Vidya Balan, in a recent interview, shed light on the many realisations she has been having during the lockdown

Courteney Cox's former husband reveals he recorded behind the scene footage from 'Friends'

In his first post-prison track 'Gooba,' Tekashi 6ix9ine flaunted his jaw-dropping performance accompanied by six women and a puppy

“Her untimely death underscores the failure of the prison system to provide even the most basic health care for treatable illnesses that justifies the petition we filed at the Supreme Court seeking the humanitarian release of the elderly and the sick who are most vulnerable to succumbing to the pandemic.”

The post Political prisoner in Tagum dies due to illness appeared first on Bulatlat.

SEIBERSDORF, Austria: Shortages of materials needed in tests for the novel coronavirus remain "critical", according to the head of a UN lab, which is supplying countries with COVID-19 detection kits.In particular the chemical reagents for the tests are still in short supply, said Giovanni Cattoli,...

SEIBERSDORF: Shortages of materials needed in tests for the novel coronavirus remain “critical”, according to the head of a UN lab, which is supplying countries with COVID-19 detection kits. In particular the chemical reagents for the tests are still in short supply, said Giovanni...

Madrid and Barcelona will not progress to the next phase of Spain's exit from one of Europe’s strictest lockdowns that will allow bars, restaurants and places of worship to reopen in some areas from Monday, the government announced.

These charts illustrate how Asian and global stock markets reacted to the COVID-19 pandemic, with market reaction closely following local outbreaks and then moving in unison with global markets amid other shocks.

Two people had the dubious distinction of being the first to wear electronic tags on their wrists for violating quarantine rules. Health authorities said the two were wearing the devices from 6 p.m. Tuesday and will have to keep them on for the rest of their self-quarantine period. One was caught in...

Dentons is now the largest global law firm in Argentina and the first truly Pan-Latin American and the Caribbean firm in the history of the legal profession.

ATA663431/54 LIN SBC including LIN Transceiver, FranVoltage Regulator, Window Watchdog and High-Side Switch

Heritage homes are fast becoming the favourite hunting grounds of luxury brands scouting for premium retailing space in India, where suitable high-end malls are too few and the sales potential at five-star hotels is still uncertain. When designer wear brand Kimaya Fashions searched for a store in Hyderabad, it settled on a 16,000-sq ft bungalow in the upscale Jubilee Hills, in a property with floor area nearly three times the size of its average outlets. French luxury brand Hermes also moved into a Victorian property in Mumbai’s Horniman Circle to retail its popular Birkin bags. “It’s not necessarily out of choice,” says Pradeep Hirani, managing director of Kimaya Fashions, “This […]

Approved project 50193-003 in India.

This brief examines the global shortage of the personal protective equipment (PPE) needed to tackle COVID-19 and suggests policy implications.

NEW DELHI: Low-cost housing, which found several mentions in BJP’s 2014 election manifesto, is likely to get infrastructure status, making it easier for real-estate developers to get finance from banks and for longer tenures, and eventually increasing the supply of houses. While developers are in favour of an infrastructure tag to the housing sector as a whole, the government is likely to grant it only to the low-cost segment, said a senior government official, who did not wish to be named. According to government definition, low-cost houses are those with an area of up to 40 sq metres. BJP’s manifesto talks about rolling out a massive low-cost housing programme to […]

NEW YORK INTERNATIONAL AUTO SHOW – HARMAN, the premium global audio and infotainment group (NYSE:HAR), is making a strong showing at this year’s New York International Auto Show, with a range of leading automakers featuring HARMAN branded audio systems in vehicles debuting at the show. In addition to the new vehicles– which run the gamut from modern sedans to sports cars, minivans and crossover SUVs – HARMAN technology and solutions can be found in automaker booths throughout the show, a reflection of HARMAN’s longstanding auto partnerships and unmatched industry achievements.

