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Frommer's Philadelphia day by day
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Portable, up-to-date, and to-the-point, Frommer's Philadelphia Day by Day is all about maximizing the time you have to spend in this fascinating and historic city. This itinerary-based book, written by long-time resident Reid Bramblett, hits all of Philly's highlights―as well as hidden gems―with plans crafted for visitors with a variety of needs and interests. Whether you want to immerse yourself in Revolutionary War history, hunt for the best cheesesteak in town, see some of the world's greatest works of art, or stroll through the city's buzziest neighborhoods, this guide is for you.
Inside the guide:
· Full-color photos and useful maps, including a tear-resistant foldout map in its own re-sealable envelope
· Best of Philadelphia itineraries for seeing the city in a limited amount of time
· Rewarding experiences for families, couples, food lovers, and those interested in Philly's rich history
· Opinionated reviews of the best attractions, shops, restaurants, spas, nightlife, and hotels in all price ranges—as well as the ones that aren't worth precious vacation time
· Helpful planning tips for getting there, getting around, saving money, and getting the most from your trip
About Frommer's: There's a reason that Frommer's has been the most trusted name in travel for more than sixty years. Arthur Frommer created the best-selling guide series in 1957 to help American servicemen fulfill their dreams of travel in Europe, and since then, we have published thousands of titles became a household name helping millions upon millions of people realize their own dreams of seeing our planet. Travel is easy with Frommer's.
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Browsing the Barnes Foundation's delightfully eclectic art collection.
16 Favorite Moments
Getting a true feeling for all that is Philadelphia means being willing to embrace extremes. One minute you're immersed in American history, the next you're elbow-to-elbow in a crowd of modern-day foodies. You'll be able to embrace nature at the largest city park in the U.S., glimpse Philly's unique brand of chic at Rittenhouse Square, see cutting-edge art in Old City—and, of course, have your fill of that special sandwich which many Philadelphians think is as important as Benjamin Franklin (well, almost).
The iconic Liberty Bell, a Philly must-see.
❶ Visit the Liberty Bell. The cracked bell that no longer tolls seems to top every tourist's to-do list. Go see it early, but also walk by it again after dusk, when its bronze cast seems to glow inside its modern glass-and-steel house. See p 9.
❷ Run like Rocky up the steps of the Philadelphia Museum of Art. When you get to the top, turn around, pump your fists in the air, and belt out a few bars of Gonna Fly Now (or just play it in your head). Then, get your photo taken with the boxer's statue at the foot of the steps. See p 45.
❸ Soak in Albert Barnes' amazingly eclectic collection. You'll find an amazing array of work from Matisse (1869–1954), Renoir (1841–1919), Picasso (1881–1973) and Cézanne (1839–1906), plus African sculpture, Pennsylvania Dutch furniture, architectural oddments, and more in this museum's hip new home on the Parkway. See p 33.
❹ Take in a Phillies game. Don't tell, but the Phillies are my favorite of all of the local pro teams, and not just because they brought home the Series in 2008 and went all the way in 2009. The Phils have a special vibe that's spirited and modest. Go catch a game at Citizens Bank Park, and when that ball soars outta here, watch—and hear—the ballpark's giant Liberty Bell ring. See p 168.
❺ Get a taste—literally—of Reading Terminal Market. You'll find dozens of local vendors here, boasting every sort of fare Philadelphia has to offer, from tandoori and cheesesteaks to cannoli and shoofly pie. Even though it's crazy-packed on Saturday mornings, that's when I like to go, to soak in the hustle and bustle—and see what everyone else is buying. See p 110.
❻ Gallery hop Old City on First Friday. Go on the first Friday of the month, and you'll be treated to edgy art, welcoming crowds, and free wine and beer—if you can snag it—mostly along North 2nd and 3rd streets. See p 32.
❼ Order a cappuccino for here at La Colombe. For less than $3, you can enjoy a silky foamed coffee in a handsome Deruta cup and discover why Food and Wine rated this spot the best cafe in the country. See p 63.
❽ Meet the Colonials. Go ahead. Strike up a chat with the 18th-century characters roaming Independence Park and Old City. Each tricorn-hatted soldier, full-skirted seamstress, fresh-faced page, and dead-ringer for Ben Franklin has an engaging personal story to tell about the birth of the nation. (Plus, they give the best directions.) See p 26.
❾ Drink a pint of hand-pumped ale at Northern Liberties' Standard Tap. You'll be participating in an age-old tradition. Before Prohibition, Philadelphia was the beer-brewing capital of the Western Hemisphere. Today, local microbreweries such as the Philadelphia Brewing Company, Yards, and Victory are reviving that legacy via delicious stouts, lagers, ambers, pilsners, and more. See p 122.
❿ Walk or bike in Fairmount Park. It's the country's largest city park; my favorite part of it to roam is called Valley Green, with wide pathways, historic bridges, and WPA-era buildings. The area is especially pretty in fall when the leaves change colors and in winter when you can just imagine the horse-and-carriages of yesteryear jingle-belling through the snow. See p 87.
The Philadelphia Phillies always attract an energetic crowd to Citizens Bank Park.
⓫ Cram yourself into DiBruno Bros. Dubbed the House of Cheese, this impossibly narrow space in the Italian Market is full of charming cheesemongers who talk you into blowing all your money on an herb-coated raw sheep's milk concoction from the wilds of Provence, or an extra-sharp Provolone aged for 2 years in Italy. See p 82.
⓬ Tour the Art Museum. For every 50 folks who jog up the Rocky Steps, maybe one bothers going inside the Philadelphia Museum of Art itself. Don't lose out on 200 rooms of exquisite works from Old Masters to Impressionists, recreated medieval cloisters to contemporary installations. Come see why this is one of the premier art galleries in North America. See p 13.
⓭ Go high-brow along Rittenhouse Square. The time to go is late afternoon to late evening, when a seat at a sidewalk table at one of the seen-and-be-seen watering holes will ensure you a view of the most stylish impromptu parade in town. See p 93.
Don't just jog up the steps a la Rocky—go inside the Philadelphia Museum of Art to enjoy its many masterpieces.
⓮ Catch the Mummers. What Mardi Gras is to New Orleans, this oddly engaging, entirely debauched New Year's Day parade is to Philadelphia, only much chillier and much less organized, if you can picture that. (Imagine a bunch of burly contractors dressed in sequins, feathers, and face paint, stopping along Broad Street to dance and strut to loud pop tunes, and you've got an idea of Mummery.) See p 20.
A costumed interpreter playing Betsy Ross engages young visitors to Independence Park.
⓯ Let the kids go nuts at Memorial Hall. It may look like an imposing venue, but ever since the Please Touch Museum moved in, it's as welcoming as a playground. Besides reversing the no touching rule, it has hundreds of exhibits encouraging kids to play and explore, ride and create, and play some more. See p 9.
⓰ Eat a cheesesteak. Preferably at a red picnic table beneath the neon lights at Pat's King of Steaks in South Philly. At 2:30am, just after the bars have all let out. (You didn't think I'd leave this off the list, did you?) See p 109. •
A horse-and-carriage ride is a fitting way to visit historic Independence Hall.
The Best in One Day
With only a day, focus on the founding of the United States. Philadelphia preserves an astounding number of the buildings, monuments, and even entire streets dating back to the Revolution and beyond. Today the country's most historic square mile will be your stomping grounds: Wear comfortable shoes, leave pocket knives at home (security checks), and don't be afraid to chat up the costumed Colonials. START: Independence Visitor Center, 6th & Market sts.
❶ ★★ Independence Visitor Center. With its self-service kiosks, concierge services, umpteen maps and brochures, and box office for tickets to Independence Hall and historic homes, this welcome center isn't just a great first stop for a tour of historic Philadelphia, it's a great first stop for any tour of Philadelphia. N ½ hr. 6th & Market sts. ☎ 800/537-7676. www.phlvisitorcenter.com. Daily 8:30am–7pm.
