ui Teens With History of Self-Poisoning Face Greater Suicide Risk By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Teens With History of Self-Poisoning Face Greater Suicide RiskCategory: Health NewsCreated: 4/25/2015 12:00:00 AMLast Editorial Review: 4/27/2015 12:00:00 AM Full Article
ui Health Visits May Offer Chance to Prevent Suicide By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Health Visits May Offer Chance to Prevent SuicideCategory: Health NewsCreated: 4/24/2015 12:00:00 AMLast Editorial Review: 4/27/2015 12:00:00 AM Full Article
ui Scientists Pinpoint Brain's 'Hunger Circuit' in Mice By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Scientists Pinpoint Brain's 'Hunger Circuit' in MiceCategory: Health NewsCreated: 4/28/2015 12:00:00 AMLast Editorial Review: 4/28/2015 12:00:00 AM Full Article
ui Study Challenges Salt Guidelines for Kids By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Study Challenges Salt Guidelines for KidsCategory: Health NewsCreated: 4/27/2015 12:00:00 AMLast Editorial Review: 4/28/2015 12:00:00 AM Full Article
ui New Guidelines Issued on Breast, Genital Plastic Surgery for Teen Girls By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: New Guidelines Issued on Breast, Genital Plastic Surgery for Teen GirlsCategory: Health NewsCreated: 4/22/2016 12:00:00 AMLast Editorial Review: 4/25/2016 12:00:00 AM Full Article
ui Young Gay, Bisexual Men May Be at Higher Risk for Suicide, Study Finds By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Young Gay, Bisexual Men May Be at Higher Risk for Suicide, Study FindsCategory: Health NewsCreated: 4/26/2016 12:00:00 AMLast Editorial Review: 4/27/2016 12:00:00 AM Full Article
ui Building Muscle Could Boost the Body's Most Important Muscle By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Building Muscle Could Boost the Body's Most Important MuscleCategory: Health NewsCreated: 4/28/2016 12:00:00 AMLast Editorial Review: 4/29/2016 12:00:00 AM Full Article
ui Teen Suicide Thoughts, Self-Harm Cases Double in a Decade By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Teen Suicide Thoughts, Self-Harm Cases Double in a DecadeCategory: Health NewsCreated: 5/4/2017 12:00:00 AMLast Editorial Review: 5/4/2017 12:00:00 AM Full Article
ui Cheap Test Might Pinpoint Where Zika Mosquitoes Lurk By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Cheap Test Might Pinpoint Where Zika Mosquitoes LurkCategory: Health NewsCreated: 5/3/2017 12:00:00 AMLast Editorial Review: 5/4/2017 12:00:00 AM Full Article
ui U.S. Illnesses Tied to Ticks, Mosquitoes Are Soaring By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: U.S. Illnesses Tied to Ticks, Mosquitoes Are SoaringCategory: Health NewsCreated: 5/1/2018 12:00:00 AMLast Editorial Review: 5/2/2018 12:00:00 AM Full Article
ui FDA Cracks Down on Dangerous E-Cig Liquids That Resemble Cookies, Candy By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: FDA Cracks Down on Dangerous E-Cig Liquids That Resemble Cookies, CandyCategory: Health NewsCreated: 5/1/2018 12:00:00 AMLast Editorial Review: 5/2/2018 12:00:00 AM Full Article
ui Food for Thought: Keys to Fruitful Fertility By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Food for Thought: Keys to Fruitful FertilityCategory: Health NewsCreated: 5/3/2018 12:00:00 AMLast Editorial Review: 5/4/2018 12:00:00 AM Full Article
ui U.S. Youth Suicide Rates Hit 19-Year High After '13 Reasons Why' By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: U.S. Youth Suicide Rates Hit 19-Year High After '13 Reasons Why'Category: Health NewsCreated: 4/30/2019 12:00:00 AMLast Editorial Review: 4/30/2019 12:00:00 AM Full Article
ui Many Cardiologists Ill-Equipped to Treat Heart Disease in Cancer Survivors By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Many Cardiologists Ill-Equipped to Treat Heart Disease in Cancer SurvivorsCategory: Health NewsCreated: 4/29/2019 12:00:00 AMLast Editorial Review: 4/30/2019 12:00:00 AM Full Article
ui Vaping and Smoking May Signal Greater Motivation to Quit By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Vaping and Smoking May Signal Greater Motivation to QuitCategory: Health NewsCreated: 4/30/2019 12:00:00 AMLast Editorial Review: 5/1/2019 12:00:00 AM Full Article
