggered by cytokines such as interleukin (IL)-1, tumor necrosis factor (TNF)-, and interferon (IFN)-. This leads to the induction of the pro-apoptotic NFB pathway, resulting in a massive reduction of the -cell.
Itraconazole has the capacity to inhibit activation including some mutations that confer level of resistance to inhibitors, and arsenic trioxide inhibits ciliary deposition
October 12, 2021 Zoe West
Itraconazole has the capacity to inhibit activation including some mutations that confer level of resistance to inhibitors, and arsenic trioxide inhibits ciliary deposition. Mouse types of MB using the Sleeping Beauty (SB) transposon program provide excellent equipment to discern drivers occasions of tumorigenesis.77 An unbiased SB transposon\based in?display screen confirmed a one\allele lack of accelerated SHH\MB formation vivo, supporting the function of being a book tumor suppressor in SHH\MBs.78 A subsequent SB transposon\mediated insertional mutagenesis display screen in single\allele Ptch1\knockout mice identified transcription factor being a driver of SHH\activated MB development, as decreased Nfia conjoined with SHH\signaling perturbations.79 In the and expression and connected with metastatic disease and poor success outcome in human topics, in SHH\MBs especially. We complex on the most recent development inside the progression of molecular subclassification, and evaluate proposed risk types across rising classification systems. We talk about discoveries predicated on preclinical versions and elaborate over the applicability of potential brand-new therapies, including Wager bromodomain inhibitors, statins, inhibitors of SMO, AURK, PLK, cMET, concentrating on stem\like cells, and rising immunotherapeutic strategies. A massive quantity of data over the hereditary history of SHH\MB possess accumulated, even so, subgroup affiliation will not offer dependable prediction about response to therapy. Rising subtypes within SHH\MB give more split risk stratifications. Rational scientific trial designs using the incorporation of obtainable molecular understanding are unavoidable. Improved collaboration over the technological community will end up being imperative for healing breakthroughs. Launch Medulloblastoma (MB) may be the most common pediatric human brain malignancy, accounting for about 20% of youth human brain malignancies and 10% of most childhood cancer fatalities. Occurrence culminates among kids youthful than 10?years, with about 50 % of situations arising prior to the age group of 5.1, 2 Up to 40% of sufferers are identified as having metastatic disease,3 using a grim view for success.4 A lot more than one\third of patients die within 5?years after medical diagnosis, and survivors encounter treatment\related long\term undesireable effects.5 MB treatment strategy involves maximal secure resection accompanied by craniospinal irradiation and cytotoxic chemotherapy, with specific type and intensity for high\ or standard/general\risk disease. Typical\risk sufferers are KRT20 over 3?years with near\total or total resection no disease dissemination, while sufferers with suboptimal tumor resection, metastasis, and/or good sized cell/anaplastic (LCA) histology are treated for great\risk disease.6 Infants under 3?years require delayed irradiation and so are treated by multiagent chemotherapy preferably, with greater results after gross total resection using the lack of dissemination in comparison to sufferers with residual or SBC-110736 metastatic disease.7, SBC-110736 8, 9 Continuing developments in neuroimaging, neurosurgical methods, rays therapy, and combined chemotherapy possess increased 5\calendar year success prices to 70C80%,1, 5 although individual responses to treatment differ and survival rates reach a plateau considerably. 10 The highly toxic and invasive multimodal therapies induce debilitating undesireable effects on the future frequently.11 Evidently, interventions ought to be spared in sufferers apt to be maximized and cured in people that have aggressive disease. The molecular period result in interesting transformations in affected individual stratifications with implications for therapeutic strategies. Predicated on molecular modifications, four subgroups became broadly recognized: sonic hedgehog\turned on (SHH\MB), wingless\turned on (WNT\MB), Group 3, and Group 4?MBs, each seen as a distinct patterns of somatic mutations, duplicate number modifications, transcriptional profiles, and clinical final results.12 SHH\activated and WNT\ MBs possess unusual activation from the WNT and SHH pathways, respectively, while zero dominant signaling pathway modifications had been identified in Group 3 and Group 4 MBs and appearance as non\WNT/non\SHH in the revised WHO classification.13 Subgroup project is prognostic highly, with different survival rates markedly.14 The 5\calendar year overall success is really as high as 95% in WNT\activated MBs. Group 3 sufferers face the most severe 5\year overall success (45C60%), low among infants especially. Group 4 and SHH\MBs are seen as a an intermediate (75C80%) 5\calendar year overall success that also depends upon disease dissemination, histology, and hereditary aberrations, such as for example oncogene and mutations amplifications.15, 16, 17, 18 Within each primary MBs, additional subtypes are rising with distinct biology and clinical outcomes,18, 19, 20 offering a constructive approach for therapy optimization.14 Here, we offer a comprehensive summary of SHH\MBs with particular focus on rising prognostication plans and book therapeutic strategies. Clinical Qualities SHH\MBs take into account ~30% of most MBs and take place within a bimodal age group distribution encompassing nearly all baby and adult, but fewer youth SBC-110736 situations15 fairly, 21, 22 (Fig.?1A). Pediatric and mature tumors are and clinically distinctive molecularly.12, 23 Approximately 21% of SHH\MBs are enriched with TP53\mutations, delineating a definite subcategory C SHH\activated TP53\wild\type is more common among adults and small children and confers an excellent prognosis with an 81% 5\calendar year overall success (OS). On the other hand, the SHH\activated TP53\mutant subtype occurs among teenagers between ages typically.