❷ ★★★ Independence Hall. Where it all went down: the Declaration of Independence, the Articles of Confederation, and the U.S. Constitution. Squeeze into the stately spaces where George Washington (1732–1799), Thomas Jefferson (1743–1826), John Adams (1735–1826), Benjamin Franklin (1706–1790), and their Colonial brethren conceived of a country affording its citizens life, liberty and the pursuit of happiness. Don't miss Washington's Rising Sun Chair, rare maps of the 13 colonies, and the tipstaff (a wooden and brass instrument used to subdue rowdy onlookers in the courtroom). Half-hour tours are guided. N 1 hr.; includes wait in line. Chestnut St., btw. 5th & 6th sts. ☎ 215/965-2305. www.nps.gov/inde. Mar 1–Dec 31, tickets are required (free at Visitor Center or $1.50 in advance online: pick up at least 1 hour before tour). Daily 9am–5pm (to 7pm in summer).
The iconic Liberty Bell glows within its modern glass-and-steel canopy.
❸ ★★★ Liberty Bell. The cracked, 1-ton symbol of American independence and equality resides in a $12.6-million glass gazebo across Chestnut Street from Independence Hall, preceded by a hall exhaustively documenting it and its role in the Revolution. N ½ hr. Free admission (tickets not required; mandatory security check). Daily 9am–5pm (to 7pm in summer).
National Constitution Center. The world's only museum devoted to the U.S. Constitution is way more fun than it sounds. A performance in the round explains the document's history, and interactive exhibits let you take the Presidential Oath of Office, don a Supreme Court robe, stand next to a Declaration signer, and examine hanging chads from the 2000 election. N 1½ hr. 525 Arch St. ☎ 215/409-6600. www.constitutioncenter.org. Admission $14.50 adults; $13 seniors & students; $11 ages 6–18. Buy tickets in advance; arrive 20 minutes early for timed theater show. Mon–Sat 9:30am–5pm, Sun noon–5pm.
❺ ★ Christ Church Burial Ground. The 1719 expansion of Christ Church (bullet ❾) included the graves of five signers of the Declaration of Independence, one of them Benjamin Franklin. Join the throngs who have tossed a penny on his grave for good luck. N ¼ hr. SE corner of 5th & Arch sts. ☎ 215/922-1695. www.christchurchphila.org. Mon–Sat 9am–5pm, Sun 12:30–5pm.
★★ High Street on Market. Step back, momentarily, into modern times for a tasty salad, sandwich, natural soda, cappuccino, and the day's papers at this gourmet cafe. For a longer lunch, try the more formal sister restaurant, Fork, next door (see p 106). 308 Market St. ☎ 215/625-0988. http://highstreetonmarket.com. $–$$.
Franklin Court. In a brick courtyard off Market St., the outline of Ben Franklin's long-since demolished home is traced by steel girders. Surrounding it is a museum that pays tribute to the many careers (printer, postmaster, publisher, fireman, scientist, politician) of America's favorite Renaissance Man. Highlights include a replica of Franklin's printing press, a post office that hand-stamps postcards, and a newer underground museum (which charges $5 admission). N 1 hr. 314–322 Market St. ☎ 215/965-2305. www.nps.gov/inde. Free admission. Daily 9am–5pm (printing office opens 10am). Post office closed Sun.
In the Colonial era, Christ Church's congregation was full of the political elite.
Museum of the American Revolution. The newest addition to Independence Park, this marvelous museum traces the American Revolution from the Sons of Liberty to the messy beginnings of the new country. Its highlight is George Washington's actual campaign tent, his wartime home-from-home. Intriguing exhibits contextualize relics from the era, like—a room dedicated to the shot heard round the world, for example, contains a fragment of the Old North Bridge at Concord, MA, flanked by rifles and equipment that belonging to soldiers from both sides of the battle. N 1½ hr. 101 S. Third St. ☎ 877/740-1776. www.amrevmuseum.org. Admission $19 adults; $17 seniors & students, $12 children 6–17. Daily 10am–5pm (Jul–Aug 9:30am–6pm)
Elfreth's Alley is the oldest continually inhabited street in the United States.
❾ ★★ Christ Church. This English Palladian landmark is perhaps the neighborhood's most important Colonial building. George Washington had his own pew here; its baptismal font, a gift from London's All Hallows' Church, was the one in which William Penn (1644–1718) was baptized. The tiny churchyard holds the tomb of Andrew Hamilton, the Philadelphia lawyer who helped establish freedom of the press. N ½ hr. 2nd & Market sts. ☎ 215/922-1695. www.christchurchphila.org. Free admission. Mon–Sat 9am–5pm; Sun 12:30–5pm. Closed Mon–Tues in Jan–Feb.
Betsy Ross House. The jury's out on whether Betsy Ross (1752–1836), the seamstress of the Stars and Stripes, actually lived in this teensy abode (or, for that matter, if she really sewed the first flag). No matter: This restored dwelling remains a classic Philly sight, from cellar kitchen to wee bedrooms to flag-filled gift shop. N ½ hr. See p 40.
⓫ ★★★ Elfreth's Alley. The oldest continuously inhabited street in the U.S.A., this narrow cobblestone lane is lined with small two-story row houses—now, as then, home to tradesmen, artisans, and urbanites of varied religions and ethnicities. Number 124–6, the Mantua Maker's House (cape maker), is the alley's museum, complete with 18th-century garden and dressmaker's shop. N ¾ hr. See p 51.
The Best in Two Days
You've done enough walking. On day two, it's time to take a load off and get the lay of the land (and visit some top sights) with a ride around Old City, Center City, Museum Mile, Penn's Landing, and Fairmount Park aboard a Victorian-style trolley. START: 5th & Market sts, or any of the 21 stops along the trolley's route.
Trolley Works Tour. A 24-hour pass for the surprisingly speedy rail-less trolleys and double-decker buses gets you the most comprehensive tour of downtown. On-and-off privileges and unlimited rides mean if Junior wants to see Eastern State Penitentiary (see p 68) again, or if you regret not grabbing those vintage earrings on Antique Row, a second chance is just a short ride away. N 1½ hr. 5th & Market sts.; 26 more stops along route, plus shuttles from hotels and other prime spots. ☎ 215/389-8687. www.phillytour.com. 24-hour pass: $35 adults, $32 seniors, $12 children 4–12. Apr–Nov daily 9:30am–5pm (to 6pm Sat); Dec–Mar daily 10am–4pm.
Victorian-style Trolley Works buses visit most major sites in the Center City and beyond.
❷ ★★★ Philadelphia Museum of Art. Hop off at this Greco-Roman temple on a hill, jog up the steps à la Rocky, and get lost in 200 galleries of art and objets, medieval cloisters, and blockbuster special exhibitions. Among the more than quarter-million works
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CRISIL's credit ratio – or the number of upgrades to downgrades – at 1.81 in the second half (H2) of fiscal 2019, is marginally up from 1.68 in the first half.
The positive trend in credit ratio is also consistent with asset quality as seen in the banking sector, where incremental slippages in non-performing assets declined sharply to 3.7% in H2, compared with 3.8% in H1 and an average of ~6% in fiscal 2017 and 2018.
CRISIL's debt-weighted credit ratio stood at 0.89 in H2, a dip from H1, primarily on account of downgrade of two large telecom companies1. Shorn of these two, which accounted for nearly 56% of downgraded debt by value, the ratio was higher at 2 times.
While increased private consumption supported by budgetary announcements augur well for the fiscal 2020 credit outlook, some headwinds are gathering. We expect moderation in the credit ratio as global growth slackens and pace of government infrastructure spending slows.
Among export-linked sectors, weak demand and constrained credit access will be a drag on the gems & jewellery sector, even as pharmaceuticals (especially bulk drugs and shrimp segments), will continue to benefit over the near-to-medium term from global capacity and supply constraints.
The role of quality in credit assessments and ratings becomes even more critical as the environment turns cautious from a credit outlook point of view. Therefore, it is imperative that lenders and investors focus on quality metrics as they differ across providers. CRISIL's default and stability rates have remained rock-solid in this environment, and are a testimony to our analytical rigour and proactive surveillance.


