Chinese e-commerce company Alibaba set the stage for the biggest IPO ever as it looks to raise $21 billion sometime in September. Conway G. Gittens reports.

Stocks moved higher in Thursdays trading session; Retail sales fell for the third straight month; Houshold net worth hit a new record. Bobbi Rebell reports.

A marble head of the Roman Emperor Octavian Augustus, stolen in Italy in the 1970s, has been returned to Italy by a museum in Belgium. Sharon Reich reports.

Stars that are similar to the sun in every way we can measure are mostly more active than the sun, which hints that the sun’s activity may ramp up someday, risking solar eruptions

Four coronaviruses cause around a quarter of all common colds, but each was probably deadly when it first made the leap to humans. We can learn a lot from what happened next

Human behaviour is key to the spread of coronavirus, so government scientists are trying to control our decisions. Does it work, and what happens when they get it wrong?

Payne Capital Management's Courtney Dominguez says the high level of investor pessimism indicates the markets may have bottomed. She says savings could make their way into stocks.

H&M, the world's second-biggest fashion retailer, said local currency sales have tumbled 57% since the start of March compared with a year ago. Ciara Lee reports

Piper Sandler senior technical analyst Craig Johnson says the S&P 500 may trade in a narrow range through the summer before breaking north.

Stocks on Wall Street jumped Friday despite historic job losses suffered by the economy. Fred Katayama reports.

White House spokeswoman Kayleigh McEnany on Friday was asked about the U.S. economy that lost a staggering 20.5 million jobs in April, the steepest plunge in payrolls since the Great Depression, and she responded saying it was 'decided' by the president to 'stop the economy' to save lives.

Title: Relistor Helps Ease Painkiller-Related Constipation
Category: Health News
Created: 4/26/2008 2:00:00 AM
Last Editorial Review: 4/28/2008 12:00:00 AM

Title: Some Diet Sodas May Ward Off Kidney Stones
Category: Health News
Created: 4/30/2009 2:00:00 AM
Last Editorial Review: 4/30/2009 12:00:00 AM

Title: Low Testosterone Raises Heart Death Rates in Impotent Men
Category: Health News
Created: 4/29/2010 2:10:00 PM
Last Editorial Review: 4/30/2010 12:00:00 AM

Title: Black Kids Less Apt to Get Meds for Stomach Pain in ER: Study
Category: Health News
Created: 4/28/2012 10:05:00 AM
Last Editorial Review: 4/30/2012 12:00:00 AM

Title: Companies to Donate Prosthetic Legs to Boston Bombing Victims in Need
Category: Health News
Created: 4/30/2013 8:35:00 PM
Last Editorial Review: 5/1/2013 12:00:00 AM

Title: Kcentra Approved to Stop Severe Bleeding in Heart Patients
Category: Health News
Created: 4/30/2013 12:35:00 PM
Last Editorial Review: 5/1/2013 12:00:00 AM

Title: Exercise May Lower Older Women's Risk for Kidney Stones
Category: Health News
Created: 5/3/2013 12:35:00 PM
Last Editorial Review: 5/3/2013 12:00:00 AM

Title: Complications Fairly Common, Costly With Some Kidney Stone Treatments
Category: Health News
Created: 4/29/2014 9:35:00 AM
Last Editorial Review: 4/29/2014 12:00:00 AM

Title: Complications Common, Costly With Some Kidney Stone Treatments
Category: Health News
Created: 4/29/2014 12:35:00 PM
Last Editorial Review: 4/30/2014 12:00:00 AM

Title: Health Food Stores Often Promote Adult-Only Supplements to Teens
Category: Health News
Created: 4/26/2015 12:00:00 AM
Last Editorial Review: 4/27/2015 12:00:00 AM

Title: Teens With History of Self-Poisoning Face Greater Suicide Risk
Category: Health News
Created: 4/25/2015 12:00:00 AM
Last Editorial Review: 4/27/2015 12:00:00 AM

Title: Day Care Babies Catch Stomach Bugs Earlier, But Get Fewer Later
Category: Health News
Created: 4/26/2016 12:00:00 AM
Last Editorial Review: 4/27/2016 12:00:00 AM

Title: Thunderstorms Can Trigger Asthma Flares, Study Finds
Category: Health News
Created: 5/1/2017 12:00:00 AM
Last Editorial Review: 5/2/2017 12:00:00 AM

Title: AHA News: A Father's Death at 37 Reveals a Hidden History of Cholesterol
Category: Health News
Created: 4/30/2019 12:00:00 AM
Last Editorial Review: 5/1/2019 12:00:00 AM

