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Female Pelvis Widens, Then Shrinks Over a Lifetime, Study Finds

Title: Female Pelvis Widens, Then Shrinks Over a Lifetime, Study Finds
Category: Health News
Created: 4/25/2016 12:00:00 AM
Last Editorial Review: 4/26/2016 12:00:00 AM




tim

Health Tip: Smart Swaps at Mealtime

Title: Health Tip: Smart Swaps at Mealtime
Category: Health News
Created: 5/1/2017 12:00:00 AM
Last Editorial Review: 5/1/2017 12:00:00 AM




tim

Psychiatric Scars of Wartime Brain Injury May Linger for Years

Title: Psychiatric Scars of Wartime Brain Injury May Linger for Years
Category: Health News
Created: 5/1/2017 12:00:00 AM
Last Editorial Review: 5/2/2017 12:00:00 AM




tim

A Toddler's Screen Time Tied to Speech Delay

Title: A Toddler's Screen Time Tied to Speech Delay
Category: Health News
Created: 5/4/2017 12:00:00 AM
Last Editorial Review: 5/4/2017 12:00:00 AM




tim

4 in 10 People Will Suffer Arthritic Hands Over Lifetime

Title: 4 in 10 People Will Suffer Arthritic Hands Over Lifetime
Category: Health News
Created: 5/4/2017 12:00:00 AM
Last Editorial Review: 5/5/2017 12:00:00 AM




tim

Could Time in a Sauna Lower Your Stroke Risk?

Title: Could Time in a Sauna Lower Your Stroke Risk?
Category: Health News
Created: 5/2/2018 12:00:00 AM
Last Editorial Review: 5/3/2018 12:00:00 AM




tim

How Much Does Your Kid Weigh? Chances Are, You're Underestimating

Title: How Much Does Your Kid Weigh? Chances Are, You're Underestimating
Category: Health News
Created: 4/28/2019 12:00:00 AM
Last Editorial Review: 4/29/2019 12:00:00 AM




tim

Returning to Intimacy After Childbirth

Title: Returning to Intimacy After Childbirth
Category: Health News
Created: 5/1/2019 12:00:00 AM
Last Editorial Review: 5/1/2019 12:00:00 AM




tim

MS Patients Now Pay 20 Times More for Drugs Than a Decade Ago

Title: MS Patients Now Pay 20 Times More for Drugs Than a Decade Ago
Category: Health News
Created: 5/1/2019 12:00:00 AM
Last Editorial Review: 5/2/2019 12:00:00 AM




tim

Love in the Time of Coronavirus: Couples Feel the Strain of Lockdown

Title: Love in the Time of Coronavirus: Couples Feel the Strain of Lockdown
Category: Health News
Created: 4/28/2020 12:00:00 AM
Last Editorial Review: 4/29/2020 12:00:00 AM




tim

Depressed Pregnant Women 3 Times More Likely to Turn to Pot

Title: Depressed Pregnant Women 3 Times More Likely to Turn to Pot
Category: Health News
Created: 3/12/2020 12:00:00 AM
Last Editorial Review: 3/13/2020 12:00:00 AM




tim

Sometimes, Aspirin May Be Enough to Ease Migraines

Title: Sometimes, Aspirin May Be Enough to Ease Migraines
Category: Health News
Created: 12/10/2019 12:00:00 AM
Last Editorial Review: 12/10/2019 12:00:00 AM




tim

CRISPR Used Inside Person's Body For First Time

Title: CRISPR Used Inside Person's Body For First Time
Category: Health News
Created: 3/4/2020 12:00:00 AM
Last Editorial Review: 3/4/2020 12:00:00 AM




tim

Screen Time for Tiniest Tots Linked to Autism-Like Symptoms

Title: Screen Time for Tiniest Tots Linked to Autism-Like Symptoms
Category: Health News
Created: 4/20/2020 12:00:00 AM
Last Editorial Review: 4/21/2020 12:00:00 AM




tim

Early High School Start Times May Hurt Attendance

Title: Early High School Start Times May Hurt Attendance
Category: Health News
Created: 5/1/2020 12:00:00 AM
Last Editorial Review: 5/4/2020 12:00:00 AM




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COMMENTARY: No Better Time to Thank Our Nurses

Medscape thanks nurses around the world during International Year of the Nurse and the Midwife and National Nurses Week. Please join us.




tim

What Is the Recovery Time for An Umbilical Hernia Surgery?