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The Deadly Secrets of C. Difficile - Insights into Host-Pathogen Interaction View all 26 Articles
Meina Neumann-Schaal
German Collection of Microorganisms and Cell Cultures GmbH (DSMZ), Germany
Imrich Barak
Institute of Molecular Biology (SAS), Slovakia
Shan Goh
University of Hertfordshire, United Kingdom
Bacteriophages
Bacteriophages Infecting C. Difficile
High Prevalence of Prophages in C. Difficile Genomes
The Consequences of Prophage Induction
Prophages Influence Toxin Production in C. Difficile
Prophage Gene Expression During Lysogeny
Other Impacts of Prophages on their Host
Conclusion and Perspectives
Mini Review ARTICLE
Front. Microbiol., 31 August 2018 | https://doi.org/10.3389/fmicb.2018.02033
Bacteriophages Contribute to Shaping Clostridioides (Clostridium) difficile Species
Louis-Charles Fortier*
Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
Bacteriophages (phages) are bacterial viruses that parasitize bacteria. They are highly prevalent in nature, with an estimated 1031 viral particles in the whole biosphere, and they outnumber bacteria by at least 10-fold. Hence, phages represent important drivers of bacterial evolution, although our knowledge of the role played by phages in the mammalian gut is still embryonic. Several pathogens owe their virulence to the integrated phages (prophages) they harbor, which encode diverse virulence factors such as toxins. Clostridioides (Clostridium) difficile is an important opportunistic pathogen and several phages infecting this species have been described over the last decade. However, their exact contribution to the biology and virulence of this pathogen remains elusive. Current data have shown that C. difficile phages can alter virulence-associated phenotypes, in particular toxin production, by interfering with bacterial regulatory circuits through crosstalk with phage proteins for example. One phage has also been found to encode a complete binary toxin locus. Multiple regulatory genes have also been identified in phage genomes, suggesting that their impact on the host can be complex and often subtle. In this minireview, the current state of knowledge, major findings, and pending questions regarding C. difficile phages will be presented. In addition, with the apparent role played by phages in the success of fecal microbiota transplantation and the perspective of phage therapy for treatment of recurrent C. difficile infection, it has become even more crucial to understand what C. difficile phages do in the gut, how they impact their host, and how they influence the epidemiology and evolution of this clinically important pathogen.
Bacteriophages (phages) are bacterial viruses that infect bacteria. At ∼1031 viral particles, they represent the most abundant biological entities in the biosphere and almost all bacteria are susceptible to phage attacks. Phages are therefore important drivers of bacterial evolution (Brüssow and Hendrix, 2002). Depending on the phages' replication strategy, their impact on bacterial populations can be drastically different. The two most frequent mechanisms of phage replication are the lytic cycle, and the lysogenic cycle (Figure 1). Phages that replicate only via the lytic pathway are referred to as "virulent" and inevitably lead to death of the host upon infection. Those phages that can replicate either by the lytic or the lysogenic cycle are said to be "temperate." When temperate phages become integrated into the host genome (i.e., prophages) their host is said to be lysogenic.
FIGURE 1. Summary of the replication strategies and multiple impacts of phages infecting C. difficile.
Most phages infecting Clostridioides (Clostridium) difficile were isolated following induction of prophages (Shan et al., 2012; Hargreaves and Clokie, 2014; Sekulovic et al., 2014). However, free phages have also been isolated directly from fecal supernatants of patients infected with C. difficile, hence prophage induction occurs in vivo (Meessen-Pinard et al., 2012). In the 1980s and 1990s, C. difficile phages were studied for their potential as strain typing tools (Sell et al., 1983; Dei, 1989; Mahony et al., 1991). Now their potential for phage therapy applications is being explored (Nale et al., 2016b, 2018). At the time of writing this manuscript, at least 24 complete phage genomes were available in public databases (Table 1). Most of them are members of the Myoviridae family of the order Caudovirales (i.e., phages with contractile tails), and six phages are members of the Siphoviridae family (i.e., phages with long non-contractile tails) (Ackermann and Prangishvili, 2012). Functional data describing the lytic cycle of C. difficile phages are quite scarce. The few one-step growth curve experiments published so far suggest highly variable latency periods (from ∼30 min to 2 h), (Goh et al., 2005b; Sekulovic et al., 2011) and burst sizes (i.e., virions released per infected cell), with as few as 5 phages/cell for phage ϕC2 (Goh et al., 2005b), to 122 phages/cell for phage 56 (Mahony et al., 1985). In addition, most phages have relatively narrow host ranges (Goh et al., 2005b; Sekulovic et al., 2011, 2014; Rashid et al., 2016), which is directly related to the availability of a suitable host receptor, the presence of endogenous prophages conferring resistance, and the presence of antiphage systems including clustered regularly interspaced short palindromic repeat sequences (CRISPRs) (Hargreaves et al., 2014a; Boudry et al., 2015), the recently described superinfection exclusion system CwpV (Sekulovic et al., 2015), and possibly others. Of particular interest, the receptor(s) used by C. difficile phages to infect their host remain(s) to be clearly identified. In other Gram-positive bacteria, different cell surface components are used as phage receptors, from single proteins to polysaccharides or teichoic acids. As examples, the Bacillus subtilis YueB (São-José et al., 2006) and Lactococcus lactis Pip (Babu et al., 1995) proteins are, respectively, used by phages SPP1 and c2 to infect their host. Different polysaccharides composing the pellicle are used as receptors by lactococcal phages such as p2 (Bebeacua et al., 2013). Of note, recent data with Diffocins, i.e., phage tail-like bacteriocins that resemble Myoviridae phage tails and that kill their host by puncturing the cell, point to a central role of the surface layer protein A (SlpA) as a general phage receptor used by Diffocins and Myoviridae phages (Gebhart et al., 2015; Kirk et al., 2017). Detailed molecular interactions between phages and the C. difficile surface need to be further investigated, in particular regarding Siphoviridae phages, and considering the potential of phages as therapeutic agents.
TABLE 1. List and relevant characteristics of C. difficile phages for which a complete genome sequence is available in GenBank.
Over 1,300 C. difficile genomes have been fully sequenced and are available in public repositories, but thousands of additional genomes have also been sequenced and are available through collaborative research (Garneau et al., 2018). Although uncommon, as many as 5–6 different prophages were identified in a single C. difficile genome (Amy et al., 2018; Ramírez-Vargas et al., 2018). However, between 1 and 3 prophages are more frequently observed, in addition to genomic "islands" containing phage-related genes. Recent studies highlighted the prevalence of large phage genomes that reside as extrachromosomal DNA in C. difficile (Garneau et al., 2018; Ramírez-Vargas et al., 2018). For example, the large phiCD211/phiCDIF1297T and related phages, with genomes of ≥131-kb, have been detected in 5% of 2,584 C. difficile genomes analyzed, spanning 21 different multi-locus sequence types (MLST) (Wittmann et al., 2015; Garneau et al., 2018). Ten other large phage genomes (∼128–135-kb), including phiCD5763, phiCD5774, and phiCD2955, were recently described in C. difficile isolates from around the world and representing seven different MLST sequence types (Ramírez-Vargas et al., 2018). Comparative genomic analyses underlined the important genetic variability among large phages, and they could eventually be used as genetic markers to subtype and monitor specific strains during epidemiological studies, as suggested for Salmonella enterica (Mottawea et al., 2018).
It is worth mentioning that extrachromosomal phage genomes can be difficult to differentiate from large plasmids containing phage genes. A study by Amy et al. (2018) reported the characterization of a large plasmid in C. difficile strain DLL3026. This 46-kb plasmid, called pDLL3026, and several other plasmids of similar size identified in other isolates, harbor a significant number of phage structural genes coding for head and tail morphogenesis, recombinases/integrases and phage regulators. The presence of partition genes like parM and parR and DNA similarity with plasmids led the authors to conclude that these were plasmids. However, the presence of partition genes like parA has also been reported in other phages, including phiCD6356 (Horgan et al., 2010), ϕCD38-2 (Sekulovic et al., 2011), and phiSemix9P1 (Riedel et al., 2017), the latter two known to be maintained as extrachromosomal DNAs in lysogenic cells. Large phage genomes such as phiCD211/phiCDIF1296T and phiCD5763 also seem to be frequently found as extrachromosomal DNA, and ParM homologs were identified in some of them (Garneau et al., 2018; Ramírez-Vargas et al., 2018). Therefore, in the absence of functional data to assess the inducibility and production of infectious particles from these large "plasmids," it is hard to conclude on their exact nature.
The identification of complete prophages in bacterial genomes has been greatly improved, thanks to the development of tools such as PHAST and PHASTER (Arndt et al., 2016, 2017). But the task is more challenging with decaying prophage remnants that have lost many of the conserved phage components such as structural genes. Yet, these remnants could still influence their host even if they can't replicate or produce complete infectious particles. Diffocins are a good example: these phage tail-like particles resemble Myoviridae phage tails, but lack a capsid and genetic material (Gebhart et al., 2012). They kill their host following induction and lysis of the cell, and also kill other competing cells around, but they can't produce infectious particles. The functional role of Diffocins remains to be clarified, but they possibly provide a competitive advantage to C. difficile strains carrying them by killing surrounding competitors (Kirk et al., 2017).