Title: Device Spots Lymphedema Early in Breast Cancer Patients, to Help Stop It
Category: Health News
Created: 5/2/2019 12:00:00 AM
Last Editorial Review: 5/3/2019 12:00:00 AM

Title: Navigating the Grocery Store Safely
Category: Health News
Created: 4/27/2020 12:00:00 AM
Last Editorial Review: 4/27/2020 12:00:00 AM

Title: Nanotechnology Might Help Fight Deadly 'Cytokine Storm' of COVID-19
Category: Health News
Created: 4/28/2020 12:00:00 AM
Last Editorial Review: 4/29/2020 12:00:00 AM

Title: New Drug Could Help Stop Blindness From Thyroid Eye Disease
Category: Health News
Created: 1/22/2020 12:00:00 AM
Last Editorial Review: 1/23/2020 12:00:00 AM

PMC marked its 10th anniversary in 2010 with a celebratory event at its annual Advisory Committee meeting, held at the National Library of Medicine last June. This milestone event was recently featured in the February 17th edition of NLM In Focus, in an article NLM Milestones: The Hits Just Keep on Coming. For more information on the ten years of PMC, see the article in the May-June issue of the NLM Technical Bulletin.

Title: Daily Aspirin Won't Stop Dementia, Study Finds
Category: Health News
Created: 3/25/2020 12:00:00 AM
Last Editorial Review: 3/26/2020 12:00:00 AM

Title: Modern Livestock Farming Can Pose Public Health Risk
Category: Health News
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/8/2020 12:00:00 AM

Title: Low Testosterone (Low-T)
Category: Diseases and Conditions
Created: 12/14/2009 12:00:00 AM
Last Editorial Review: 12/2/2019 12:00:00 AM

Title: Testosterone Supplements Won't Help Most Men, Doctors' Group Says
Category: Health News
Created: 1/6/2020 12:00:00 AM
Last Editorial Review: 1/7/2020 12:00:00 AM

Title: Xiaflex (collagenase clostridium histolyticum)
Category: Medications
Created: 3/3/2020 12:00:00 AM
Last Editorial Review: 3/3/2020 12:00:00 AM

Title: High Testosterone Levels Have Different Health Impact for Men and Women
Category: Health News
Created: 2/10/2020 12:00:00 AM
Last Editorial Review: 2/11/2020 12:00:00 AM

Title: Back in Touch: Technology Restores Hand Sensitivity to Young Quadraplegic
Category: Health News
Created: 4/23/2020 12:00:00 AM
Last Editorial Review: 4/24/2020 12:00:00 AM

Title: What Is a Hepaticojejunostomy?
Category: Procedures and Tests
Created: 4/22/2020 12:00:00 AM
Last Editorial Review: 4/22/2020 12:00:00 AM

Title: What Is a Choledochojejunostomy?
Category: Procedures and Tests
Created: 5/6/2020 12:00:00 AM
Last Editorial Review: 5/6/2020 12:00:00 AM

Title: How Long Does a Cholecystostomy Tube Stay In?
Category: Procedures and Tests
Created: 5/7/2020 12:00:00 AM
Last Editorial Review: 5/7/2020 12:00:00 AM

Title: Cough: 19 Tips on How to Stop a Cough
Category: Diseases and Conditions
Created: 5/24/2016 12:00:00 AM
Last Editorial Review: 4/14/2020 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

Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse "de novo" clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due to convergence recombination of multiple nucleotide sequences to encode the same amino acid sequence, as well as the use of shorter complementarity-determining regions 3 (CDR3s) with fewer nucleotide additions (i.e., sequences closer to germ line). Moreover, the two most immunodominant HLA-A2-restricted EBV epitopes, BRLF1₁₀₉ and BMLF1₂₈₀, show highly distinct antigen-specific public (i.e., shared between individuals) features. In fact, TCRα CDR3 motifs played a dominant role, while TCRβ played a minimal role, in the selection of TCR repertoire to an immunodominant EBV epitope, BRLF1. This contrasts with the majority of previously reported repertoires, which appear to be selected either on TCRβ CDR3 interactions with peptide/major histocompatibility complex (MHC) or in combination with TCRα CDR3. Understanding of how TCR-peptide-MHC complex interactions drive repertoire selection can be used to develop optimal strategies for vaccine design or generation of appropriate adoptive immunotherapies for viral infections in transplant settings or for cancer.