Title: What Is the Recovery Time for An Umbilical Hernia Surgery?
Category: Procedures and Tests
Created: 4/15/2020 12:00:00 AM
Last Editorial Review: 4/15/2020 12:00:00 AM




tim

Spring Time Change Tied to More Fatal Car Crashes

Title: Spring Time Change Tied to More Fatal Car Crashes
Category: Health News
Created: 1/30/2020 12:00:00 AM
Last Editorial Review: 1/31/2020 12:00:00 AM




tim

A Consistent Bedtime Is Good for Your Heart

Title: A Consistent Bedtime Is Good for Your Heart
Category: Health News
Created: 4/3/2020 12:00:00 AM
Last Editorial Review: 4/6/2020 12:00:00 AM




tim

Reflections: My Time as JDE Editor




tim

In Vivo Targeting of Clostridioides difficile Using Phage-Delivered CRISPR-Cas3 Antimicrobials

ABSTRACT

Clostridioides difficile is an important nosocomial pathogen that causes approximately 500,000 cases of C. difficile infection (CDI) and 29,000 deaths annually in the United States. Antibiotic use is a major risk factor for CDI because broad-spectrum antimicrobials disrupt the indigenous gut microbiota, decreasing colonization resistance against C. difficile. Vancomycin is the standard of care for the treatment of CDI, likely contributing to the high recurrence rates due to the continued disruption of the gut microbiota. Thus, there is an urgent need for the development of novel therapeutics that can prevent and treat CDI and precisely target the pathogen without disrupting the gut microbiota. Here, we show that the endogenous type I-B CRISPR-Cas system in C. difficile can be repurposed as an antimicrobial agent by the expression of a self-targeting CRISPR that redirects endogenous CRISPR-Cas3 activity against the bacterial chromosome. We demonstrate that a recombinant bacteriophage expressing bacterial genome-targeting CRISPR RNAs is significantly more effective than its wild-type parent bacteriophage at killing C. difficile both in vitro and in a mouse model of CDI. We also report that conversion of the phage from temperate to obligately lytic is feasible and contributes to the therapeutic suitability of intrinsic C. difficile phages, despite the specific challenges encountered in the disease phenotypes of phage-treated animals. Our findings suggest that phage-delivered programmable CRISPR therapeutics have the potential to leverage the specificity and apparent safety of phage therapies and improve their potency and reliability for eradicating specific bacterial species within complex communities, offering a novel mechanism to treat pathogenic and/or multidrug-resistant organisms.

IMPORTANCE Clostridioides difficile is a bacterial pathogen responsible for significant morbidity and mortality across the globe. Current therapies based on broad-spectrum antibiotics have some clinical success, but approximately 30% of patients have relapses, presumably due to the continued perturbation to the gut microbiota. Here, we show that phages can be engineered with type I CRISPR-Cas systems and modified to reduce lysogeny and to enable the specific and efficient targeting and killing of C. difficile in vitro and in vivo. Additional genetic engineering to disrupt phage modulation of toxin expression by lysogeny or other mechanisms would be required to advance a CRISPR-enhanced phage antimicrobial for C. difficile toward clinical application. These findings provide evidence into how phage can be combined with CRISPR-based targeting to develop novel therapies and modulate microbiomes associated with health and disease.




tim

Estimating the Timing of Early Simian-Human Immunodeficiency Virus Infections: a Comparison between Poisson Fitter and BEAST

ABSTRACT

Many HIV prevention strategies are currently under consideration where it is highly informative to know the study participants’ times of infection. These can be estimated using viral sequence data sampled early in infection. However, there are several scenarios that, if not addressed, can skew timing estimates. These include multiple transmitted/founder (TF) viruses, APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like)-mediated mutational enrichment, and recombination. Here, we suggest a pipeline to identify these problems and resolve the biases that they introduce. We then compare two modeling strategies to obtain timing estimates from sequence data. The first, Poisson Fitter (PF), is based on a Poisson model of random accumulation of mutations relative to the TF virus (or viruses) that established the infection. The second uses a coalescence-based phylogenetic strategy as implemented in BEAST. The comparison is based on timing predictions using plasma viral RNA (cDNA) sequence data from 28 simian-human immunodeficiency virus (SHIV)-infected animals for which the exact day of infection is known. In this particular setting, based on nucleotide sequences from samples obtained in early infection, the Poisson method yielded more accurate, more precise, and unbiased estimates for the time of infection than did the explored implementations of BEAST.