After partial thickness burn wound formation, the wound size increased slightly on the first three days and formed eschars compared to the initial wound area
May 28, 2021 Zoe West
After partial thickness burn wound formation, the wound size increased slightly on the first three days and formed eschars compared to the initial wound area. the additional hand, increasing studies have verified that cells from spheroids can better simulate the biological microenvironment and may enhance the manifestation of stemness markers. However, a three-dimensional (3D) scaffold that can harbor implanted cells and may serve as a skin-repaired alternative still suffers from deficiency. In this study, we applied a gelatin/microbial transglutaminase (mTG) hydrogel to encapsulate hASC spheroids to evaluate the overall performance of 3D cells on pores and skin wound healing. The results showed the hydrogel is not toxic to the wound and that cell spheroids have significantly improved wound healing compared to cell suspension encapsulated in the hydrogel. Additionally, a hydrogel with cell spheroids was much more effective than additional organizations in angiogenesis since the cell spheroid has the possibility of cellCcell signaling to promote vascular generation. < 0.05. 3. Result and Discussion 3.1. Cell Viability and Morphology in Hydrogel Biocompatibility is an important indicator to evaluate whether the material will Rabbit polyclonal to IPMK impact the organism. Consequently, the cell viability and distribution of stem cells in the 3D hydrogel were evaluated through live/deceased assays that showed the viability of cells in the hydrogel and the distribution of surviving spheroid cells (Number 1 and Number S1 (Supplementary Materials)). The images show the cell suspensions and cell Madecassic acid spheroids recognized fewer red signal (deceased cells) and higher green signal (live cells) after 7 days of tradition. We found that the encapsulated cells and cell spheroids offered good viability and that few deceased cell signals were detected after 7 days of tradition. For the cell suspension group, 3D confocal laser scanning microscope images showed the cells were equally distributed in the 3D hydrogel. By comparison, the 3D images of the cell spheroid group showed that the shape of the spheroid was no longer complete and that the cells migrate widely from your spheroid to the 3D hydrogel. In order to observe the cell viability of the hASCs cultivated in the 3D hydrogel system, the cell morphology images were taken by microscopy. The cell suspension group showed that hASCs spread widely after 7 days of incubation and that cell morphology had not changed significantly. For the cell spheroid group, hASCs started to migrate from your cell spheroid and proliferated after a 3-day time tradition. In addition, the cells also spread widely in the 3D hydrogel after a 7 day time tradition (Number S2). As a result, live/deceased staining demonstrated that a gelatin enzyme cross-linked hydrogel offers good biocompatibility with the hASCs. Moreover, relating to 3D images, cell spheroid and cell suspension organizations both shown that hASCs can equally spread and have great proliferation. Open in a separate window Number 1 Three-dimensional live/deceased staining image of human being adipose-derived stem cells (hASCs) in the 3D hydrogel system after 7 day time incubation (green: live and reddish: deceased), Madecassic acid scale pub = 200 mm. 3.2. Evaluation of the Wound Healing Ability Before carrying out histological analysis on the skin of the burn injury site, the wound areas were visualized as images and monitored at days 0, 3, 7, 10 and 14 (Number 2a). Then, the wound contraction rate was calculated to evaluate the wound healing effect in the experimental group (Number 2b). The cell spheroid with hydrogel group accomplished the highest wound contraction rate of 55.3%, followed by cell suspension with hydrogel (45.2%), hydrogel (37.1%), cell suspension (32.3%), and control (30.2%) on day time 14. This result demonstrates that the design concept of combining stem cells and hydrogels accelerated the wound healing process of burn wound models. The cell spheroid with hydrogel-treated animal group showed a wound area that decreased significantly faster than all other treatment methods on day time 10. This indicates the cell spheroid with hydrogel has a higher effectiveness when accelerating wound contraction. Open in a Madecassic acid separate window Number 2 (a) Photographs of representative wounds and (b) wound contraction rates like a function of wound healing effect as estimated by ImageJ analysis of wound size (n = 4): samples were analyzed with one-way ANOVA, * < 0.05. Error bars symbolize mean s.d. A wound-healing index was founded attempting to quantify effectiveness compared to the five treatment organizations. The degree of brownish discoloration and scabbing/hardness is definitely displayed by a score of 0 to 4, and the results are demonstrated in Number 3. Fine detail for the wound-healing.