ui Measles Case Leads to Quarantine of Cruise Ship in St. Lucia By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Measles Case Leads to Quarantine of Cruise Ship in St. LuciaCategory: Health NewsCreated: 5/2/2019 12:00:00 AMLast Editorial Review: 5/2/2019 12:00:00 AM Full Article
ui An Expert's Guide to Healthier Grocery Shopping By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: An Expert's Guide to Healthier Grocery ShoppingCategory: Health NewsCreated: 5/2/2019 12:00:00 AMLast Editorial Review: 5/2/2019 12:00:00 AM Full Article
ui 'Ringing in the Ears' May Drive Some to the Brink of Suicide By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: 'Ringing in the Ears' May Drive Some to the Brink of SuicideCategory: Health NewsCreated: 5/2/2019 12:00:00 AMLast Editorial Review: 5/3/2019 12:00:00 AM Full Article
ui Trump Says Federal Guidelines on Social Distancing Set to Expire By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: Trump Says Federal Guidelines on Social Distancing Set to ExpireCategory: Health NewsCreated: 4/30/2020 12:00:00 AMLast Editorial Review: 4/30/2020 12:00:00 AM Full Article
ui CDC Draft Guidelines For Reopening U.S. Being Reviewed by White House By www.medicinenet.com Published On :: Sat, 9 May 2020 00:00:00 PDT Title: CDC Draft Guidelines For Reopening U.S. Being Reviewed by White HouseCategory: Health NewsCreated: 5/1/2020 12:00:00 AMLast Editorial Review: 5/1/2020 12:00:00 AM Full Article
ui Pregnancy Guidelines During COVID-19 Pandemic By www.medicinenet.com Published On :: Thu, 2 Apr 2020 00:00:00 PDT Title: Pregnancy Guidelines During COVID-19 PandemicCategory: Health NewsCreated: 4/2/2020 12:00:00 AMLast Editorial Review: 4/2/2020 12:00:00 AM Full Article
ui Will a Jolt of Java Get Your Creative Juices Flowing? By www.medicinenet.com Published On :: Mon, 9 Mar 2020 00:00:00 PDT Title: Will a Jolt of Java Get Your Creative Juices Flowing?Category: Health NewsCreated: 3/9/2020 12:00:00 AMLast Editorial Review: 3/9/2020 12:00:00 AM Full Article
ui The Sooner Young Smokers Start, The Less Likely They Are to Quit By www.medicinenet.com Published On :: Tue, 14 Apr 2020 00:00:00 PDT Title: The Sooner Young Smokers Start, The Less Likely They Are to QuitCategory: Health NewsCreated: 4/13/2020 12:00:00 AMLast Editorial Review: 4/14/2020 12:00:00 AM Full Article
ui More Guidance on Inpatient Management of Blood Glucose in COVID-19 By www.webmd.com Published On :: Wed, 06 May 2020 12:05:04 EST Two new graphics from Diabetes UK's COVID-19 task force address inpatient use of subcutaneous insulin for managing hyperglycemia and ketoacidosis when intravenous equipment is unavailable. Full Article
ui Volunteer Physicians Procure PPE, Build Largest Platform By www.webmd.com Published On :: Thu, 07 May 2020 10:49:57 EST When pleas for protective equipment failed to produce results, individuals decided to take matters in their own hands and set up a distribution channel, now the most centralized platform in the US. Full Article
ui Evidence Builds Linking Anticoagulation to COVID-19 Survival By www.webmd.com Published On :: Fri, 08 May 2020 13:13:56 EST Data from a large US cohort suggest systemic anticoagulation may confer a survival benefit in hospitalized patients without a spike in bleeding events. Full Article
ui First-Ever Journal Article Tag Suite Conference (JATS-Con) to be Held in November 2010 By www.ncbi.nlm.nih.gov Published On :: Thu, 17 Jun 2010 08:00:00 EST 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. Full Article
ui Updated PMC journal review process and minimum requirements By www.ncbi.nlm.nih.gov Published On :: Tue, 15 Dec 2015 08:00:00 EST The PMC Overview and FAQ have been updated to provide more information on the Scientific Quality Review Process for journals that apply to participate in PMC.In 2014, PMC implemented a scientific and editorial quality review procedure whereby expert consultants from outside the National Library of Medicine (NLM) conduct an independent review of journals seeking to participate in PMC. This was in response to a significant increase in new publishers and journals applying to participate in PMC, many of which are unknown to NLM in terms of quality and publishing practices. The independent review, which was approved by the PMC National Advisory Committee (see minutes from June 10, 2014), follows an assessment by NLM that the journal meets NLM’s criteria for its collection, as outlined in the Collection Development Manual.PMC also recently updated the minimum requirement on the number of substantive, peer-reviewed articles needed before a journal can apply to PMC. The new 25-article minimum ensures that the reviewers have a sufficient amount of content on which to base their recommendation for inclusion in PMC. The new minimum article requirement takes effect on January 1, 2016. Publishers are encouraged to use the 25-article minimum as a guideline in the interim when submitting applications. Full Article