The role of prophages in the physiology and virulence of C. difficile is a topic of great interest, considering their prevalence and diversity, and the historical role prophages played in the virulence of other bacterial pathogens (Brüssow et al., 2004; Fortier and Sekulovic, 2013). Prophage stability is critical because of the direct consequence on the viability of the host itself and susceptible surrounding strains/species that can be re-infected. Induction can occur spontaneously, but is promoted by common antibiotics and various environmental stresses (Rokney et al., 2008; Meessen-Pinard et al., 2012; Shan et al., 2012). Of note, prophage induction triggered by antibiotics promote horizontal gene transfer and spreading of antibiotic resistance genes in mice (Modi et al., 2013). In vitro, phage ϕC2 was shown to mediate transduction of the Tn6215 transposon between C. difficile strains (Goh et al., 2013). Differences in abundance and diversity of gut phages has also been associated with diseases and could be the result of prophage induction (Norman et al., 2015; Manrique et al., 2016). Hence, better understanding the role of prophage induction in complex ecosystems such as the gut is of great interest.
Induction of prophages and phage-related elements can also have other important physiological roles in C. difficile. For example, excision of the phage-related mobile element called skinCd is important during the sporulation process (Haraldsen and Sonenshein, 2003; Saujet et al., 2014). The skinCd is a putative prophage remnant similar to the one identified in B. subtilis (skinBs) that interrupts the coding sequence of SigK, a sporulation-associated alternative sigma factor. Excision of the skinCd element at a specific time point during the sporulation process restores the coding sequence of the gene, allowing expression of sigK (Saujet et al., 2014; Fimlaid and Shen, 2015). Control of the excision of the skin element remains unclear, but a putative site-specific recombinase similar to SpoIVCA, encoded by cd1231 and located within skinCd, is suspected to be involved. Some crosstalk between prophages has been reported (Lemire et al., 2011; Sekulovic and Fortier, 2015), including between their recombinases (Singh et al., 2014). Therefore, other phage-encoded recombinases could possibly participate in skinCd excision as well, and thus influence sporulation (Saujet et al., 2014).
The main virulence factors of C. difficile are the large TcdA and TcdB exotoxins. They are encoded on a 19.6-kb pathogenicity locus, the PaLoc (Rupnik et al., 2009). The PaLoc is thought to originate from an ancient prophage, since it shares a number of features with phages, in particular the tcdE gene encoding a phage-like holin involved in toxin secretion (Govind and Dupuy, 2012; Govind et al., 2015; Monot et al., 2015). Prophage induction per se has not been directly associated with toxin release or synthesis in C. difficile, as opposed to Shiga toxin-encoding phages in Escherichia coli (Kimmitt et al., 1999; Zhang et al., 2000) but some prophages interfere with toxin synthesis. For example, phage ϕCD119 was shown to express the RepR repressor, capable to bind a DNA region in the promoter of tcdR in the PaLoc, resulting in repression of toxin genes (Govind et al., 2009). On the contrary, phage ϕCD38-2 was shown to increase transcription of all five PaLoc genes by a yet unknown mechanism, resulting in more toxins produced in vitro. However, the impact of ϕCD38-2 on toxin synthesis was strain-dependent (Sekulovic et al., 2011) and similar observations were reported with other C. difficile phages (Goh et al., 2005a), suggesting that the influence of a prophage on its host partly depends on the genetic background.
A complete binary toxin locus (CdtLoc) has been recently identified in the genome of phage phiSemix9P1 (Riedel et al., 2017). The binary toxin, normally located on a 6.2-kb chromosomal locus called CdtLoc comprises 2 genes coding for the toxin components, cdtA and cdtB, as well as a regulator encoded by cdtR (Carman et al., 2011; Gerding et al., 2014). Of note, all three genes from the CdtLoc were shown to be transcribed from the phiSemix9P1 prophage, suggesting that it is functional, although no toxin assays have been performed (Riedel et al., 2017). The CdtLoc is present only in a subset of C. difficile isolates, including the epidemic ribotype 027 isolates (Bauer et al., 2011), and studies suggest that CDT contributes to virulence by promoting adhesion to epithelial cells (Schwan et al., 2009, 2014; Gerding et al., 2014). phiSemix9P1 has limited DNA homology with another C. difficile phage, ϕCD505, and the large pCDBI1 plasmid, suggesting that it is genetically unique. The identification of a CDT-encoding phage is intriguing but it might represent a rare isolated case, since it has never been observed in other C. difficile phages, including the numerous prophages identified in the course of genome sequencing projects. Nevertheless, it further supports the evolutionary role of phages in toxin conversion of C. difficile (Riedel et al., 2017).
During active phage replication, the transcriptional program of the host is profoundly restructured and metabolic resources are redirected toward phage replication. However, during the lysogenic cycle, prophages are generally quiescent and minimal gene transcription is observed from the prophage itself. Only a few gene products are required to establish and maintain lysogeny (Ainsworth et al., 2013), the CI repressor from the E. coli phage Lambda being the most well-characterized gene expressed during lysogeny (Oppenheim et al., 2005; Rokney et al., 2008).
Very little is known about transcriptional reprogramming during phage infection or lysogeny in C. difficile. In fact, only one study has looked at global gene expression during lysogeny (Sekulovic and Fortier, 2015). In that study, the ϕCD38-2 prophage was introduced into the epidemic strain R20291 and mRNA levels were assessed by RNAseq. It is important to mention that the prophage was maintained as a circular extrachromosomal DNA, so the host genome integrity was unaffected. On a genome-wide scale, the expression of 39 genes was significantly altered by the introduction of the prophage, including genes from the phi027 prophage already present in the host. This further supports the existence of some crosstalk between prophages (Sekulovic and Fortier, 2015). Two-thirds of the differentially expressed genes were downregulated twofold to threefold, and half of the differentially expressed genes were related to sugar uptake and metabolism, suggesting a possible impact on growth kinetics. Of note, the cwpV gene encoding a conserved surface protein was induced 20-fold in the lysogen. Transcription of cwpV is dependent on the configuration of a genetic switch located between the promoter and the gene. Recombination of the switch, catalyzed by the host-encoded RecV recombinase, turns transcription of cwpV ON or OFF in a phase-variable manner (Reynolds et al., 2011; Fagan and Fairweather, 2014). Only ∼5% of bacterial cells in culture express the CwpV protein at their surface, but in the R20291 lysogen carrying ϕCD38-2, this proportion increased to 95%, hence explaining the higher mRNA levels observed. The exact mechanism by which ϕCD38-2 influences phase variation remains unknown (Sekulovic and Fortier, 2015). CwpV is a large conserved cell wall protein suspected to contribute to cell adhesion and biofilm formation, and possibly immune evasion (Reynolds et al., 2011). The location of the protein at the cell surface and its apparent link with lysogeny suggested that it could play some role in phage infection. It turned out that CwpV has strong antiphage activity against several C. difficile phages of the Siphoviridae and Myoviridae families when overexpressed from a plasmid or from a "locked-ON" strain. Current data suggest that CwpV functions as a superinfection exclusion system (Sekulovic et al., 2015) that blocks phage DNA injection. The biological relevance of such an antiphage system seems obvious in the context of the gut microbiota. CwpV-ON strains would be protected from lytic phage attacks, which are expected to be relatively frequent in the gut due to high phage and bacterial densities (Manrique et al., 2016, 2017). Higher numbers of CwpV-ON cells could also contribute to colonization of the gut through increased bacterial adhesion and biofilm formation. Maybe of greater concern, however, is the fact that cwpV-expressing cells are naturally occurring in vitro due to phase variation and these cells are resistant to phage infection. Hence, looking at future phage therapy perspectives (Nale et al., 2016b), naturally occurring CwpV-positive cells in the gut could potentially compromise the efficacy of therapeutic phages. Further in vivo assays will be required to clarify the biological role and consequences of CwpV expression.
Several phage genomes carry cargo genes unrelated to the phage replication cycle, and their expression is often independent from the phage circuitry and occurs during lysogeny. The genes often code for virulence factors, including toxins, superantigens, and hydrolytic enzymes (Brüssow et al., 2004; Fortier and Sekulovic, 2013). Certain prophage genes can also provide phage immunity via superinfection exclusion (Mahony et al., 2008; Labrie et al., 2010).
The genomes of many C. difficile prophages encode genes that are suspected to influence their host. For example, the large phiCD211-like phages encode putative multidrug resistance genes, spore proteases, and multiple regulators that could interfere with host regulation (Garneau et al., 2018). A CRISPR array with a cas3 gene was also identified, suggesting that phiCD211-like phages possibly participate in CRISPR interference. The presence of CRISPR arrays has been reported in other C. difficile phages, including the two prophages from strain 630 (Hargreaves et al., 2014a; Boudry et al., 2015) as well as the phi027 prophage present in the epidemic strain R20291 and most R027 isolates (Sekulovic and Fortier, 2015). Transcriptomic analyses by RNAseq showed that these CRISPR arrays are transcribed and thus, possibly contribute to C. difficile resistance to invading DNA (Boudry et al., 2015; Sekulovic and Fortier, 2015).