3 CMP5 causes apoptosis in GBMDC and decreases self-renewal capacity in GBMNS
3 CMP5 causes apoptosis in GBMDC and decreases self-renewal capacity in GBMNS. screened using an in vitro GBM neurosphere model and an in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence. Results In vitro and in vivo studies exposed that among the 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated main patient derived GBM cells into a nonreplicative senescent state. Summary In vivo antitumor effectiveness combined with the specificity of CMP5 underscores the importance of developing it for translation. mutant zebrafish (= 24/group); 0.05). (C) Spinning disk confocal fluorescent imaging of relative tumor growth (±)-ANAP on day time 5 (day time of treatment initiation) and day time 10 post tumor cell implantation in one representative fish from (±)-ANAP each group from your survival study in (B) (pub: 50 m). MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. PRMT5 Inhibitors Are Effective in an In Vivo Zebrafish GBM Model We utilized a zebrafish GBM model to display these medicines for potential anti-GBM effectiveness.15 Briefly zebrafish implanted with GFP expressing GBMNS-30 were treated with DMSO or the indicated compounds for 5 days delivered in the fish water inside a 24-well plate, and the animals were observed for survival (= 24/group) (Supplementary Number S3A). Fig. 1B shows the KaplanCMeier survival curves of tumor-bearing fish treated with the indicated medicines at close to LD50 concentrations of each agent (Fig. 1A). While control DMSO-treated animals died having a median survival of 8 days, animals treated with HLCL65 or CMP12 showed significant improvement in survival, with the median survival advantage of >1.5-fold compared with control animals. Interestingly, animals treated with HLCL66, the drug that showed the highest potency in vitro, did not show a survival benefit after treatment. More significantly, more than 50% of animals treated with CMP5 were long-term survivors, indicating the potential antitumor effectiveness of CMP5 in vivo. Consistent with the survival of tumor-bearing animals, fluorescent imaging of (±)-ANAP a (±)-ANAP representative animal from each group for GFP-positive tumor progression over time exposed obvious tumor shrinkage in fish treated with CMP5 and HLCL65 (Fig. 1C and Supplementary Number S3B). To test the potential toxicity of (±)-ANAP these compounds, we evaluated the survival of non-tumor-bearing zebrafish, treated with the indicated compounds in water (= 24/group) (Supplementary Number S3C). In the doses used in the effectiveness study, HLCL66 was harmful to zebrafish, and treated animals died having a median survival of 13 days (< 0.001) (Supplementary Number S3C). None of them of the additional compounds showed any significant toxicity in non-tumor-bearing zebrafish ( 1 between DMSO and CMP5, CMP12, and HLCL65). CMP5 Decreases the Proliferation of GBMNS The above results indicated that both CMP5 and HLCL65 experienced antiglioma effects as well as a beneficial security profile. Our initial pharmacokinetic study with 3 different formulations of CMP5 (Fig. 2A, Supplementary Table S2) exposed CMP5 to have brain tissue build up after i.p. injection without causing toxicity in mice. Therefore we selected CMP5 like a potential drug candidate for further development. We evaluated the effect of CMP5 on PRMT5 function by comparing the methylation status of histone H4 on arginine 3 and histone H3 on arginine 8 [S(Me2)-H4R3 and S(Me2)-H3R8] by western blot after treatment of GBMNS-30 and GBMNS-X12 cells produced as neurospheres (Fig. 2B). CMP5 reduced the methylation of both PRMT5 target histones. Immunofluorescence for H4R3 further confirmed the reduction in PRMT5 activity in Rabbit Polyclonal to RPL26L GBMNS-30 treated with CMP5 (notice the absence of green H4R3 staining in cells indicated by reddish arrows after treatment; Fig. 2C). Interestingly CMP5 treatment completely abolished the presence of histone methylation markers in only a portion of glioma cells. Since obstructing PRMT5 function inhibits H4R3 and H3R8 methylation but does not demethylate histones that have already been methylated by PRMT5 prior to its inhibition, this likely reflects the long half-life of H4R3 methylation in different cells. Methylated histones have been previously explained to have a long half-life.16,17 Thus while reduced methylation indicates PRMT5 inhibition, complete loss of this marker is not observed in all.
Furthermore, upregulation of glycolysis correlates with increased tumor aggressiveness and multidrug resistance (40,41)
Furthermore, upregulation of glycolysis correlates with increased tumor aggressiveness and multidrug resistance (40,41). Gene set enrichment analysis identified glycolysis-related pathways (false discovery rate < 0.001) upregulated in ER-activated mammospheres. We observed that tamoxifen or fulvestrant alone was insufficient to block proliferation of patient-derived BSCs while this could be accomplished by a selective inhibitor of ER (PHTPP; 53.7% in luminal and 45.5% in triple-negative breast cancers). Furthermore, PHTPP reduced tumor initiation in two patient-derived xenografts (75.9% and 59.1% reduction in tumor volume, respectively) and potentiated tamoxifen-mediated inhibition of tumor growth in MCF7 xenografts. Conclusion: We identify ER as a mediator of estrogen action in BSCs and a novel target for endocrine therapy. The existence of breast cancer cells with stem cellClike capacity has been suggested as a likely explanation to therapeutic Trimebutine resistance and tumor relapse (1). Serial passaging of cells growing as nonadherent spheres can be applied to isolate and propagate both normal mammary stem cells (MSCs) and breast cancer stem cells (BSCs) (1,2). BSCs are highly tumorigenic in mouse transplantation assays compared with differentiated cancer cells (3). In addition, the majority of mammospheres are phenotypically CD24(-), CD44(+), EpCAM(+) (3,4), and/or with high activity of aldehyde dehydrogenase 1 (ALDH1) (5,6). Approximately 75% of all breast cancers are positive for estrogen receptor (ER) (ESR1), which in turn positively correlates with response to endocrine therapy (7). The second estrogen receptor, ER (ESR2), has in some studies been RGS17 associated with improved survival in tamoxifen-treated patients (8C10). The two ER subtypes are encoded by genes on different chromosomes and activate estrogen Trimebutine response elements (ERE) in reporter gene assays (11). Although considered ER-negative, BSC and MSC numbers can be expanded by incubation with estradiol (12,13), previously explained by paracrine stimulation (14,15). To dissect the role of estrogen receptors within BSCs, we performed a comprehensive analysis of mammospheres generated from patient-derived cancer cells and from normal benign breast epithelium. Methods Clinical Material Between 2009 and 2015, fresh primary breast cancer specimens from 88 patients were collected at the Karolinska University Hospital. Biobanking was approved by the local biobank board and the Department of Pathology. Experimental procedures and protocols were approved by the regional ethics review board (Etikpr?vningsn?mnden) in Stockholm. Tumor tissues with corresponding clinical data were obtained after signed informed consent from each patient. Anonymized normal breast specimens from elective Trimebutine reduction mammoplasties at the Capio St G?rans Hospital, Stockholm, Sweden, were also used. Trimebutine Mouse Experiments All mouse experiments were approved by the local animal welfare board at Karolinska Institutet and in accordance with institution guidelines. Intact or ovariectomized SCID/NOD female mice three to eight weeks old were transplanted with MCF7 cells, MDA-MB-231 cells, or patient-derived breast tumor fragments HCI001 and HCI002 into the fourth mammary gland fat pad. Four or five mice per group were assigned to different treatment conditions according to the aims of each experiment. Exact numbers are given in the Results and in the figure legends. Detailed procedures are provided in the Supplementary Materials (available online). Statistical Analyses Two-tailed test was used to test statistical significance in the assays, real-time quantitative polymerase chain reaction (qPCR) experiments, and mouse experiments. Tests were either paired or independent depending on experimental setup (paired or unpaired samples). Extreme outlier values of technical causes (<10% of samples per group) have been excluded from analysis. Kruskal-Wallis nonparametric test was used to compare the ER protein expression between the molecular subtypes. Spearmans rank order correlation was used to test the association between ER and ER expression. A < .49) was not associated with any certain molecular subtype, and no correlation was found between the ER mRNA and ER protein expression profiles as assessed by Spearman rank Trimebutine correlation (= .98, = .0017) (Figure 1A;Supplementary Figure 1A, available online). Next, dual immunohistochemical staining with ER and CD44 was performed, showing ER protein expression in 79.2% of all breast.