IMPORTANCE Several lines of evidence suggest that TCRα and TCRβ repertoires play a role in disease outcomes and treatment strategies during viral infections in transplant patients and in cancer and autoimmune disease therapy. Our data suggest that it is essential that we understand the basic principles of how to drive optimum repertoires for both TCR chains, α and β. We address this important issue by characterizing the CD8 TCR repertoire to a common persistent human viral infection (EBV), which is controlled by appropriate CD8 T cell responses. The ultimate goal would be to determine if the individuals who are infected asymptomatically develop a different TCR repertoire than those that develop the immunopathology of AIM. Here, we begin by doing an in-depth characterization of both CD8 T cell TCRα and TCRβ repertoires to two immunodominant EBV epitopes over the course of AIM, identifying potential factors that may be driving their selection.

ABSTRACT

Reversible repression of HIV-1 5' long terminal repeat (5'-LTR)-mediated transcription represents the main mechanism for HIV-1 to maintain latency. Identification of host factors that modulate LTR activity and viral latency may help develop new antiretroviral therapies. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are known to regulate gene expression and possess multiple physiological functions. hnRNP family members have recently been identified as the sensors for viral nucleic acids to induce antiviral responses, highlighting the crucial roles of hnRNPs in regulating viral infection. A member of the hnRNP family, X-linked RNA-binding motif protein (RBMX), has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5'-LTR-driven transcription of viral genome in CD4⁺ T cells. Mechanistically, RBMX binds to HIV-1 proviral DNA at the LTR downstream region and maintains the repressive trimethylation of histone H3 lysine 9 (H3K9me3), leading to a blockage of the recruitment of the positive transcription factor phosphorylated RNA polymerase II (RNA pol II) and consequential impediment of transcription elongation. This RBMX-mediated modulation of HIV-1 transcription maintains viral latency by inhibiting viral reactivation from an integrated proviral DNA. Our findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies.

IMPORTANCE HIV-1 latency featuring silence of transcription from HIV-1 proviral DNA represents a major obstacle for HIV-1 eradication. Reversible repression of HIV-1 5'-LTR-mediated transcription represents the main mechanism for HIV-1 to maintain latency. The 5'-LTR-driven HIV gene transcription can be modulated by multiple host factors and mechanisms. The hnRNPs are known to regulate gene expression. A member of the hnRNP family, RBMX, has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5'-LTR-driven transcription of viral genome in CD4⁺ T cells and maintains viral latency. These findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies.

ABSTRACT

Candida auris has emerged globally as a multidrug-resistant yeast that can spread via nosocomial transmission. An initial phylogenetic study of isolates from Japan, India, Pakistan, South Africa, and Venezuela revealed four populations (clades I, II, III, and IV) corresponding to these geographic regions. Since this description, C. auris has been reported in more than 30 additional countries. To trace this global emergence, we compared the genomes of 304 C. auris isolates from 19 countries on six continents. We found that four predominant clades persist across wide geographic locations. We observed phylogeographic mixing in most clades; clade IV, with isolates mainly from South America, demonstrated the strongest phylogeographic substructure. C. auris isolates from two clades with opposite mating types were detected contemporaneously in a single health care facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 360 years; outbreak-causing clusters from clades I, III, and IV originated 36 to 38 years ago. We observed high rates of antifungal resistance in clade I, including four isolates resistant to all three major classes of antifungals. Mutations that contribute to resistance varied between the clades, with Y132F in ERG11 as the most widespread mutation associated with azole resistance and S639P in FKS1 for echinocandin resistance. Copy number variants in ERG11 predominantly appeared in clade III and were associated with fluconazole resistance. These results provide a global context for the phylogeography, population structure, and mechanisms associated with antifungal resistance in C. auris.

IMPORTANCE In less than a decade, C. auris has emerged in health care settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other Candida species, C. auris is unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting new C. auris introductions. Through a global collaboration, we assessed genome evolution of isolates of C. auris from 19 countries. Here, we described estimated timing of the expansion of each C. auris clade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology.

Current health inequities are rooted in more than simple systems failures and inefficiencies. Historical legacy has corrupted health outcomes, and resolution requires both acknowledgment and intention.