ui Updated guidance on data deposit and linking in PMC By www.ncbi.nlm.nih.gov Published On :: Mon, 30 Oct 2017 08:00:00 EST In response to the growing interest in the availability of data associated with articles, PMC is reviewing current practices around data and seeking feedback on how to best serve the data needs of the research community.As part of these efforts, the PMC policy statement on supplementary data was recently updated to more clearly articulate the requirement that any supplementary data (images, tables, video, or other documents / files) that are associated with an article must be deposited in PMC with an article. The search filter "has suppdata[filter]" can be used in PMC to discover records with associated supplementary data files.In addition to providing supplementary data with an article, NLM is also encouraging journals and authors to make research data available in a public repository and include the relevant data citation(s) in the paper. Guidance for PMC data providers on tagging data citations is available in the Tagging Guidelines. This guidance is based on the JATS4R recommendations on data citations.Starting this month, the NIH Manuscript Submission (NIHMS) system will also accept deposits of small datasets accompanying deposits of funded author manuscripts for inclusion of PMC. (Guidance for authors is available in the NIHMS FAQ.)If you have suggestions on future directions in data for PMC to consider, please let us know at pubmedcentral@ncbi.nlm.nih.gov. Full Article
ui PMC Tagging Guidance for Peer Review Documents Now Available By www.ncbi.nlm.nih.gov Published On :: Wed, 31 Jul 2019 08:00:00 EST 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. Full Article
ui New PubMed Updated: Homepage, User Guide, My NCBI Alerts and Collections, and More By www.nlm.nih.gov Published On :: Tue, 08 Oct 2019 09:00:00 EST Several new features have been added to the new PubMed including an updated homepage, an online user guide, the CSV file format, My NCBI Filters, My Bibliography and Collections, and search integration with the MeSH and NLM Catalog databases. Full Article
ui An Expert's Guide to a Safe Run in Cold Weather By www.medicinenet.com Published On :: Mon, 16 Mar 2020 00:00:00 PDT Title: An Expert's Guide to a Safe Run in Cold WeatherCategory: Health NewsCreated: 3/14/2020 12:00:00 AMLast Editorial Review: 3/16/2020 12:00:00 AM Full Article
ui How Long Does It Take to Recover from Laparoscopic Inguinal Hernia Surgery? By www.medicinenet.com Published On :: Fri, 1 May 2020 00:00:00 PDT Title: How Long Does It Take to Recover from Laparoscopic Inguinal Hernia Surgery?Category: Procedures and TestsCreated: 5/1/2020 12:00:00 AMLast Editorial Review: 5/1/2020 12:00:00 AM Full Article
ui A Woman's Guide to Skin Care During and After Menopause By www.medicinenet.com Published On :: Mon, 24 Feb 2020 00:00:00 PDT Title: A Woman's Guide to Skin Care During and After MenopauseCategory: Health NewsCreated: 2/23/2020 12:00:00 AMLast Editorial Review: 2/24/2020 12:00:00 AM Full Article
ui Heavy Pot Use Linked to Mental Problems, Even After Quitting By www.medicinenet.com Published On :: Fri, 1 May 2020 00:00:00 PDT Title: Heavy Pot Use Linked to Mental Problems, Even After QuittingCategory: Health NewsCreated: 4/30/2020 12:00:00 AMLast Editorial Review: 5/1/2020 12:00:00 AM Full Article
ui Got Flu? Deal Quickly With Complications By www.medicinenet.com Published On :: Mon, 3 Feb 2020 00:00:00 PDT Title: Got Flu? Deal Quickly With ComplicationsCategory: Health NewsCreated: 2/2/2020 12:00:00 AMLast Editorial Review: 2/3/2020 12:00:00 AM Full Article
ui AI May Help Guide Patients to Most Effective Antidepressant By www.medicinenet.com Published On :: Tue, 11 Feb 2020 00:00:00 PDT Title: AI May Help Guide Patients to Most Effective AntidepressantCategory: Health NewsCreated: 2/10/2020 12:00:00 AMLast Editorial Review: 2/11/2020 12:00:00 AM Full Article