You heard it here first: in 2018, HARMAN received a record-breaking 53 product design and technology awards, bringing our six-year-total to more than 300 awards for 190 different products.   This unprecedented number is a direct reflection of our...

It’s the most wonderful time of year again. That’s right, CES 2016 is upon us! This year in Las Vegas, you will experience firsthand a great suite of premium innovations from HARMAN - the premier connected technologies company for automotive, consumer and enterprise markets - featuring HARMAN’s unique approach to design and engineering. Can’t wait until January to see what’s new? Here’s a sneak peak of what to expect for CES and the year ahead. HARMAN will demonstrate the latest innovations and technologies in lifestyle audio and connected car to illustrate the future of connected lifestyle experiences.

LOS ANGELES, CA – HARMAN International Industries, Inc. (NYSE:HAR), the premium audio and infotainment group, will have a major presence at the 137th Audio Engineering Society Convention as it returns to the Los Angeles Convention Center Thursday, October 9 through Sunday, October 12 for the first time in twelve years. HARMAN, the premiere sponsor of both the annual AES President’s Reception and the AES Student Zone, will present several research papers, highlight new Professional audio equipment, and demonstrate the company’s latest innovative music restoration technology, Clari-Fi, throughout the week.

Thousands of cyclists took over streets in the center of the Slovenian capital Ljubljana on Friday evening to protest against the government of Prime Minister Janez Jansa and the restrictions it has imposed to fight the coronavirus.

For orangutans, scratching is contagious – but unexpectedly, the behaviour is transmitted more between individuals that do not know each other well

Thousands of cyclists took over streets in the center of the Slovenian capital Ljubljana on Friday evening to protest against the government of Prime Minister Janez Jansa and the restrictions it has imposed to fight the coronavirus.

At this year’s North American International Auto Show (NAIAS) in Detroit, HARMAN and its automotive partners brought the latest evolution of premium in-car experiences that reflect and seamlessly connect with your lifestyle. Ensuring users are...

Opera singer Victoria Robertson is accustomed to performing on stages much bigger than the five-foot wide front porch of her San Diego home. But with concert venues closed and work at a standstill due to the coronavirus pandemic, she decided to make the most of it.

A Backstage Pass with Christopher Dragon: Creating that HARMAN Experience at the World's Largest Technology Show Around the world, many companies are preparing to close out the year, but for HARMAN, it’s time to head to Las Vegas once again for the...

This year's Tour of Spain will not go through Portugal as planned because of the COVID-19 crisis, organisers said on Saturday.

For orangutans, scratching is contagious – but unexpectedly, the behaviour is transmitted more between individuals that do not know each other well

Title: LeAnn Rimes Brings Battle With Psoriasis to Center Stage
Category: Health News
Created: 4/23/2010 10:10:00 AM
Last Editorial Review: 4/26/2010 12:00:00 AM

Title: HPV-Linked Oral Cancers May Not Be 'Contagious'
Category: Health News
Created: 4/29/2014 2:36:00 PM
Last Editorial Review: 4/30/2014 12:00:00 AM

Title: U.S. Moves to Avert Shortage of Yellow Fever Vaccine
Category: Health News
Created: 4/28/2017 12:00:00 AM
Last Editorial Review: 5/1/2017 12:00:00 AM

Title: The Other Opioid Crisis: Shortages at U.S. Hospitals
Category: Health News
Created: 5/2/2018 12:00:00 AM
Last Editorial Review: 5/2/2018 12:00:00 AM

Title: After Trump Hypes Use of a Lupus Med Against COVID-19, Lupus Patients Face Shortages
Category: Health News
Created: 4/25/2020 12:00:00 AM
Last Editorial Review: 4/27/2020 12:00:00 AM

PMC is pleased to announce the first of what we hope will be an annual series of conferences for users of the Journal Article Tag Suite, that is, for users of any of the “NLM DTDs”. The Journal Article Tag Suite Conference (JATS-Con) is a peer-reviewed conference that will feature a broad range of content on the Tag Suite—from the technical components to publishing theory—as well as the latest news on the Tag Suite. The conference will be hosted by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine on the NIH campus in Bethesda, Maryland on November 1 & 2, 2010.