IMPORTANCE The inference of the time of infection is a critical parameter in testing the efficacy of clinical interventions in protecting against HIV-1 infection. For example, in clinical trials evaluating the efficacy of passively delivered antibodies (Abs) for preventing infections, accurate time of infection data are essential for discerning levels of the Abs required to confer protection, given the natural Ab decay rate in the human body. In such trials, genetic sequences from early in the infection are regularly sampled from study participants, generally prior to immune selection, when the viral population is still expanding and genetic diversity is low. In this particular setting of early viral growth, the Poisson method is superior to the alternative approach based on coalescent methods. This approach can also be applied in human vaccine trials, where accurate estimates of infection times help ascertain if vaccine-elicited immune protection wanes over time.




tim

Romo1-Derived Antimicrobial Peptide Is a New Antimicrobial Agent against Multidrug-Resistant Bacteria in a Murine Model of Sepsis

ABSTRACT

To overcome increasing bacterial resistance to conventional antibiotics, many antimicrobial peptides (AMPs) derived from host defense proteins have been developed. However, there are considerable obstacles to their application to systemic infections because of their low bioavailability. In the present study, we developed an AMP derived from Romo1 (AMPR-11) that exhibits a broad spectrum of antimicrobial activity. AMPR-11 showed remarkable efficacy against sepsis-causing bacteria, including multidrug-resistant strains, with low toxicity in a murine model of sepsis after intravenous administration. It seems that AMPR-11 disrupts bacterial membranes by interacting with cardiolipin and lipid A. From the results of this study, we suggest that AMPR-11 is a new class of agent for overcoming low efficacy in the intravenous application of AMPs and is a promising candidate to overcome multidrug resistance.

IMPORTANCE Abuse of antibiotics often leads to increase of multidrug-resistant (MDR) bacteria, which threatens the life of human beings. To overcome threat of antibiotic resistance, scientists are developing a novel class of antibiotics, antimicrobial peptides, that can eradicate MDR bacteria. Unfortunately, these antibiotics have mainly been developed to cure bacterial skin infections rather than others, such as life-threatening sepsis. Major pharmaceutical companies have tried to develop antiseptic drugs; however, they have not been successful. Here, we report that AMPR-11, the antimicrobial peptide (AMP) derived from mitochondrial nonselective channel Romo1, has antimicrobial activity against Gram-positive and Gram-negative bacteria comprising many clinically isolated MDR strains. Moreover, AMPR-11 increased the survival rate in a murine model of sepsis caused by MDR bacteria. We propose that AMPR-11 could be a novel antiseptic drug candidate with a broad antimicrobial spectrum to overcome MDR bacterial infection.




tim

Global Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in Klebsiella pneumoniae

ABSTRACT

In Gram-negative bacteria, the permeability of the outer membrane governs rates of antibiotic uptake and thus the efficacy of antimicrobial treatment. Hydrophilic drugs like β-lactam antibiotics depend on diffusion through pore-forming outer membrane proteins to reach their intracellular targets. In this study, we investigated the distribution of porin genes in more than 2,700 Klebsiella isolates and found a widespread loss of OmpK35 functionality, particularly in those strains isolated from clinical environments. Using a defined set of outer-membrane-remodeled mutants, the major porin OmpK35 was shown to be largely responsible for β-lactam permeation. Sequence similarity network analysis characterized the porin protein subfamilies and led to discovery of a new porin family member, OmpK38. Structure-based comparisons of OmpK35, OmpK36, OmpK37, OmpK38, and PhoE showed near-identical pore frameworks but defining differences in the sequence characteristics of the extracellular loops. Antibiotic sensitivity profiles of isogenic Klebsiella pneumoniae strains, each expressing a different porin as its dominant pore, revealed striking differences in the antibiotic permeability characteristics of each channel in a physiological context. Since K. pneumoniae is a nosocomial pathogen with high rates of antimicrobial resistance and concurrent mortality, these experiments elucidate the role of porins in conferring specific drug-resistant phenotypes in a global context, informing future research to combat antimicrobial resistance in K. pneumoniae.

IMPORTANCE Klebsiella pneumoniae is a pathogen of humans with high rates of mortality and a recognized global rise in incidence of carbapenem-resistant K. pneumoniae (CRKP). The outer membrane of K. pneumoniae forms a permeability barrier that modulates the ability of antibiotics to reach their intracellular target. OmpK35, OmpK36, OmpK37, OmpK38, PhoE, and OmpK26 are porins in the outer membrane of K. pneumoniae, demonstrated here to have a causative relationship to drug resistance phenotypes in a physiological context. The data highlight that currently trialed combination treatments with a carbapenem and β-lactamase inhibitors could be effective on porin-deficient K. pneumoniae. Together with structural data, the results reveal the role of outer membrane proteome remodeling in antimicrobial resistance of K. pneumoniae and point to the role of extracellular loops, not channel parameters, in drug permeation. This significant finding warrants care in the development of phage therapies for K. pneumoniae infections, given the way porin expression will be modulated to confer phage-resistant—and collateral drug-resistant—phenotypes in K. pneumoniae.