Supplementary MaterialsSupplementary Information
Supplementary MaterialsSupplementary Information. The inhibitory effect of GUTK on cell cycle re-entry was significantly reduced in cells overexpressing c-MYC. The protein level of FBXW7, a subunit of E3 ubiquitin ligase responsible for degradation of c-MYC, was reduced upon the release from the quiescence. In contrast, GUTK stabilized FBXW7 protein levels during release from the quiescence. The critical role of FBXW7 was confirmed using siRNA knockdown, which impaired the inhibitory effect of GUTK on c-MYC protein levels and cell cycle re-entry. Administration of GUTK, either prior to transplantation or phosphorylation, thereby inhibiting the normal function of GSK3in destabilizing c-MYC via phosphorylation at Thr58.16 Hence, an increase in c-MYC Rabbit Polyclonal to MNT protein stability can be expected when ERK1/2 GSK2656157 and AKT are activated, which is common through gain-of-function mutations in RAS17 or GSK2656157 loss-of-function mutations or deletion of PTEN18 in prostate cancer. Another mechanism of c-MYC regulation is through FBXW7 (F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase), which plays a key role in c-MYC protein degradation in a Thr58-dependent manner,19 and this mechanism has been shown to play a critical role in leukemia-initiating cells.20 We have previously shown that Guttiferone K (GUTK), a bioactive polycyclic polyprenylated acylphloroglucinol, has the capability to induce cell cycle arrest at the G0/G1 phase in colon cancer cells.21 However, the mechanism of action, and whether GUTK can also impede cell cycle re-entry in quiescent cancer cells, has not been determined. In this present study, we describe for the first time that GUTK impedes cell cycle re-entry of quiescent PTENnull/p53WT and PTENnull/p53mut prostate cancer cells via stabilization of FBXW7 and subsequent c-MYC degradation. Results GUTK inhibits DNA synthesis after release from quiescence in prostate cancer cells Experimental quiescence was achieved by serum withdrawal for 7 days in LNCaP cells (PTENnull/p53WT) or contact inhibition for 3 days in PC-3 cells (PTENnull/p53mut), and verified by propidium iodide (PI) analysis by flow cytometry and Ki-67 immunostaining (Supplementary Figures S1 and S2). These quiescent cancer cells were induced to re-enter cell cycle by either serum replenishment in LNCaP cells or re-plating of PC-3 cells at low density. The hallmark for cell cycle re-entry is the re-synthesis of DNA.22 We monitored the change in DNA content upon cell cycle re-entry in the presence or absence of Guttiferone K (GUTK; Figure 1a) with a SYBR Green assay. GUTK, introduced at the time when the cells were released from the quiescence, repressed the increase in DNA content seen in vehicle-treated control (dimethyl sulfoxide GSK2656157 (DMSO)) in a dose- and time-dependent manner (Figures 1b and c). By comparing with the DNA content immediately before the induction for cell cycle re-entry GSK2656157 (quiescence), GUTK was cytostatic at 2.5C10?control. Control cells (DMSO) were induced to re-enter the cell cycle in DMSO-containing medium without GUTK. Quiescent cells were analyzed to show DNA content prior to induction of cell cycle re-entry GUTK delays cell cycle re-entry and division in prostate cancer cells To examine the effects of GUTK on cell cycle progression, we first calculated the concentrations of GUTK at which the cytostatic action or growth inhibition (GI) reached 25% (GI25), 50% (GI50) and 75% (GI75) in LNCaP and PC-3 cells (Table 1). Next, quiescent LNCaP and PC-3 cells were induced to re-enter the cell cycle in the absence or presence of GUTK at GI75. The cells were harvested at 8?h intervals and subjected to PI staining and subsequent flow cytometric analysis. Upon release from quiescence, control LNCaP cells re-entered the cell cycle after approximately 24?h, as shown by a decreased proportion of cells in the G0/G1 phase, and increased the GSK2656157 percentage of cells in the S and G2/M phases (Figures 2a and b). GUTK significantly.