For more information on the conference, see https://jats.nlm.nih.gov/jats-con.

Note: There is no charge for the conference; however, space is limited so preregistration is required.

Peer review documents, including review reports and editor decision letters, are increasingly being published along with the articles they review. This practice is intended to make the publishing process more transparent. To support these efforts, PMC’s Tagging Guidelines have been updated to include the tagging of peer review documents. NLM encourages PMC-participating publishers, journals, and data providers to review this guidance. Please contact us at pubmedcentral@ncbi.nlm.nih.gov if you have any questions.

Title: Is Balanitis Contagious?
Category: Diseases and Conditions
Created: 5/28/2015 12:00:00 AM
Last Editorial Review: 12/4/2019 12:00:00 AM

Title: Research Finds Contagious Staph in Lupus-Related Skin Rashes
Category: Health News
Created: 2/28/2020 12:00:00 AM
Last Editorial Review: 3/2/2020 12:00:00 AM

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (^–/–) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.­

ABSTRACT

Cryptosporidium parvum and Cryptosporidium hominis have emerged as major enteric pathogens of infants in the developing world, in addition to their known importance in immunocompromised adults. Although there has been recent progress in identifying new small molecules that inhibit Cryptosporidium sp. growth in vitro or in animal models, we lack information about their mechanism of action, potency across the life cycle, and cidal versus static activities. Here, we explored four potent classes of compounds that include inhibitors that likely target phosphatidylinositol 4 kinase (PI4K), phenylalanine-tRNA synthetase (PheRS), and several potent inhibitors with unknown mechanisms of action. We utilized monoclonal antibodies and gene expression probes for staging life cycle development to define the timing of when inhibitors were active during the life cycle of Cryptosporidium parvum grown in vitro. These different classes of inhibitors targeted different stages of the life cycle, including compounds that blocked replication (PheRS inhibitors), prevented the segmentation of daughter cells and thus blocked egress (PI4K inhibitors), or affected sexual-stage development (a piperazine compound of unknown mechanism). Long-term cultivation of C. parvum in epithelial cell monolayers derived from intestinal stem cells was used to distinguish between cidal and static activities based on the ability of parasites to recover from treatment. Collectively, these approaches should aid in identifying mechanisms of action and for designing in vivo efficacy studies based on time-dependent concentrations needed to achieve cidal activity.

IMPORTANCE Currently, nitazoxanide is the only FDA-approved treatment for cryptosporidiosis; unfortunately, it is ineffective in immunocompromised patients, has varied efficacy in immunocompetent individuals, and is not approved in infants under 1 year of age. Identifying new inhibitors for the treatment of cryptosporidiosis requires standardized and quantifiable in vitro assays for assessing potency, selectivity, timing of activity, and reversibility. Here, we provide new protocols for defining which stages of the life cycle are susceptible to four highly active compound classes that likely inhibit different targets in the parasite. We also utilize a newly developed long-term culture system to define assays for monitoring reversibility as a means of defining cidal activity as a function of concentration and time of treatment. These assays should provide valuable in vitro parameters to establish conditions for efficacious in vivo treatment.