Phage phiCDHM1 and other predicted C. difficile prophages encode homologs of an Agr-like quorum sensing (QS) system (Hargreaves et al., 2014b). QS is used to coordinate specific phenotypes at the whole population level in function of cell density. QS has been implicated in virulence of several pathogens, by coordinating toxin secretion, biofilm production, motility, and sporulation (Novick and Geisinger, 2008; Antunes et al., 2010; Rutherford and Bassler, 2012). The Agr system of Staphylococcus aureus is the most well-characterized QS system in Gram-positive bacteria, and regulates the expression of hundreds of genes, including exotoxins and surface proteins. It is encoded by an operon of four genes, agrD-agrB-agrC-agrA (Novick and Geisinger, 2008). At least two types of QS systems have been described in C. difficile; one is similar to the S. aureus Agr, while the other is related to the luxS/AI-2 from Vibrio harveyi (Stabler et al., 2009). Both systems control the expression of C. difficile toxins in function of cell density (Lee and Song, 2005; Martin et al., 2013; Darkoh et al., 2015). During lysogeny, the agrB and agrC genes are expressed from the phiCDHM1 prophage, suggesting that these components of the QS system are active. However, in the absence of an agrA homolog in phiCDHM1, it is impossible to conclude if the system is functional or not and whether it participates in some way to QS. We can speculate that AgrB and AgrC contribute to autoinducer secretion and signal detection, but no response would be elicited due to the absence of an associated response regulator. Alternatively, these phage-encoded genes could partly complement another Agr system from the host (Hargreaves et al., 2014b). QS likely affects multiple phenotypes in C. difficile (Martin et al., 2013) so it will be interesting to establish whether phage-encoded QS genes influence virulence-associated phenotypes such as toxin production, sporulation, or biofilm formation. QS signals detected by the phage-encoded AgrC could also lead to prophage induction, as observed with soil bacteria (Ghosh et al., 2009). This could be a means for the prophage to "determine" the best moment to initiate a replication cycle that will ensure its successful propagation into the bacterial population. It is therefore reasonable to hypothesize that during infection of the gut, high cell densities would trigger prophage induction, hence promoting phage dissemination and possibly horizontal gene transfer. Further research on the impact of QS on prophage stability would be necessary.
The contribution of phages to the evolution and virulence of C. difficile remains to be clarified (Fortier and Sekulovic, 2013). So far, prophages seem to impact C. difficile's lifestyle and biology in subtle ways, depending on the genetic background of the host. Studying phage–host interactions requires extensive knowledge of the biology of the phage and the host. Unfortunately, many phage genes have no homologs in databases or have no assigned function. Therefore, one way to investigate the impact of a prophage on its host is to introduce a given temperate phage into a susceptible bacterial host to create a new lysogen and to study various phenotypes in comparison with the parental strain lacking that prophage. However, bacterial genomes often carry multiple prophages and phenotypes can sometimes result from the cumulative effects of more than one prophages, like reported for the DNAses secreted by Streptococcus pyogenes SF370 (Euler et al., 2016). In addition, natural lysogens have been carrying prophages for extensive periods of time and as such, the prophages' regulatory circuits are often seamlessly integrated into the host network (Ehrbar and Hardt, 2005). Therefore, a better alternative is to remove parts or whole prophages from their natural lysogen to study their impact. Such "prophage-cured" strains can then be compared with the lysogenic parental strain. Curing lysogens from their prophages can be quite challenging depending on the host and the availability of molecular tools. Reports of successful curing using extensive screening for spontaneous prophage-cured mutants, or using allelic exchange with counter selection methods have been published in Gram-negative (e.g., E. coli) and Gram-positive bacteria (e.g., S. pyogenes, S. aureus). These studies have shed light on the role of individual prophages as well as their combined contribution to virulence of their host (Bae et al., 2006; Wang et al., 2010; Euler et al., 2016). Of note, curing of one of the two prophages from C. difficile strain 630 has been recently reported, and involved the use of the CRISPR technology (Hong et al., 2018). This first example of prophage curing in C. difficile paves the way for additional studies on the role of prophages in this pathogen, in particular in epidemic strains such as the R20291 that carries the conserved phi027 prophage (Stabler et al., 2009). Better understanding how phages interact with C. difficile at the molecular level will be essential, especially for future phage therapy applications. Hence research focusing on identifying the cell receptor(s) and the phages' receptor binding protein and how these two influence the phages' host range will be crucial. In addition, understanding how phages affect C. difficile and whole bacterial populations in complex ecosystems such as the gut microbiota will be determinant as well. For instance, transfer of certain phages from donors to recipients seems to contribute to the success of fecal microbiota transplantation to treat recurrent C. difficile infections (Zuo et al., 2017). Studying the interplay between the virome and the microbiome in health and disease is thus of high relevance. In conclusion, there is a lot more to discover about C. difficile phages and the newly developed molecular tools and the availability of bacterial genome sequences will certainly foster research in this domain.
L-CF collected the ideas, concepts, and interpretations, as well as wrote the manuscript.
This work was supported by a discovery grant from the Natural Sciences and Engineering Research Council of Canada (NSERC; RGPIN-2015-06334). L-CF is a member of the Centre de Recherche du CHUS.
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Meessen-Pinard, M., Sekulovic, O., and Fortier, L.-C. C. (2012). Evidence of in vivo prophage induction during Clostridium difficile infection. Appl. Environ. Microbiol. 78, 7662–7670. doi: 10.1128/AEM.02275-12
Modi, S. R., Lee, H. H., Spina, C. S., and Collins, J. J. (2013). Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499, 219–222. doi: 10.1038/nature12212
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Mottawea, W., Duceppe, M.-O., Dupras, A. A., Usongo, V., Jeukens, J., Freschi, L., et al. (2018). Salmonella enterica prophage sequence profiles reflect genome diversity and can be used for high discrimination subtyping. Front. Microbiol. 9:836. doi: 10.3389/fmicb.2018.00836
Nale, J., Redgwell, T., Millard, A., and Clokie, M. (2018). Efficacy of an optimised bacteriophage cocktail to clear Clostridium difficile in a batch fermentation model. Antibiotics 7:13. doi: 10.3390/antibiotics7010013
Nale, J. Y., Chutia, M., Carr, P., Hickenbotham, P. T., and Clokie, M. R. J. (2016a). Biofilm and wax moth (Galleria mellonella) models reveal new insights into the therapeutic potential of Clostridium difficile bacteriophages. Front. Microbiol. 7:1383. doi: 10.3389/fmicb.2016.01383
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Ramírez-Vargas, G., Goh, S., and Rodríguez, C. (2018). The novel phages phiCD5763 and phiCD2955 represent two groups of big plasmidial siphoviridae phages of Clostridium difficile. Front. Microbiol. 9:26. doi: 10.3389/fmicb.2018.00026
Rashid, S. J., Barylski, J., Hargreaves, K. R., Millard, A. A., Vinner, G. K., and Clokie, M. R. J. (2016). Two novel myoviruses from the north of iraq reveal insights into Clostridium difficile phage diversity and biology. Viruses 8:310. doi: 10.3390/v8110310
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Singh, S., Rockenbach, K., Dedrick, R. M., VanDemark, A. P., and Hatfull, G. F. (2014). Cross-talk between Diverse Serine Integrases. J. Mol. Biol. 426, 318–331. doi: 10.1016/j.jmb.2013.10.013
Stabler, R. A., He, M., Dawson, L., Martin, M., Valiente, E., Corton, C., et al. (2009). Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium. Genome Biol. 10:R102. doi: 10.1186/gb-2009-10-9-r102
Wang, X., Kim, Y., Ma, Q., Hong, S. H., Pokusaeva, K., Sturino, J. M., et al. (2010). Cryptic prophages help bacteria cope with adverse environments. Nat. Commun. 1:147. doi: 10.1038/ncomms1146
Wittmann, J., Riedel, T., Bunk, B., Spröer, C., Gronow, S., and Overmann, J. (2015). Complete Genome Sequence of the Novel Temperate Clostridium difficile Phage phiCDIF1296T. Genome Announc. 3:e00839-15. doi: 10.1128/genomeA.00839-15
Zhang, X., McDaniel, A. D., Wolf, L. E., Keusch, G. T., Waldor, M. K., and Acheson, D. W. (2000). Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J. Infect. Dis. 181, 664–670. doi: 10.1086/315239
Zuo, T., Wong, S. H., Lam, K., Lui, R., Cheung, K., Tang, W., et al. (2017). Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome. Gut 67, 634–643. doi: 10.1136/gutjnl-2017-313952
Keywords: Clostridium difficile, Clostridioides difficile, bacteriophages, prophages, toxins, virulence, lysogenic conversion
Citation: Fortier L-C (2018) Bacteriophages Contribute to Shaping Clostridioides (Clostridium) difficile Species. Front. Microbiol. 9:2033. doi: 10.3389/fmicb.2018.02033
Received: 30 June 2018; Accepted: 13 August 2018;
Published: 31 August 2018.
Meina Neumann-Schaal, Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), Germany
Imrich Barak, Institute of Molecular Biology (SAS), Slovakia
Shan Goh, University of Hertfordshire, United Kingdom
Copyright © 2018 Fortier. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Louis-Charles Fortier, Louis-Charles.Fortier@USherbrooke.ca