Studies of the former NE England coalfield in Tyneside demonstrated that heat flow perturbations in boreholes were due to the entrainment and lateral dispersion of heat from deeper in the subsurface through flooded mine workings. This work assesses the influence of historical mining on geothermal observations across Greater Glasgow. The regional heat flow for Glasgow is 60 mW m^–2 and, after correction for palaeoclimate, is estimated as c. 80 mW m^–2. An example of reduced heat flow above mine workings is observed at Hallside (c. 10 km SE of Glasgow), where the heat flow through a 352 m deep borehole is c. 14 mW m^–2. Similarly, the heat flow across the 199 m deep GGC01 borehole in the Glasgow Geothermal Energy Research Field Site is c. 44 mW m^–2. The differences between these values and the expected regional heat flow suggest a significant component of horizontal heat flow into surrounding flooded mine workings. This deduction also influences the quantification of deeper geothermal resources, as extrapolation of the temperature gradient above mine workings would underestimate the temperature at depth. Future projects should consider the influence of historical mining on heat flow when temperature datasets such as these are used in the design of geothermal developments.

Supplementary material: Background information on the chronology of historical mining at each borehole location and a summary of groundwater flow in mine workings beneath Glasgow are available at https://doi.org/10.6084/m9.figshare.c.4681100

Thematic collection: This article is part of the ‘Early Career Research’ available at: https://www.lyellcollection.org/cc/SJG-early-career-research

Brucella spp. are facultative intracellular bacteria notorious for their ability to induce a chronic, and often lifelong, infection known as brucellosis. To date, no licensed vaccine exists for prevention of human disease, and mechanisms underlying chronic illness and immune evasion remain elusive. We and others have observed that B cell-deficient mice challenged with Brucella display reduced bacterial burden following infection, but the underlying mechanism has not been clearly defined. Here, we show that at 1 month postinfection, B cell deficiency alone enhanced resistance to splenic infection ~100-fold; however, combined B and T cell deficiency did not impact bacterial burden, indicating that B cells only enhance susceptibility to infection when T cells are present. Therefore, we investigated whether B cells inhibit T cell-mediated protection against Brucella. Using B and T cell-deficient Rag1^–/– animals as recipients, we demonstrate that adoptive transfer of CD4⁺ T cells alone confers marked protection against Brucella melitensis that is abrogated by cotransfer of B cells. Interestingly, depletion of CD4⁺ T cells from B cell-deficient, but not wild-type, mice enhanced susceptibility to infection, further confirming that CD4⁺ T cell-mediated immunity against Brucella is inhibited by B cells. In addition, we found that the ability of B cells to suppress CD4⁺ T cell-mediated immunity and modulate CD4⁺ T cell effector responses during infection was major histocompatibility complex class II (MHCII)-dependent. Collectively, these findings indicate that B cells modulate CD4⁺ T cell function through an MHCII-dependent mechanism which enhances susceptibility to Brucella infection.

The development of pastoralism transformed human diets and societies in grasslands worldwide. The long-term success of cattle herding in Africa has been sustained by dynamic food systems, consumption of a broad range of primary and secondary livestock products, and the evolution of lactase persistence (LP), which allows digestion of lactose...

Proteasomes are essential protease complexes that maintain cellular homeostasis, and aberrant proteasomal activity supports cancer development. The regulatory mechanisms and biological function of the ubiquitin-26S proteasome have been studied extensively, while those of the ubiquitin-independent 20S proteasome system remain obscure. Here, we show that the cap ’n’ collar (CNC) family transcription factor NRF3 specifically enhances 20S proteasome assembly in cancer cells and that 20S proteasomes contribute to colorectal cancer development through ubiquitin-independent proteolysis of the tumor suppressor p53 and retinoblastoma (Rb) proteins. The NRF3 gene is highly expressed in many cancer tissues and cell lines and is important for cancer cell growth. In cancer cells, NRF3 upregulates the assembly of the 20S proteasome by directly inducing the gene expression of the 20S proteasome maturation protein POMP. Interestingly, NRF3 knockdown not only increases p53 and Rb protein levels but also increases p53 activities for tumor suppression, including cell cycle arrest and induction of apoptosis. Furthermore, protein stability and cell viability assays using two distinct proteasome inhibitor anticancer drugs, the 20S proteasome inhibitor bortezomib and the ubiquitin-activating enzyme E1 inhibitor TAK-243, show that the upregulation of the NRF3-POMP axis leads to ubiquitin-independent proteolysis of p53 and Rb and to impaired sensitivity to bortezomib but not TAK-243. More importantly, the NRF3-POMP axis supports tumorigenesis and metastasis, with higher NRF3/POMP expression levels correlating with poor prognoses in patients with colorectal or rectal adenocarcinoma. These results suggest that the NRF3-POMP-20S proteasome assembly axis is significant for cancer development via ubiquitin-independent proteolysis of tumor suppressor proteins.