ABSTRACT

The ubiquitous parasite Toxoplasma gondii exhibits an impressive ability to maintain chronic infection of its host for prolonged periods. Despite this, little is known regarding whether and how T. gondii bradyzoites, a quasi-dormant life stage residing within intracellular cysts, manipulate the host cell to maintain persistent infection. A previous proteomic study of the cyst wall, an amorphous layer of proteins that forms underneath the cyst membrane, identified MYR1 as a putative cyst wall protein in vitro. Because MYR1 is known to be involved in the translocation of parasite-derived effector proteins into the host cell, we sought to determine whether parasites transitioning toward the bradyzoite life stage retain the capacity to translocate proteins via this pathway. By epitope tagging the endogenous loci of four known effectors that translocate from the parasitophorous vacuole into the host cell nucleus, we show, by immunofluorescence assays, that most effectors accumulate in the host nucleus at early but not late time points after infection, during the tachyzoite-to-bradyzoite transition and when parasites further along the bradyzoite differentiation continuum invade a new host cell. We demonstrate that the suppression of interferon gamma signaling, which was previously shown to be mediated by the effector TgIST, also occurs in the context of prolonged infection with bradyzoites and that TgIST export is a process that occurs beyond the early stages of host cell infection. These findings have important implications regarding how this highly successful parasite maintains persistent infection of its host.

IMPORTANCE Toxoplasma bradyzoites persist within tissue cysts and are refractory to current treatments, serving as a reservoir for acute complications in settings of compromised immunity. Much remains to be understood regarding how this life stage successfully establishes and maintains persistent infection. In this study, we investigated whether the export of parasite effector proteins into the host cell occurs during the development of in vitro tissue cysts. We quantified the presence of four previously described effectors in host cell nuclei at different time points after bradyzoite differentiation and found that they accumulated largely during the early stages of infection. Despite a decline in nuclear accumulation, we found that one of these effectors still mediated its function after prolonged infection with bradyzoites, and we provide evidence that this effector is exported beyond early infection stages. These findings suggest that effector export from within developing tissue cysts provides one potential mechanism by which this parasite achieves chronic infection.

ABSTRACT

Marine sponges have been a prolific source of unique bioactive compounds that are presumed to act as a deterrent to predation. Many of these compounds have potential therapeutic applications; however, the lack of efficient and sustainable synthetic routes frequently limits clinical development. Here, we describe a metagenomic investigation of Mycale hentscheli, a chemically gifted marine sponge that possesses multiple distinct chemotypes. We applied shotgun metagenomic sequencing, hybrid assembly of short- and long-read data, and metagenomic binning to obtain a comprehensive picture of the microbiome of five specimens, spanning three chemotypes. Our data revealed multiple producing species, each having relatively modest secondary metabolomes, that contribute collectively to the chemical arsenal of the holobiont. We assembled complete genomes for multiple new genera, including two species that produce the cytotoxic polyketides pateamine and mycalamide, as well as a third high-abundance symbiont harboring a proteusin-type biosynthetic pathway that appears to encode a new polytheonamide-like compound. We also identified an additional 188 biosynthetic gene clusters, including a pathway for biosynthesis of peloruside. These results suggest that multiple species cooperatively contribute to defensive symbiosis in M. hentscheli and reveal that the taxonomic diversity of secondary-metabolite-producing sponge symbionts is larger and richer than previously recognized.

IMPORTANCE Mycale hentscheli is a marine sponge that is rich in bioactive small molecules. Here, we use direct metagenomic sequencing to elucidate highly complete and contiguous genomes for the major symbiotic bacteria of this sponge. We identify complete biosynthetic pathways for the three potent cytotoxic polyketides which have previously been isolated from M. hentscheli. Remarkably, and in contrast to previous studies of marine sponges, we attribute each of these metabolites to a different producing microbe. We also find that the microbiome of M. hentscheli is stably maintained among individuals, even over long periods of time. Collectively, our data suggest a cooperative mode of defensive symbiosis in which multiple symbiotic bacterial species cooperatively contribute to the defensive chemical arsenal of the holobiont.