redpajama_set_name: RedPajamaCommonCrawl


On behalf of Cal Bomar of Bomar Law Firm, LLC posted in Audits on Tuesday, January 20, 2015.
Some companies in Georgia may have experience with IRS business audits. Although these audits have the potential to be stressful experiences for business owners, it may be possible to mitigate their operational impact through careful preparation and planning.
During an IRS audit, there are a number of documents that a business may be required to make available. The IRS will often require the production of any and all electronic and online records related to the business, such as receipts and bank statements. In addition, it may be necessary to supply copies of the leases to any properties the business has rented or purchased, as well as whatever ledgers or appointment logs are available. Transactions made in cash may need to be validated with documentation such as petty cash vouchers and receipts.
Before an IRS business audit begins, there are some measures that can be taken to facilitate the process as much as possible. For example, the business might wish to organize its documents as neatly as possible in order to generate credibility with the auditor. If the business has claimed any deductions or credits on its tax returns for the years in question, these will likely need to be supported during the audit. In such a case, it may be advisable to research applicable tax laws or supply documentation that establishes why the deduction or credit was claimed.
A business undergoing an IRS audit may wish to secure some form of legal representation before it is scheduled to take place. An attorney may be able to help review the circumstances of the business to identify areas that may be of concern to the IRS and resolve these wherever possible. In addition, an attorney might also help to justify claimed tax exemptions by the production of appropriate documentation.


WASHINGTON (AP) – The head of the federal disaster response agency is resigning, months after an investigation found he misused government vehicles to travel to his home in North Carolina. Brock Long said in a letter to Federal Emergency Management Agency employees that he was resigning to spend more time with his family. Long was under investigation by the Homeland Security Department's watchdog, and word of it leaked just as Hurricane Florence struck last fall.
WASHINGTON (AP) – Democratic lawmakers challenged top executives of T-Mobile and Sprint over their pledge not to raise prices for wireless services or hurt competition if their $26.5 billion merger goes through. At a hearing by a House committee, the two executives defended the deal, which would combine the nation's third- and fourth-largest wireless companies and create a behemoth about the size of industry giants Verizon and AT&T.
STRASBOURG, France& (Reuters) – The European Commission added Saudi Arabia, Panama, Nigeria and other jurisdictions to a blacklist of nations that pose a threat because of lax controls on terrorism financing and money laundering, the EU executive said on Wednesday.


The Association for Environmental Health and Sciences Foundation attributes the success of the Annual East Coast Conference in large part to a very dedicated and hard working Scientific Advisory Board (SAB). The SAB evaluates abstract submissions, recommends invited papers and presenters, advises with regard to session topics, and serves as conference ambassadors. The SAB is crucial to the conference development. Care is taken to create a Board that represents philosophical, scientific, regulatory, and geographical balance.
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text:
Q: Merging nested list of objects into a single list I have a list of objects, one of which is another list (or actually, Seq[Row] - these are RDDs) and I want to merge them together. There is a list with rows <a, b, c, d> where d is itself another list <q, r, s, t>, one of which is another nested list but let's ignore that for simplicity. I want to change this into a list of <a, b, c, q1, r1, s1, t1>, <a, b, c, q2, r2, s2, t2> ...
I can extract the information into case classes etc. and then put them together, but I feel there should be a way to use zip and map etc. to write this in a better functional manner, how should I do so?
Edit Detailed description:
The lists are from nested RDD table on hdfs.
parent: <Long, String, String, Long, String, Float, Seq[Row] foolist >
foolist: <String, String, Long, Int, Seq[Row] barlist >
barlist: <String, Boolean, Int, Long, Seq[Row] list1, Seq[Row] list2 >

They have more fields than stated. Other than the parent object I don't need to filter out any fields in the final result, in which a single row in the parent would become a collection of the values in
{parent row}, {foo row 1}, {barlist row 1}
{parent row}, {foo row 1}, {barlist row 2}
{parent row}, {foo row 1}, {barlist row N}
{parent row}, {foo row 2}, {barlist row 1}
{parent row}, {foo row 2}, {barlist row N}
...
{parent row}, {foo row M}, {barlist row N}

which are not tuples, just a plain list of fields (Long, String, String, Long, String, Float, String, String, Long, Int, String, Boolean, Int, Long ..)