ui Some Cities' Smog Can Ruin Your Vacation By www.medicinenet.com Published On :: Tue, 3 Dec 2019 00:00:00 PDT Title: Some Cities' Smog Can Ruin Your VacationCategory: Health NewsCreated: 12/3/2019 12:00:00 AMLast Editorial Review: 12/3/2019 12:00:00 AM Full Article
ui Decitabine Response in Breast Cancer Requires Efficient Drug Processing and Is Not Limited by Multidrug Resistance By mct.aacrjournals.org Published On :: 2020-05-04T05:39:42-07:00 Dysregulation of DNA methylation is an established feature of breast cancers. DNA demethylating therapies like decitabine are proposed for the treatment of triple-negative breast cancers (TNBC) and indicators of response need to be identified. For this purpose, we characterized the effects of decitabine in a panel of 10 breast cancer cell lines and observed a range of sensitivity to decitabine that was not subtype specific. Knockdown of potential key effectors demonstrated the requirement of deoxycytidine kinase (DCK) for decitabine response in breast cancer cells. In treatment-naïve breast tumors, DCK was higher in TNBCs, and DCK levels were sustained or increased post chemotherapy treatment. This suggests that limited DCK levels will not be a barrier to response in patients with TNBC treated with decitabine as a second-line treatment or in a clinical trial. Methylome analysis revealed that genome-wide, region-specific, tumor suppressor gene–specific methylation, and decitabine-induced demethylation did not predict response to decitabine. Gene set enrichment analysis of transcriptome data demonstrated that decitabine induced genes within apoptosis, cell cycle, stress, and immune pathways. Induced genes included those characterized by the viral mimicry response; however, knockdown of key effectors of the pathway did not affect decitabine sensitivity suggesting that breast cancer growth suppression by decitabine is independent of viral mimicry. Finally, taxol-resistant breast cancer cells expressing high levels of multidrug resistance transporter ABCB1 remained sensitive to decitabine, suggesting that the drug could be used as second-line treatment for chemoresistant patients. Full Article
ui State Licensing Board Requirements for Entry into the Dental Hygiene Profession By jdh.adha.org Published On :: 2020-04-30T12:39:03-07:00 Purpose: The purpose of this study was to identify current requirements for initial licensure and entry into the dental hygiene profession across state dental and dental hygiene licensing boards in the United States.Methods: A non-experimental study design was used to study dental and dental hygiene board licensing requirements in the United States, Puerto Rico and the Virgin Islands. Each regulatory board website was searched for requirements for entry-level dental hygiene licensure. Requirements were recorded on an Excel spreadsheet. State dental practice acts were reviewed to gather further information and 20 regulatory bodies were contacted to verify accuracy. Descriptive statistics were used to analyze data.Results: Information from a total of 52 dental boards (n=52) was examined for this study. Nearly all boards (n=51, 98.1%), with the exception of Alabama, required completion of entry-level education from a CODA accredited dental hygiene program and successful completion of the National Board Dental Hygiene Examination. Most states (n=51, 98.1%), except Delaware, also required a live-patient, a clinical board examination. Application fees ranged from $47.70 to $600. States varied considerably in terms of requirements for background checks, age, military status, and infection control training.Conclusion: Although the majority of regulatory bodies require completion of entry-level dental hygiene education from a CODA accredited program and successful completion of national board and a live-patient, clinical examination, there is considerable variation in other additional requirements for initial dental hygiene licensure. Full Article
ui Challenges with Adherence to Clinical Practice Guidelines: Lessons for Implementation Science By jdh.adha.org Published On :: 2020-04-30T12:39:03-07:00 Full Article