ABSTRACT

Theory, simulation, and experimental evolution demonstrate that diversified CRISPR-Cas immunity to lytic viruses can lead to stochastic virus extinction due to a limited number of susceptible hosts available to each potential new protospacer escape mutation. Under such conditions, theory predicts that to evade extinction, viruses evolve toward decreased virulence and promote vertical transmission and persistence in infected hosts. To better understand the evolution of host-virus interactions in microbial populations with active CRISPR-Cas immunity, we studied the interaction between CRISPR-immune Sulfolobus islandicus cells and immune-deficient strains that are infected by the chronic virus SSV9. We demonstrate that Sulfolobus islandicus cells infected with SSV9, and with other related SSVs, kill uninfected, immune strains through an antagonistic mechanism that is a protein and is independent of infectious virus. Cells that are infected with SSV9 are protected from killing and persist in the population. We hypothesize that this infection acts as a form of mutualism between the host and the virus by removing competitors in the population and ensuring continued vertical transmission of the virus within populations with diversified CRISPR-Cas immunity.

IMPORTANCE Multiple studies, especially those focusing on the role of lytic viruses in key model systems, have shown the importance of viruses in shaping microbial populations. However, it has become increasingly clear that viruses with a long host-virus interaction, such as those with a chronic lifestyle, can be important drivers of evolution and have large impacts on host ecology. In this work, we describe one such interaction with the acidic crenarchaeon Sulfolobus islandicus and its chronic virus Sulfolobus spindle-shaped virus 9. Our work expands the view in which this symbiosis between host and virus evolved, describing a killing phenotype which we hypothesize has evolved in part due to the high prevalence and diversity of CRISPR-Cas immunity seen in natural populations. We explore the implications of this phenotype in population dynamics and host ecology, as well as the implications of mutualism between this virus-host pair.

There is increasing interest in developing diagnostics that discriminate individual mutagenic mechanisms in a range of applications that include identifying population-specific mutagenesis and resolving distinct mutation signatures in cancer samples. Analyses for these applications assume that mutagenic mechanisms have a distinct relationship with neighboring bases that allows them to be distinguished. Direct support for this assumption is limited to a small number of simple cases, e.g., CpG hypermutability. We have evaluated whether the mechanistic origin of a point mutation can be resolved using only sequence context for a more complicated case. We contrasted single nucleotide variants originating from the multitude of mutagenic processes that normally operate in the mouse germline with those induced by the potent mutagen N-ethyl-N-nitrosourea (ENU). The considerable overlap in the mutation spectra of these two samples make this a challenging problem. Employing a new, robust log-linear modeling method, we demonstrate that neighboring bases contain information regarding point mutation direction that differs between the ENU-induced and spontaneous mutation variant classes. A logistic regression classifier exhibited strong performance at discriminating between the different mutation classes. Concordance between the feature set of the best classifier and information content analyses suggest our results can be generalized to other mutation classification problems. We conclude that machine learning can be used to build a practical classification tool to identify the mutation mechanism for individual genetic variants. Software implementing our approach is freely available under an open-source license.

The translocated actin recruiting phosphoprotein (Tarp) is a multidomain type III secreted effector used by Chlamydia trachomatis. In aggregate, existing data suggest a role of this effector in initiating new infections. As new genetic tools began to emerge to study chlamydial genes in vivo, we speculated as to what degree Tarp function contributes to Chlamydia’s ability to parasitize mammalian host cells. To address this question, we generated a complete tarP deletion mutant using the fluorescence-reported allelic exchange mutagenesis (FRAEM) technique and complemented the mutant in trans with wild-type tarP or mutant tarP alleles engineered to harbor in-frame domain deletions. We provide evidence for the significant role of Tarp in C. trachomatis invasion of host cells. Complementation studies indicate that the C-terminal filamentous actin (F-actin)-binding domains are responsible for Tarp-mediated invasion efficiency. Wild-type C. trachomatis entry into HeLa cells resulted in host cell shape changes, whereas the tarP mutant did not. Finally, using a novel cis complementation approach, C. trachomatis lacking tarP demonstrated significant attenuation in a murine genital tract infection model. Together, these data provide definitive genetic evidence for the critical role of the Tarp F-actin-binding domains in host cell invasion and for the Tarp effector as a bona fide C. trachomatis virulence factor.