Supplementary Materials Supplemental Data supp_292_31_12842__index
December 14, 2020 Zoe West
Supplementary Materials Supplemental Data supp_292_31_12842__index. network marketing leads to postmitotic neuron-like differentiation with lack of malignant features in specific solid tumor cell lines. The regulatory aftereffect of these enzymes in neuronal differentiation resided in their intrinsic activity in embryonic neural precursor/progenitor cells. We further found that a major part of pan-cancer-promoting genes and the signal transducers of the pan-cancer-promoting signaling pathways, including the epithelial-to-mesenchymal transition (EMT) mesenchymal marker genes, display neural specific expression during embryonic neurulation. In contrast, many tumor suppressor genes, including the EMT epithelial marker gene that encodes cadherin 1 ( 0.01; ***, 0.001. and supplemental Table S1). Therefore, the inhibitor combination suppresses efficiently malignant features. We confirmed the efficiency of Rabbit polyclonal to AGO2 these inhibitors and their effect on chromatin modification. DNMT1 methylates CpG residues of DNA, EZH2 catalyzes H3K27me3, HDACs are responsible for the lysine deacetylation of proteins, and LSD1 catalyzes the demethylation of H3K4me1/me2. LSD1 inhibitor up-regulated transcriptional active marks H3K4me1, -me2, and -me3 (supplemental Fig. S1, and and (Fig. 2(Fig. 2ESR in ESR-dependent breast cancer (Fig. 3and and and and and Table S2). In agreement with the data, intraperitoneal injection of a composite of the four inhibitors efficiently repressed tumor formation of the grafted 22Rv1 (Fig. 4, and and test. Data are presented as mean S.E. ( 0.05; **, 0.01; ***, 0.001. Knockdown of chromatin modification enzymes induces neuron-like differentiation in cancer cell lines To verify that the noticed Ropinirole HCl differentiation had not been a side-effect, the result was examined by us of gene knockdown on cancer cell differentiation. HepG2, RKO, MCF7, or U2Operating-system cells displayed assorted response to knockdown of the gene using shRNA (Fig. 5, and and and and and was localized to neural precursor/progenitor cells. In tail bud embryos (NF phases 29C44) where cells and organs are shaped, they were primarily transcribed in the CNS and neural crest-derived cells (Fig. 6showed no manifestation in neural cells in neurula embryos. Nevertheless, it showed particular manifestation in the CNS (Fig. 6embryos. hybridization (WMISH) recognition of manifestation of genes coding for chromatin changes enzymes. and it is Ropinirole HCl demonstrated as control. Mid- to past due neurula and tailbud embryos had been used. Typical manifestation domains are tagged, however the same expression domain in various is probably not tagged repeatedly. Each embryo can be oriented using the anterior towards the of each had been exclusively indicated in neural cells. -manifestation was also extremely enriched in neural cells in a history of ubiquitous manifestation (Fig. 6(Fig. 6was localized to neural crest cells (Fig. 6was recognized just in non-neural epidermis in tail and neurula bud embryos, identical towards the epidermal marker gene in (Fig. 6neurula embryos and in the CNS later on (supplemental Desk S4), such as for example (Fig. 7 and supplemental Desk S4). Besides, WNT, TGF, FGF, NOTCH, and HH pathways play intensive roles during cancer development and progression. Correspondingly, transcription of the major signal transducers, such as and ?and77 and supplemental Fig. S4and Table S8). Some of the pan-cancer-promoting genes are known markers for embryonic or adult neural stem/progenitor cells, such as may not be labeled repeatedly. are expressed weakly or partially Ropinirole HCl in neural tissues of neurula embryos, whereas shows weakened epidermal manifestation, and are not really significantly indicated (supplemental Fig. S5are expressed specifically in the neural cells in neurula embryos and in CNS later (Fig. 8shows expression in both neural and mesodermal tissues. is present in neural cells in neurula and localized to developing eye lens and midbrain-hindbrain boundary. and are expressed weakly in neural tissue in neurula embryos, and there was no detectable expression later on (Fig. 8is in the cement gland primordium in neurula and in cement gland, somites, lens, and ear vesicle. expression is localized to the medial stripe of primary neurons and, later on, to the trigeminal nerve and notochord. and show no obvious transcription in neurula embryos but are transcribed in CNS in tail bud embryos. exhibits expression in the cement gland primordium. transcription is usually localized strongly to somite but not detected in neurula embryos (Fig. 8embryos. embryos. Among the genes playing dual roles,.