ui Host Mucin Is Exploited by Pseudomonas aeruginosa To Provide Monosaccharides Required for a Successful Infection By mbio.asm.org Published On :: 2020-03-03T01:30:27-08:00 ABSTRACT One of the primary functions of the mucosal barrier, found lining epithelial cells, is to serve as a first-line of defense against microbial pathogens. The major structural components of mucus are heavily glycosylated proteins called mucins. Mucins are key components of the innate immune system as they aid in the clearance of pathogens and can decrease pathogen virulence. It has also been recently reported that individual mucins and derived glycans can attenuate the virulence of the human pathogen Pseudomonas aeruginosa. Here, we show data indicating that mucins not only play a role in host defense but that they can also be subverted by P. aeruginosa to cause disease. We found that the mucin MUL-1 and mucin-derived monosaccharides N-acetyl-galactosamine and N-acetylglucosamine are required for P. aeruginosa killing of Caenorhabditis elegans. We also found that the defective adhesion of P. aeruginosa to human lung alveolar epithelial cells, deficient in the mucin MUC1, can be reversed by the addition of individual monosaccharides. The monosaccharides identified in this study are found in a wide range of organisms where they act as host factors required for bacterial pathogenesis. While mucins in C. elegans lack sialic acid caps, which makes their monosaccharides readily available, they are capped in other species. Pathogens such as P. aeruginosa that lack sialidases may rely on enzymes from other bacteria to utilize mucin-derived monosaccharides. IMPORTANCE One of the first lines of defense present at mucosal epithelial tissues is mucus, which is a highly viscous material formed by mucin glycoproteins. Mucins serve various functions, but importantly they aid in the clearance of pathogens and debris from epithelial barriers and serve as innate immune factors. In this study, we describe a requirement of host monosaccharides, likely derived from host mucins, for the ability of Pseudomonas aeruginosa to colonize the intestine and ultimately cause death in Caenorhabditis elegans. We also demonstrate that monosaccharides alter the ability of bacteria to bind to both Caenorhabditis elegans intestinal cells and human lung alveolar epithelial cells, suggesting that there are conserved mechanisms underlying host-pathogen interactions in a range of organisms. By gaining a better understanding of pathogen-mucin interactions, we can develop better approaches to protect against pathogen infection. Full Article
ui Reply to Losick, "Concerns about Continuing Claims that a Protein Complex Interacts with the Phosphorelay" By mbio.asm.org Published On :: 2020-03-10T01:30:41-07:00 Full Article
ui Concerns about Continuing Claims that a Protein Complex Interacts with the Phosphorelay By mbio.asm.org Published On :: 2020-03-10T01:30:42-07:00 Full Article
ui Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract By mbio.asm.org Published On :: 2020-03-17T01:30:14-07:00 ABSTRACT While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4+ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host’s ability to sense the cytokine gamma interferon (IFN-). However, it is unclear what role NR1 production or sensing of IFN- plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis. Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-–/–, and IFN-R–/– NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis. We also determined that protection against infection requires production of IFN- from either NR1 T cells or endogenous cells, further highlighting the importance of IFN- in clearing C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4+ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis. Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis. Full Article