When transitioning from the environment, pathogenic microorganisms must adapt rapidly to survive in hostile host conditions. This is especially true for environmental fungi that cause opportunistic infections in immunocompromised patients since these microbes are not well adapted human pathogens. Cryptococcus species are yeastlike fungi that cause lethal infections, especially in...

Large-scale metagenomic and metatranscriptomic data analyses are often restricted by their gene-centric approach, limiting the ability to understand organismal and community biology. De novo assembly of large and mosaic eukaryotic genomes from complex meta-omics data remains a challenging task, especially in comparison with more straightforward bacterial and archaeal systems. Here, we use a transcriptome reconstruction method based on clustering co-abundant genes across a series of metagenomic samples. We investigated the co-abundance patterns of ~37 million eukaryotic unigenes across 365 metagenomic samples collected during the Tara Oceans expeditions to assess the diversity and functional profiles of marine plankton. We identified ~12,000 co-abundant gene groups (CAGs), encompassing ~7 million unigenes, including 924 metagenomics-based transcriptomes (MGTs, CAGs larger than 500 unigenes). We demonstrated the biological validity of the MGT collection by comparing individual MGTs with available references. We identified several key eukaryotic organisms involved in dimethylsulfoniopropionate (DMSP) biosynthesis and catabolism in different oceanic provinces, thus demonstrating the potential of the MGT collection to provide functional insights on eukaryotic plankton. We established the ability of the MGT approach to capture interspecies associations through the analysis of a nitrogen-fixing haptophyte-cyanobacterial symbiotic association. This MGT collection provides a valuable resource for analyses of eukaryotic plankton in the open ocean by giving access to the genomic content and functional potential of many ecologically relevant eukaryotic species.

Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A, and RAD21, cohesin in somatic cells contains one of two orthologous STAG subunits, STAG1 or STAG2. How these variable subunits affect the function of the cohesin complex is still unclear. STAG1- and STAG2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of STAG1 and STAG2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either STAG1 or STAG2. Following rapid depletion of either subunit, we perform high-resolution Hi-C, gene expression, and sequential ChIP studies to show that STAG1 and STAG2 do not co-occupy individual binding sites and have distinct ways by which they affect looping and gene expression. These findings are further supported by single-molecule localizations via direct stochastic optical reconstruction microscopy (dSTORM) super-resolution imaging. Since somatic and congenital mutations of the STAG subunits are associated with cancer (STAG2) and intellectual disability syndromes with congenital abnormalities (STAG1 and STAG2), we verified STAG1-/STAG2-dependencies using human neural stem cells, hence highlighting their importance in particular disease contexts.

Extensive studies have shown that the ₁ receptor (₁R) interacts with and modulates the activity of multiple proteins with important biological functions. Recent crystal structures of ₁R as a homotrimer differ from a dimer-tetramer model postulated earlier. It remains inconclusive whether ligand binding regulates ₁R oligomerization. Here, novel nondenaturing gel methods and mutational analysis were used to examine ₁R oligomerization. In transfected cells, ₁R exhibited as multimers, dimers, and monomers. Overall, ₁R agonists decreased, whereas ₁R antagonists increased ₁R multimers, suggesting that agonists and antagonists differentially affect the stability of ₁R multimers. Endogenous ₁R in rat liver membranes also showed similar regulation of oligomerization as in cells. Mutations at key residues lining the trimerization interface (Arg119, Asp195, Phe191, Trp136, and Gly91) abolished multimerization without disrupting dimerization. Intriguingly, truncation of the N terminus reduced ₁R to apparent monomer. These results demonstrate that multiple domains play crucial roles in coordinating high-order quaternary organization of ₁R. The E102Q ₁R mutant implicated in juvenile amyotrophic lateral sclerosis formed dimers only, suggesting that dysregulation of ₁R multimeric assembly may impair its function. Interestingly, oligomerization of ₁R was pH-dependent and correlated with changes in [³H](+)-pentazocine binding affinity and B_max. Combined with mutational analysis, it is reasoned that ₁R multimers possess high-affinity and high-capacity [³H](+)-pentazocine binding, whereas monomers likely lack binding. These results suggest that ₁R may exist in interconvertible oligomeric states in a dynamic equilibrium. Further exploration of ligand-regulated ₁R multimerization may provide novel approaches to modulate the function of ₁R and its interacting proteins.