A: You can use flatMap for that:
seq.flatMap {case (a,b,c,d) => d.map {case (q,r,s,t) => (a,b,c,q,r,s,t)}}
Or:
val res = for {
  (a,b,c,d) <- seq;
  (q,r,s,t) <- d
} yield (a,b,c,q,r,s,t)

A: You can use this:
def flat(seq: Seq[Any]):Seq[Any] = seq flatMap {
  case sq:Seq[_] => flat(sq)
  case x => Seq(x)
}

Edit:
if you want to flatten row, you can try:
def flat(seq: Seq[Any]):Seq[Any] = seq flatMap {
  case Seq(row) => flat(row.toSeq)
  case x => Seq(x)
}

redpajama_set_name: RedPajamaStackExchange


The library will be closed on Monday, May 30, in observance of Memorial Day. The library is open Saturday so you can check out all the reading and watching materials you need for the long weekend!!
The Poestenkill Memorial Day Parade kicks off at 11am on Monday.


C Case was born on September 1, 1893. C died in November 1968 at 75 years of age. We know that C Case had been residing in Erie, Erie County, Pennsylvania.
C Case's biography is built and maintained by people like you. Create an online profile of C so that their life is remembered forever. If any factual information is incorrect, please edit C's biography.
This genealogy profile is dedicated to the life and ancestry of C Case and their immediate Case family. Add to C Case's genealogy page to share your memories & historical research with their family and other genealogy hobbyists.
Do you know the final resting place - gravesite in a cemetery or location of cremation - of C Case? Add burial and funeral information.
C Case lived 3 years longer than the average Case family member when they died at the age of 75.
It is unknown if C Case is a military veteran.
1893 - In the year that C Case was born, on February 1st, Thomas Edison's motion picture studio on his laboratory grounds in West Orange New Jersey was completed. The studio was called "Black Maria" and the first movie made and viewed in it was of 3 people pretending to be blacksmiths.
1905 - C was just 12 years old when the German born physicist, Albert Einstein, proposed the Special Theory of Relativity: 1) that observers can never detect uniform motion except relative to other objects and that 2) unlike the velocity of massive objects, the speed of light is a constant and is the same for all observers independent of their constant velocity toward or away from the light source. Not such simple concepts that lead to the equation everyone now knows: E = mc2.
1916 - At the age of 23 years old, C was alive when the Battle of Verdun was fought from February through December. It was the largest and longest battle of World War I, lasting 303 days. The original estimates were 714,231 casualties - 377,231 French and 337,000 German, an average of 70,000 casualties a month. Current estimates are even larger. The Battle of the Somme was also fought from July through September of the same year. Original estimates were 485,000 British and French casualties and 630,000 German casualties.
1952 - This person was 59 years old when on July 2, Dr. Jonas E. Salk tested the first dead-virus polio vaccine on 43 children. The worst epidemic of polio had broken out that year - in the U.S. there were 58,000 cases reported. Of these, 3,145 people had died and 21,269 were left with mild to disabling paralysis.
1968 - In the year of C Case's passing, on April 4th, Dr. Martin Luther King, Jr., the civil rights leader, was shot and killed by an assassin in Memphis. James Earl Ray was apprehended and plead guilty to shooting Dr. King. Ray died in jail in 1998.
This obit of C Case is updated by the community. Edit this biography to contribute to their obituary. Include details such as cemetery, burial, newspaper obituary and grave or marker inscription if available.
C Case died in November 1968 at 75 years of age. There is no listed cause of death. C was born on September 1, 1893. We are unaware of information about C's immediate family. We know that C Case had been residing in Erie, Erie County, Pennsylvania.
What do you remember about C Case? Share your memories of special moments and stories you have heard about them. Or just leave a comment to show the world that C is remembered.


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text:
George Albert Frost  (December 23, 1843 – November 13, 1907) was an American artist of the 19th century. He was born in Boston, Massachusetts and had a studio in North Cambridge, Massachusetts for several years.   He studied under Nicolas de Keyser at the Academy Royale de Belgique in Antwerp. His paintings were mostly landscapes, and he is considered a member of the White Mountain art group of painters.

Career
Frost was born in Boston in 1843.  He left school at age eleven to work on a farm where he had no opportunity to follow his artistic inclinations.  At the outbreak of the Civil War, he enlisted and served for more than two years.  In 1865 he joined Colonel Franklin L. Pope's division of the Western Union surveying party to British Columbia for which he produced sketches.  In 1866 he was assigned to Siberia with the purpose of selecting a route to connect a telegraph line from San Francisco to Moscow (Russian-American telegraph).  He exhibited at the San Francisco Art Association in 1874, then studied at the Belgian Royal Academy of Fine Arts, Antwerp, with Nicolas de Keyser from 1874 to 1876, and for the next ten years had a studio in North Cambridge, Massachusetts.  In 1883 he produced his earliest known White Mountain work.

In 1885 he accompanied George Kennan on a second trip to Siberia to record the life of Russian exiles, during which time Frost painted several Siberian scenes.  The trip was commissioned by The Century Magazine, and Frost and Kennan took numerous photographs which later were given to the Library of Congress and are now housed in the Library's Prints and Photographs Division. Selections from the George Kennan Collection in Meeting of Frontiers consists of 256 photographs taken in a wide range of locations in Siberia.  Frost's drawings, some of which were copied from photographs taken during the trip, were used to illustrate Kennan's book, Siberia and the Exile System.

For a good many years, Frost had a summer home in Brownfield, Maine, near the Conway area of New Hampshire. He painted many scenes along the Saco River. He was a member of the Boston Art Club and exhibited there during the years 1896 to 1908.  His last known address was Cambridge, Massachusetts.

His works are at the California State Library and the California Historical Society.

Franconia Notch

Signed and dated lower right:  G. A. Frost. 1883. Oil on canvas, 28 x 48 inches. Private collection

The vista into Franconia Notch from the south became known as the "Artist's View."  Boston artist George Albert Frost expands our understanding of the White Mountains with an imaginative interpretation of Franconia Notch.  Classically composed, with dark foliage framing the left side of the canvas and an expansive open space in the middle ground, giving way to atmospheric mountains in the distance, the notch is presented as an Arcadian idyll.   Franconia Notch's appeal as a subject may reflect that life in the area was still slow-paced.  Its virgin landscape was as yet hardly altered by railroads, hotels, and related improvements.

Personal life
George A. Frost was married in 1882 to Adelia Dunham.  They had two sons: Paul Rubens Frost (1883–1957), a notable landscape gardener, and Norman Wentworth Frost, a teacher and charter member of the American Esperanto Club.

Exhibits
Concord, New Hampshire, Consuming Views: Art and Tourism in the White Mountains, 1850–1900, September 16, 2006 through October 8, 2007, #16

Bibliography
 .
 Campbell, Catherine H.  New Hampshire Scenery.  Canaan, New Hampshire: Phoenix Publishing, 1985.
 Chadbourne, Janice H. and Karl Gabosh and Charles O. Vogel, ed.  The Boston Art Club Exhibition Record, 1873-1909.  Madison, Connecticut: Sound View Press, 1991.
 Consuming Views: Art & Tourism in the White Mountains, 1850–1900.  Concord NH: Hanover NH: New Hampshire Historical Society; Distributed by University Press of New England, 2006.
 Falk, Peter Hastings, ed.  Who Was Who in American Art, 1564-1975.   3 vols.  Madison, Connecticut: Sound View Press, 1999.
 Henderson, John J., "19th Century Artists in the White Mountains of New Hampshire," Heart of New Hampshire, Fall 2005.
 Henderson, John J. and Roger E. Belson, "Art & Tourism in the White Mountains, 1850-1900," American Art Review, Vol. XIX, No. 2, 2007, 109.