ui Linking Human Milk Oligosaccharides, Infant Fecal Community Types, and Later Risk To Require Antibiotics By mbio.asm.org Published On :: 2020-03-17T01:30:15-07:00 ABSTRACT Human milk oligosaccharides (HMOs) may provide health benefits to infants partly by shaping the development of the early-life intestinal microbiota. In a randomized double-blinded controlled multicentric clinical trial, healthy term infants received either infant formula (control) or the same formula with two HMOs (2'-fucosyllactose and lacto-N-neotetraose; test) from enrollment (0 to 14 days) to 6 months. Then, all infants received the same follow-up formula without HMOs until 12 months of age. Breastfed infants (BF) served as a reference group. Stool microbiota at 3 and 12 months, analyzed by 16S rRNA gene sequencing, clustered into seven fecal community types (FCTs) with marked differences in total microbial abundances. Three of the four 12-month FCTs were likely precursors of the adult enterotypes. At 3 months, microbiota composition in the test group (n = 58) appeared closer to that of BF (n = 35) than control (n = 63) by microbiota alpha (within group) and beta (between groups) diversity analyses and distribution of FCTs. While bifidobacteriaceae dominated two FCTs, its abundance was significantly higher in one (FCT BiH for Bifidobacteriaceae at high abundance) than in the other (FCT Bi for Bifidobacteriaceae). HMO supplementation increased the number of infants with FCT BiH (predominant in BF) at the expense of FCT Bi (predominant in control). We explored the association of the FCTs with reported morbidities and medication use up to 12 months. Formula-fed infants with FCT BiH at 3 months were significantly less likely to require antibiotics during the first year than those with FCT Bi. Previously reported lower rates of infection-related medication use with HMOs may therefore be linked to gut microbiota community types. (This study has been registered at ClinicalTrials.gov under registration number NCT01715246.) IMPORTANCE Human milk is the sole and recommended nutrition for the newborn infant and contains one of the largest constituents of diverse oligosaccharides, dubbed human milk oligosaccharides (HMOs). Preclinical and clinical association studies indicate that HMOs have multiple physiological functions largely mediated through the establishment of the gut microbiome. Until recently, HMOs were not available to investigate their role in randomized controlled intervention trials. To our knowledge, this is the first report on the effects of 2 HMOs on establishing microbiota in newborn infants. We provide a detailed description of the microbiota changes observed upon feeding a formula with 2 HMOs in comparison to breastfed reference infants' microbiota. Then, we associate the microbiota to long-term health as assessed by prescribed antibiotic use. Full Article
ui Avoiding Drug Resistance by Substrate Envelope-Guided Design: Toward Potent and Robust HCV NS3/4A Protease Inhibitors By mbio.asm.org Published On :: 2020-03-31T01:30:58-07:00 ABSTRACT Hepatitis C virus (HCV) infects millions of people worldwide, causing chronic liver disease that can lead to cirrhosis, hepatocellular carcinoma, and liver transplant. In the last several years, the advent of direct-acting antivirals, including NS3/4A protease inhibitors (PIs), has remarkably improved treatment outcomes of HCV-infected patients. However, selection of resistance-associated substitutions and polymorphisms among genotypes can lead to drug resistance and in some cases treatment failure. A proactive strategy to combat resistance is to constrain PIs within evolutionarily conserved regions in the protease active site. Designing PIs using the substrate envelope is a rational strategy to decrease the susceptibility to resistance by using the constraints of substrate recognition. We successfully designed two series of HCV NS3/4A PIs to leverage unexploited areas in the substrate envelope to improve potency, specifically against resistance-associated substitutions at D168. Our design strategy achieved better resistance profiles over both the FDA-approved NS3/4A PI grazoprevir and the parent compound against the clinically relevant D168A substitution. Crystallographic structural analysis and inhibition assays confirmed that optimally filling the substrate envelope is critical to improve inhibitor potency while avoiding resistance. Specifically, inhibitors that enhanced hydrophobic packing in the S4 pocket and avoided an energetically frustrated pocket performed the best. Thus, the HCV substrate envelope proved to be a powerful tool to design robust PIs, offering a strategy that can be translated to other targets for rational design of inhibitors with improved potency and resistance profiles. IMPORTANCE Despite significant progress, hepatitis C virus (HCV) continues to be a major health problem with millions of people infected worldwide and thousands dying annually due to resulting