Transient receptor potential (TRP) melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (A-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (N-[(R)-3,3-difluoro-4-hydroxy-1-(2H-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels. Intravenously administered KPR-5714 inhibited the hyperactivity of mechanosensitive C-fibers of bladder afferents and dose-dependently increased the intercontraction interval shortened by intravesical instillation of acetic acid in anesthetized rats. Furthermore, we examined the effects of KPR-5714 on voiding behavior in conscious rats with cerebral infarction and in those exposed to cold in metabolic cage experiments. Cerebral infarction and cold exposure induced a significant decrease in the mean voided volume and increase in voiding frequency in rats. Orally administered KPR-5714 dose-dependently increased the mean voided volume and decreased voiding frequency without affecting total voided volume in these models. This study demonstrates that KPR-5714 improves OAB in three different models by inhibiting exaggerated activity of mechanosensitive bladder C-fibers and suggests that KPR-5714 may provide a new and useful approach to the treatment of OAB.

¹⁸F-rhPSMA-7 (radiohybrid prostate-specific membrane antigen [PSMA]) is a novel ligand for PET imaging. Here, we present data from a retrospective analysis using PET/CT and PET/MRI examinations to investigate the efficacy of ¹⁸F-rhPSMA-7 PET for primary N-staging of patients with prostate cancer (PC) compared with morphologic imaging (CT or MRI) and validated by histopathology. Methods: Data from 58 patients with high-risk PC (according to the D’Amico criteria) who were staged with ¹⁸F-rhPSMA-7 PET/CT or PET/MRI at our institution between July 2017 and June 2018 were reviewed. The patients had a median prescan prostate-specific antigen value of 12.2 ng/mL (range, 1.2–81.6 ng/mL). The median injected activity of ¹⁸F-rhPSMA-7 was 327 MBq (range, 132–410 MBq), with a median uptake time of 79.5 min (range, 60–153 min). All patients underwent subsequent radical prostatectomy and extended pelvic lymph node dissection. The presence of lymph node metastases was determined by an experienced reader independently for both the PET and the morphologic datasets using a template-based analysis on a 5-point scale. Patient-level and template-based results were both compared with histopathologic findings. Results: Lymph node metastases were present in 18 patients (31.0%) and were located in 52 of 375 templates (13.9%). Receiver-operating-characteristic analyses showed ¹⁸F-rhPSMA-7 PET to perform significantly better than morphologic imaging on both patient-based and template-based analyses (areas under curve, 0.858 vs. 0.649 [P = 0.012] and 0.765 vs. 0.589 [P < 0.001], respectively). On patient-based analyses, the sensitivity, specificity, and accuracy of ¹⁸F-rhPSMA-7 PET were 72.2%, 92.5%, and 86.2%, respectively, and those of morphologic imaging were 50.0%, 72.5%, and 65.5%, respectively. On template-based analyses, the sensitivity, specificity, and accuracy of ¹⁸F-rhPSMA-7 PET were 53.8%, 96.9%, and 90.9%, respectively, and those of morphologic imaging were 9.6%, 95.0%, and 83.2%, respectively. Conclusion: ¹⁸F-rhPSMA-7 PET is superior to morphologic imaging for N-staging of high-risk primary PC. The efficacy of ¹⁸F-rhPSMA-7 is similar to published data for ⁶⁸Ga-PSMA-11.

Background

COPD patients account for a large proportion of lung transplants; lung transplantation survival benefit for COPD patients is not well established.