Footnotes

External links
 Chronology
 New Hampshire Historical Society
 Artwork by George Albert Frost

1843 births
1907 deaths
19th-century American painters
American male painters
20th-century American painters
American landscape painters
Royal Academy of Fine Arts (Antwerp) alumni
Artists from Boston
People from Brownfield, Maine
19th-century American male artists
20th-century American male artists
Hudson River School painters

redpajama_set_name: RedPajamaWikipedia


Silversea advertised the experience as an adventure for "the true 1% of the 1%."
Luxury cruise company Silversea has announced a new "Legends of Cruising World Cruise" that will take passengers through all seven continents.
The journey begins in Fort Lauderdale, Florida, and travels through 32 countries in 140 days.
Suites begin at $62,000 and range up to $240,000.
If you're one of those people who claims cruises are just "not your thing," it may be time to think again. Privately owned luxury line, Silversea, just announced an EPIC Legends of Cruising World Cruise that will truly satisfy your wanderlust by taking you to all seven continents. If riding elephants in Phuket or taking tango lessons in Buenos Aires (in the same trip!) has been on your bucket list for some time, scroll down below to learn more about the once-in-a-lifetime getaway that promises to give your friends some serious travel envy.
This dream adventure pushes off from a port in Fort Lauderdale, Florida and takes 600 passengers to 32 countries over the course of 140 days. Sure, taking nearly five months of PTO isn't easy for most people, but that's exactly the liner's positioning. The brand is not shy about advertising this deluxe experience as a voyage for "the true 1% of the 1%."
A private butler and view of the ocean is included in each room.
It should come as no surprise that the starting fee for the cruise caters to this top tier as well. The suites start at $62,000 and range up to $240,000. (For that price tag, a private butler and ocean-facing veranda are included with each room.) Other boat amenities include several world-class restaurants, designer boutiques, an elite spa, and even a card room to keep guests pampered and entertained for all 140 days of their voyage.
All that said, one could say it's hard to put a price on a several weeks' excursion to exotic countries, complete with organized outings to get a true cultural experience. Our faves from their impressive list of activities include a dune buggy adventure in Brazil, kayaking around Tonga, taking a Nile River cruise in Egypt, bridge climbing in Australia, and enjoying authentic cooking lessons in Italy. If you're saying "yasss, please!" to all of these, the good news is that you have until 2020 (when the cruise leaves) to save enough funds for a ticket.
Head on over to Silversea's site to get the DL on this world-class experience that may just be worth breaking the bank for (but we'll leave that up to you).


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Cape Town - South Africa's Jbe Kruger has ended his seven-year drought on the Asian Tour by winning the Shinhan Donghae Open on Sunday.
Kruger carded a final round of six-under par 65 to win by two shots at the Bear's Best Cheongna Golf Club.
Kruger has not won another Asian Tour title since his lone win at the Avantha Masters in India in 2012.
He trailed overnight leader Scott Vincent of Zimbabwe by two shots, the South African went on to produce a commanding performance as he did not drop a single shot in his last 37 holes.
"It all changed on the seventh hole when I made my second birdie and I could feel the momentum then. It was in the Lord's plan whether I would win again today. But as for me, I started to feel good and after the 11th hole, I had a good feeling it was my time again," said Kruger after his win.
"I would say what went right today was probably my putting. I obviously didn't hit it as well as I could have but my chipping and my putting saved me multiple times and that's why I didn't make bogeys. I'm a professional and this is what I do for a living, so I will probably go where the money is, go there and play well.
"I have been a big fan of playing in Japan, but you can't really get into that Tour if you haven't gone to Q school. But now, things have changed."
With this win Kruger secures a two-year exemption on the Asian Tour after being ranked 95th on the Order of Merit the previous week.
The 33-year-old has also recorded four career wins on the Sunshine Tour with the latest title coming at the Sun Carnival City Challenge in 2017.
(Sport24; 2019.09.23; Sunshine Tour)
https://www.sport24.co.za/Golf/SunshineTour/kruger-ends-7-year-title-drought-on-asian-tour-20190923


More Photos of SAMREEN RIZWAN.
Assalam-o-Alikum ham apni sister ke lye aik acha rishta dekh Rahe hai Jo achi family se belong karta ho educated ho caring ho serious families contact keratin baqi or Jo kuch ap Janna chahen to contact ker sakte hain.
Life Partner detail and requirements are not provided by SAMREEN RIZWAN.


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EU Court Ruling on Google Links Could Encourage Paywalls
Research and data mining also will be made more painful by the ruling, says the CCIA
By Jennifer Baker
Brussels correspondent, IDG News Service |
An EU court ruling Tuesday that Google must delete links to private data could encourage online publishers to put more information behind paywalls, according to a legal expert.
"This will have commercial consequences, by making newspaper and other media archive paywalls more economically attractive," saidA Simon McGarr, lead solicitor at McGarr Solicitors in Ireland. "If a researcher can't be sure that a Google index will return all the relevant returns on an individual, the value of reliable private archives is bound to increase. It makes economic sense as researchers looking for reliable information are frequently those who are most willing to pay."
The European Court of Justice ruled against the advice of its advocate general, saying that even linking to lawfully available information could breach privacy laws.
Google was ordered to remove links to a Spanish newspaper article about a mortgage foreclosure against Costeja GonzA!lez, because it infringed his right to privacy. The newspaper was not ordered to remove the information, but GonzA!lez successfully argued that the links displayed by Google to the information about him had become inadequate and irrelevant over time.
The Computer & Communications Industry Association also expressed concerns about the potential impact of the ruling for research and data mining.
"If I'm a historian and I want to find information that may at the time have seemed mundane but has now become relevant, that is going to become a very laborious process," said CCIA Vice President James Waterworth. "Whether publishers or information sources keep their information behind paywalls is not strictly relevant, because the whole research process is going to become more painful."
This ruling opens the door to large-scale private censorship in Europe, Waterworth warned, saying "it will likely affect all companies providing links on the Internet."
"Up to now companies left decisions to courts to decide on a case-by-case basis. But this ruling seems to place more responsibility on the private actor with no accompanying process. For the time being, there is a greater risk for them if they don't take links down," he added.
However, McGarr said that discussions and tussles on a case-by-case basis still seem likely to dominate this legislative area for years to come.
"This is just one ruling and I think we will have to wait and look at other rulings jurisdiction by jurisdiction before we can derive a general legal framework on this issue," he said.
A new EU law on data protection could also have a major impact. The proposed Data Protection Regulation includes a "right to be forgotten."
"Today's ruling seems to pre-empt the law-making process," said Waterworth. But it is likely to be several years before the data protection law comes into force.
Follow Jennifer on Twitter at @BrusselsGeek or email tips and comments to jennifer_baker@idg.com.
Vertical Industries
Jennifer Baker reports on the European Union: Commission, Parliament, technology policy, regulation, and competition.


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Wojciech Lisicki (ur. 25 kwietnia 1969 w Sopocie), znany również jako Transcendental Protagonist – polski muzyk, kompozytor, wokalista, producent muzyczny i multiinstrumentalista. W 1993 roku Lisicki wraz z gitarzystą Michaelem Nicklassonem i perkusistą Peterem Anderssonem założył zespół Luciferion. Nagrał z grupą dwa albumy studyjne: wydany w 1994 roku Demonication (The Manifest) oraz The Apostate z 2003 roku. Wkrótce potem Luciferion został rozwiązany. W międzyczasie występował w deathmetalowej grupie Einhorn. W 1998 roku dołączył do powermetalowej grupy Lost Horizon. W 2005 roku wystąpił gościnnie na albumie grupy Hypnos pt. Rabble Mänifesto. W latach 2005-2011 występował w amerykańskiej formacji Against the Plagues. Lisicki współpracował ponadto z zespołem Jaggernaut.

Dyskografia
 Luciferion - Demonication (The Manifest) (1994, Listenable Records)
 Damnation - Resist (2000, Dark Realm Records, gościnnie)
 Lost Horizon - Awakening the World (2001, Music for Nations)
 Luciferion - The Apostate (2003, Listenable Records)
 Lost Horizon - A Flame to the Ground Beneath (2003, Music for Nations)
 Hypnos - Rabble Mänifesto (2005, Morbid Records, gościnnie)
 Against the Plagues - The Architecture of Oppression (2007, wydanie własne)
 Against the Plagues - Decoding the Mainframe (2010, Vic Records)

Przypisy

Polscy basiści metalowi
Polscy gitarzyści metalowi
Polscy keyboardziści metalowi
Polscy kompozytorzy muzyki rozrywkowej
Polscy multiinstrumentaliści
Polscy perkusiści metalowi
Polscy producenci muzyczni
Polscy wokaliści metalowi
Ludzie urodzeni w Sopocie
Urodzeni w 1969


text:
module ComposableBuilders
  VERSION = '0.1.2'
end

redpajama_set_name: RedPajamaGithub