complications. Recent antiviral combinations can achieve >95% cure, but late diagnosis, low access to treatment, and treatment failure due to drug resistance continue to be roadblocks against eradication of the virus. We report the rational design of two series of HCV NS3/4A protease inhibitors with improved resistance profiles by exploiting evolutionarily constrained regions of the active site using the substrate envelope model. Optimally filling the S4 pocket is critical to avoid resistance and improve potency. Our results provide drug design strategies to avoid resistance that are applicable to other quickly evolving viral drug targets. Full Article
ui Nonproteolytic K29-Linked Ubiquitination of the PB2 Replication Protein of Influenza A Viruses by Proviral Cullin 4-Based E3 Ligases By mbio.asm.org Published On :: 2020-04-07T01:31:16-07:00 ABSTRACT The multifunctional nature of viral proteins is essentially driven by posttranslational modifications (PTMs) and is key for the successful outcome of infection. For influenza A viruses (IAVs), a composite pattern of PTMs regulates the activity of viral proteins. However, almost none are known that target the PB2 replication protein, except for inducing its degradation. We show here that PB2 undergoes a nonproteolytic ubiquitination during infection. We identified E3 ubiquitin ligases catalyzing this ubiquitination as two multicomponent RING-E3 ligases based on cullin 4 (CRL4s), which are both contributing to the levels of ubiquitinated forms of PB2 in infected cells. The CRL4 E3 ligase activity is required for the normal progression of the viral cycle and for maximal virion production, indicating that the CRL4s mediate a ubiquitin signaling that promotes infection. The CRL4s are recruiting PB2 through an unconventional bimodal interaction with both the DDB1 adaptor and DCAF substrate receptors. While able to bind to PB2 when engaged in the viral polymerase complex, the CRL4 factors do not alter transcription and replication of the viral segments during infection. CRL4 ligases catalyze different patterns of lysine ubiquitination on PB2. Recombinant viruses mutated in the targeted lysines showed attenuated viral production, suggesting that CRL4-mediated ubiquitination of PB2 contributes to IAV infection. We identified K29-linked ubiquitin chains as main components of the nonproteolytic PB2 ubiquitination mediated by the CRL4s, providing the first example of the role of this atypical ubiquitin linkage in the regulation of a viral infection. IMPORTANCE Successful infection by influenza A virus, a pathogen of major public health importance, involves fine regulation of the multiple functions of the viral proteins, which often relies on post-translational modifications (PTMs). The PB2 protein of influenza A viruses is essential for viral replication and a key determinant of host range. While PTMs of PB2 inducing its degradation have been identified, here we show that PB2 undergoes a regulating PTM signaling detected during infection, based on an atypical K29-linked ubiquitination and mediated by two multicomponent E3 ubiquitin ligases. Recombinant viruses impaired for CRL4-mediated ubiquitination are attenuated, indicating that ubiquitination of PB2 is necessary for an optimal influenza A virus infection. The CRL4 E3 ligases are required for normal viral cycle progression and for maximal virion production. Consequently, they represent potential candidate host factors for antiviral targets. Full Article
ui Building local connections could help reduce violent encounters between police, black men By thenationshealth.aphapublications.org Published On :: 2020-05-01T05:00:17-07:00 Finding common ground and building trust between local stakeholders could help prevent violent encounters between police and young black men, new research finds. Full Article
ui We need equity-oriented solutions to COVID-19: Asians facing stigma, discrimination, fear during pandemic By thenationshealth.aphapublications.org Published On :: 2020-05-01T05:00:17-07:00 APHA member Elena Ong, PHN, MS, past president and founding CEO of the Asian & Pacific Islander Caucus for Public Health, a recent APHA Executive Board member, and a past vice president of the Southern California Public Health Association, discusses discrimination against Asians in the U.S. and beyond. Full Article