History: Mucosal melanomas including melanomas of the urogenital tract represent a rare type of melanoma characterized by low mutational burden and poor prognosis
History: Mucosal melanomas including melanomas of the urogenital tract represent a rare type of melanoma characterized by low mutational burden and poor prognosis. intralesional application of Talimogene laherparepvec. Case Report: A 78-years aged female patient was diagnosed with an advanced mucosal melanoma of the urethra with inguinal lymph node metastases and intravaginal mucosal metastases. Shortly after surgical resection of the tumor mass, intravaginal mucosal metastases, and new nodal metastases in proximity of the left iliac vessels were diagnosed. The patient was treated with the anti-PD1 antibody pembrolizumab and attained a well balanced disease long lasting for 30 weeks. Nevertheless, upon checkpoint inhibition the individual created a loco-regional intensifying disease featuring blood loss intravaginal metastases, while nodal metastases continued to be stable. We stopped treatment with pembrolizumab and administered T-VEC in to the intravaginal mucosal metastases directly. After five shots T-VEC yielded a incomplete response with scientific regression from the injected mucosal metastases. Disease continued to be steady for 16 weeks under biweekly T-VEC treatment. Thereafter the individual showed disease development in nodal metastases. T-VEC was discontinued. Immunotherapy with pembrolizumab was restarted but didn't achieve a reply. Finally, targeted therapy with imatinib was induced in existence of the druggable mutation, resulting in a significant response of most tumor sites that's still ongoing. Bottom line: T-VEC symbolizes a highly effective and well-tolerated treatment choice for sufferers with loco-regionally advanced mucosal melanoma. In conjunction with immunotherapy, T-VEC bears the potential of synergistic results to overcome the precise primary level of resistance of mucosal melanoma to immune system checkpoint blockade. and so are less widespread in mucosal melanoma, targeted therapy is available for a little subset of sufferers. Some mucosal melanoma harbor mutations targetable by imatinib or nilotinib (4). Tumor infiltrating lymphocytes could be discovered less often in mucosal melanoma than in cutaneous melanoma (5). As a result, it's been hypothesized that mucosal melanomas have a tendency to end up being less immunogenic and so are therefore often mainly resistant to immune system checkpoint blockade. In sufferers with locally advanced or unresectable cutaneous melanoma the oncolytic viral immunotherapy Talimogene laherparepvec (T-VEC) represents yet another therapeutic choice. Acceptance was granted by EMA and FDA in 2016 for the neighborhood shot in cutaneous, nodal and subcutaneous metastases in unresectable stage IIIB-IVM1a melanoma sufferers. T-VEC is certainly a genetically customized herpes virus type 1 merging immediate oncolytic effects with local and systemic, immune-mediated anti-tumor response (6, 7). The phase III trial (OPTiM) which led to approval of T-VEC demonstrated an overall response rate of 26,4 %, including 10.8% complete responses (8). Patients with mucosal melanoma were excluded from your trial. To our knowledge there is no published data about intralesional treatment of mucosal melanoma or mucosal metastases with T-VEC so far. Here we statement the case of a patient with intravaginal metastases of a melanoma of the urethra responding to intralesional treatment with T-VEC. Case Statement A 78-years aged female patient was diagnosed with a mucosal melanoma of the urethra (patient characteristics: see Table 1). Table 1 Medical history, clinical, histological, and molecular characteristic of the patient. wtwtmutation exon Cdh15 11, c.1672_1674dupp.K558dupAdjuvant therapyNoneMedical historyHysterectomy due to myomasArterial hypertoniaHypercholesterolemiaFamily historyNegative family history of melanomaPsychosocial historyWidowed, 2 children and grandchildren Open in a separate window gene and a p.K558dup mutation of in exon 11. Because from the advanced, inoperable melanoma a systemic therapy using the PD-1 inhibitor pembrolizumab was short-term and Cor-nuside induced obtained steady disease. After administration of 10 cycles of pembrolizumab the individual started to have problems with recurrent vaginal blood loss, which significantly limited the patient's standard of living. Clinical examinations uncovered ulcerated pigmented intravaginal metastases. Imaging verified loco-regional improvement without faraway metastases (Body 2). Hence, four weeks following the last dosage anti-PD1 antibody and in contract with our individual, we initiated treatment using the oncolytic pathogen T-VEC (initial administration 106 PFU/ml, accompanied by 108 PFU/ml at week 3 and implemented Q2W, 1C3 mL). In co-operation with this section of gynecology T-VEC was injected Cor-nuside in to the intravaginal mucosal metastases directly. The shots provoked moderate regional bleeding from the mucosa, and the individual experienced from flu-like symptoms a couple of hours after injections. The individual did not show any indicators of a herpes contamination at any time. Our individual reported that this T-VEC applications were tolerable and that the side effects did not restrict her daily life. Laboratory investigations did not reveal any significant pathologic findings. After the 1st injections, metastases slightly seemed Cor-nuside to increase in size, but vaginal bleeding amazingly ameliorated. After five injections T-VEC yielded a partial response with considerable regression of the injected mucosal metastases and cessation of intravaginal bleedings (Number 2). Overall nine cycles of T-VEC were given. The uninjected iliac lymph node metastases did not.
Supplementary MaterialsData_Sheet_1
August 9, 2020 Zoe West
Supplementary MaterialsData_Sheet_1. decrease in snare serine-protease and development creation, & most hyphal traps made by mutants didn't form an unchanged hyphal NF-ATC loop; therefore, significantly fewer nematodes had been captured with the mutants than with the WT stress. In conclusion, an Ime2-MAPK is certainly identified right here for the first time from a nematode-trapping fungus, and the kinase is usually shown to be involved in the legislation of mycelial advancement and development, conidiation, osmolarity, and pathogenicity in have already been reported: the Fus3/Kss1-homolog, Slt2-homolog, and Hog1-homolog pathways (Jiang et al., 2018). Furthermore, a 4th MAPK pathway, the inducer KU-57788 irreversible inhibition of meiosis 2 (Ime2)-homolog pathway, was within several fungi, such as for example (Bayram et al., 2009), (Liu and Shen, 2011), (Hutchison and Cup, 2010), and (Garrido et al., 2004). Unlike in the three traditional MAPK pathways, the MAPKKK and MAPKK in the Ime2-MAPK cascade unidentified stay, and therefore these kinases participate in a definite Ime2-MAPK course (Garrido and Prez-Martn, 2003; Schindler et al., 2003). Ime2 homologs are conserved in not merely in fungi, but also all eukaryotic taxa analyzed (Krylov et al., 2003), and the normal feature of the kinases is certainly that their was initially identified in being a gene that's expressed solely during meiosis (Smith and Mitchell, 1989; Yoshida et al., 1990), and, eventually, was been shown to be also involved with regular spore development (Sari et al., 2008) and pseudohyphal development (Strudwick et al., 2010). Lately, Ime2 homologs from several fungal types have already been proven to function in not merely the control of meiosis more and more, KU-57788 irreversible inhibition however the legislation of different mobile procedures also, including ascospore development, pseudohyphal development, and sexual duplication in response to KU-57788 irreversible inhibition light and nutritional deprivation (Irniger, 2011). For instance, Crk1, a homolog of fungus Ime2, was initially identified directly into take part in the legislation of morphogenesis and seed infections (Garrido et al., 2004), and afterwards reported to operate in the harmful legislation of mating in (Liu and Shen, 2011). The Ime2 homolog ImeB was discovered to be not necessary for meiosis in mutants was reduced, and completely fertile ascospores had been stated in morphologically regular cleistothecia (Bayram et al., 2009). Furthermore, an Ime2-like MAPK was been shown to be involved with cellulase appearance in (Chen et al., 2015). As a result, the conserved Ime2-family members proteins display an urgent diversification within their mobile features in fungi. Nematode-trapping (NT) fungi constitute several fungi that may catch nematodes; NT fungi develop particular trapping gadgets (traps) for nematode predation (such as for example adhesive systems, adhesive knobs, and constricting bands), are distributed in terrestrial and aquatic ecosystems broadly, and survive generally as saprophytes and enter a predacious stage in response to indicators released by nematodes (Ahrn et al., 1998; Nordbring-Hertz et al., 2001; Su et al., 2017). The traps made by NT fungi harbor many electron-dense (ED) systems, but regular vegetative hyphae absence ED systems (Veenhuis et al., 1985, 1989). Traps are important tools utilized by NT fungi and their integrity impacts the nematode-predation performance from the fungi. Furthermore, NT fungi make extracellular serine proteases that may degrade the nematode cuticle and thus facilitate fungal penetration and colonization (Tunlid et al., 1994; Yang et al., 2013). As a result, NT fungi are potential agencies for controlling parasitic nematodes of pets and plant life. (Yang et al., 2011) and discovered several signaling protein involved in development, conidiation, and pathogenicity, like the MAPK proteins AoSlt2 (Zhen et al., 2018) and the Rab protein AoRab-7A (Yang et al., 2018). However, little is known regarding the role of the Ime2-homolog MAPK in NT fungi. Here, we recognized AoIme2, an ortholog of Ime2 in Fres. (ATCC 24927) and mutants were cultured on potato dextrose agar (PDA) plates at 28C. strain FY834 utilized for building recombinant plasmid vectors was cultured in yeast extract peptone dextrose (YPD) medium. Plasmids pRS426 and pCSN44 were maintained in strain DH5 (TaKaRa, Shiga, Japan). Protoplasts of were regenerated on.
Early brain patterning depends upon proper arrangement of positional information. a
May 20, 2017 Zoe West	Leave a comment
Early brain patterning depends upon proper arrangement of positional information. a cell reads its placement and establishes its developmental destiny/response regarding to a focus gradient of the extracellular elements [1]. These morphogens type long-range focus gradients emanating from discrete resources and diffusing over the focus on fields [2]C[5]. The procedure of neurulation in vertebrates suggests a significant morphogenetic stage for the initiation of human brain regionalization. Localized signaling centers along the pipe (called supplementary organizers) as well as the morphogens emanating from their website have an integral function in refining the subdivisions from the embryonic human brain. Among various other morphogens, Fibroblast Development Factors (FGFs) certainly are a category of structurally related polypeptides with pleiotropic actions and are involved with a signaling program conserved from pests to human beings [6]. Many FGFs mediate their natural replies as extracellular proteins by binding to and activating cell surface area tyrosine kinase receptors (FGFRs). BTZ044 Three receptors, FgfR1, 2 and 3, are portrayed in the vertebrate neural pipe [7], [8], FgfR1 getting the very important to morphogenetic Rabbit Polyclonal to Cytochrome P450 26A1. activity of FGF8. From the 22 known FGFS, FGF8 provides been proven to be always a essential morphogen for early vertebrate human brain patterning [9]C[12]. is certainly expressed on the so-called extra organizers [13]C[16] preferentially. For greater than a 10 years, the Isthmic organizer (IsO) continues to be used being a model to comprehend the morphogenetic activity of FGF8 as well as the planar induction systems during mes- and rhombencephalon advancement in vertebrates [17]C[22]. Inactivation of transcription at early neural dish stages causes loss of life of the complete mesencephalic and cerebellar primordia uncovering a requirement of FGF8 sign in success of neural progenitors [22]. If FGF8 activity is decreased, the anterior midbrain shows up regular, but posterior midbrain, vermis and isthmus are dropped indicating focus dependency of the sign activity [23], [24]. Furthermore, misexpression of (among the harmful responses modulators of FGF8 signaling; [25], [26]) reasonably decreases FGF8 signaling in the IsO leading to cell loss of life in the anterior mesencephalon and rostralization of the rest of the caudal midbrain epithelium recommending that cell success and patterning are indie properties [27]. Eight FGF8 isoforms have already been identified up to now, but just FGF8b and FGF8a isoforms have already been related to IsO activity [28], [29]. They possess different signaling actions within the neural pipe with regards to the sign receptor and focus binging affinity [9], [29], [30]. Just a solid FGF sign mediated by FGF8b activates the Ras extracellular BTZ044 signal-regulated kinase (ERK) pathway, which is enough to induce cerebellar advancement [31]. In chick, ERK1/2 induction is certainly downregulated by appearance in the IsO soon after, and the effectiveness of its sign activity appear to be essential for the standards of these human brain locations [35]. Three main intracellular signaling pathways can perform the transduction of FGF sign during embryogenesis: PI3Kinase, PLC-gamma and Ras/MAPK (evaluated by [12], [36]). Phosphorylation of Extracellular sign Regulated Kinase 1/2 (ERK1/2) is certainly a crucial stage from the Ras-MAPK intracellular pathway. In early frog, seafood, mouse and chick embryos, ERK1/2 activity depends upon FGF signaling producing the recognition of di-phosphorylated types of ERK1 and ERK2 (dpERK) useful readouts of FGF activity. In vertebrate embryos, ERK1/2 phosphorylation design profile is certainly discrete, powerful and it correlates and with gene appearance domains [24] generally, [37]C[39]. The suggested mechanism where the signaling of FGF8 spreads more than a BTZ044 field of focus on cells in zebrafish is set up and preserved by two important factors: firstly, free of charge diffusion of one FGF8 molecules from the secretion supply through the extracellular BTZ044 space and secondly, a sink function from the getting cells controlled by receptor-mediated endocytosis [40], [41]. Nevertheless, the complete form of the FGF8 morphogenetic activity is unclear through the early mammalian brain regionalization still. Additionally it is important to BTZ044 know how the FGF8 signaling expands through the IsO to become interpreted as positional details by the close by neuroepithelial cells. Right here, we address these relevant questions using the mouse IsO as experimental super model tiffany livingston system. The scholarly research discloses position related preferences of.
BTZ044Rabbit Polyclonal to Cytochrome P450 26A1.


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XyGone
News/Press / 3 August 2020 30 November 2020
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Do Host Countries Do Well At The Olympics? Not So Much
This article originally appeared in the 2021 Year In Review edition of SwimSwam Magazine. Subscribe here. At the 2020 Olympic Games, host country Japan won both its highest number of gold medals at an Olympics (27) and its highest number of medals (58) to date. This placed them third at […]
This article originally appeared in the 2021 Year In Review edition of SwimSwam Magazine. Subscribe here.
At the 2020 Olympic Games, host country Japan won both its highest number of gold medals at an Olympics (27) and its highest number of medals (58) to date. This placed them third at the medal table only behind the United States and China. It was the most successful Summer Olympics in Japan's history.
It was not a surprise. Usually, the host country surpasses its medal count from past Olympics.
Data shows, almost without exception, that Olympic athletes from the host country end up on the podium more often and take home more gold medals than they do when competing away from home.
However, an interesting phenomenon happens in swimming.
Analyzing the numbers
Let's go back to 1996. In Atlanta, the United States was the overwhelming favorite to top the medal count in swimming, and they did not disappoint. Led by Amy Van Dyken, Brooke Bennett, Jeff Rouse and Tom Dolan, the Americans won 26 in the pool, 13 of them gold.
In 2000, the Australians, with Ian Thorpe, Grant Hackett, Michael Klim and Susie O'Neill, represented a real threat to U.S. domination. But the Americans performed even better than they had done on their home turf four years earlier: they won no less than 33 medals, 14 of them gold. Australia won 18 medals, five of them gold.
Four years later, Australia sent a strong women's team to Athens, plus Thorpe and Hackett. Although they made the podium fewer times than in Sydney (15), they won more gold medals (7).
Greece did not win any medals in either 2004 and 2008, so it's not considered in this analysis.
In Beijing in 2008, China won a lone gold medal in the pool with Liu Zige in the women's 200 fly. Overall that year, Chinese swimmers won six medals. In 2012, they were much better: 10 medals, five gold, led by Ye Shiwen and Sun Yang.
In London, the British swimmers ended up with no gold medals and three medals overall. Four years later, in Rio, a remarkable improvement: they won one gold and six medals.
In Rio in 2016, Brazilian swimmers walked out of the pool without any medals, which is something rare in recent Olympics. The only Brazilian swimmer to win a medal in that year was Poliana Okimoto, a bronze in the women's aquatic marathon. This year, in Tokyo, a much better campaign: two medals in the pool and one gold medal in the aquatic marathon.
In other words, in the last 25 years, without exception, the swimmers from the host country have taken fewer gold medals than they would eventually win in the following Olympics.
This is quite rare if we take all sports into account. In fact, since 1996, only Great Britain in 2016 and Brazil in 2021 increased their medal tally at the Olympics right after having hosted them.
Why does this happen in Olympic swimming?
One could argue that the whopping amount invested in creating a world-class sporting infrastructure during the host year would translate into medal gains only a few years later. But if that were true for swimming, it would also be true for other sports, and it doesn't seem to happen.
Maybe it is related to the amount of pressure involved. Swimming is one of the most watched sports at the Olympic Games. It is so popular during the Olympics that the swimming finals took place during the morning in Tokyo in order to maximize the American TV audience rates.
With a big audience comes pressure, and that's an issue extensively addressed by the Australians in 2000, the British in 2012, and the Brazilians in 2016. They faced a scenario of high pressure they had never experienced before, and it's difficult to be prepared for that. The expectation is often raised by the fact that swimming is one of the first sports in every Olympics to distribute medals, and the pressure certainly doesn't help.
The British fans were expecting Rebecca Adlington to win two gold medals in 2012, but she didn't perform well. She was the only gold medal prospect among British swimmers in the pool at that time. That's a problem when a country depends on the success of few swimmers. It happened with the Chinese in 2008, with the Brazilians in 2016, and even with the Australians in 2000.
Some very strong Japanese contenders succumbed in Tokyo, like Daiya Seto and Shoma Sato. Yui Ohashi was the sole Japanese swimmer to win gold medals. Will the trend continue in 2024 and Japan will be another country to improve its performance in comparison to its home-based Olympics? We will have to wait and see.
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