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Coping with COVID: How a Research Team Learned To Stay Engaged in This Time of Physical Distancing

ABSTRACT

Physical distancing imposed by the COVID-19 pandemic has led to alterations in routines and new responsibilities for much of the research community. We provide some tips for how research teams can cope with physical distancing, some of which require a change in how we define productivity. Importantly, we need to maintain and strengthen social connections in this time when we can’t be physically together.




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Optimization of an Experimental Vaccine To Prevent Escherichia coli Urinary Tract Infection

ABSTRACT

Urinary tract infections (UTI) affect half of all women at least once during their lifetime. The rise in the numbers of extended-spectrum beta-lactamase-producing strains and the potential for carbapenem resistance within uropathogenic Escherichia coli (UPEC), the most common causative agent of UTI, create an urgent need for vaccine development. Intranasal immunization of mice with UPEC outer membrane iron receptors FyuA, Hma, IreA, and IutA, conjugated to cholera toxin, provides protection in the bladder or kidneys under conditions of challenge with UPEC strain CFT073 or strain 536. On the basis of these data, we sought to optimize the vaccination route (intramuscular, intranasal, or subcutaneous) in combination with adjuvants suitable for human use, including aluminum hydroxide gel (alum), monophosphoryl lipid A (MPLA), unmethylated CpG synthetic oligodeoxynucleotides (CpG), polyinosinic:polycytidylic acid (polyIC), and mutated heat-labile E. coli enterotoxin (dmLT). Mice intranasally vaccinated with dmLT-IutA and dmLT-Hma displayed significant reductions in bladder colonization (86-fold and 32-fold, respectively), with 40% to 42% of mice having no detectable CFU. Intranasal vaccination of mice with CpG-IutA and polyIC-IutA significantly reduced kidney colonization (131-fold) and urine CFU (22-fold), respectively. dmLT generated the most consistently robust antibody response in intranasally immunized mice, while MPLA and alum produced greater concentrations of antigen-specific serum IgG with intramuscular immunization. On the basis of these results, we conclude that intranasal administration of Hma or IutA formulated with dmLT adjuvant provides the greatest protection from UPEC UTI. This report advances our progress toward a vaccine against uncomplicated UTI, which will significantly improve the quality of life for women burdened by recurrent UTI and enable better antibiotic stewardship.

IMPORTANCE Urinary tract infections (UTI) are among the most common bacterial infection in humans, affecting half of all women at least once during their lifetimes. The rise in antibiotic resistance and health care costs emphasizes the need to develop a vaccine against the most common UTI pathogen, Escherichia coli. Vaccinating mice intranasally with a detoxified heat-labile enterotoxin and two surface-exposed receptors, Hma or IutA, significantly reduced bacterial burden in the bladder. This work highlights progress in the development of a UTI vaccine formulated with adjuvants suitable for human use and antigens that encode outer membrane iron receptors required for infection in the iron-limited urinary tract.




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It's Time for Private Sector Business to Come to the Health Care Table

With rising costs and below-average outcomes, North Carolina's health care value proposition is upside down. It's time for employers to lead transformative change.




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Sometimes You Seek the Spotlight. Sometimes it Finds You.

For decades, government, health systems, universities, foundations, exceptional individuals, and thought leaders across North Carolina have been testing, implementing, modifying, and just plain trying new ways of improving the way we seek, receive, and experience health care.

More recently, North Carolina has been striving to not simply address the cost, efficiency, and value that are so frustratingly elusive in health care, but also recognizing that we simply need to improve the health of our residents. We have looked to interventions both compatible with and beyond health care to do this.

The National Academy of Medicine, formerly the National Institute of Medicine, since 2016 has boldly laid out Vital Directions in Health Care, focusing on 19 priority issues and recommendations for health policy to better achieve health and well-being for all Americans. They have taken their show on the road, beyond the halls of Congress and think tanks and universities to the people on the ground in states across the country to present, discuss, listen, and learn how policy recommendations come to life.

This issue of the journal highlights the National Academy of Medicine bringing its spotlight to North Carolina last November, an acknowledgment that states are often where policy is put into action, and that North Carolina has been a leader in innovating, planning, implementing, and evaluating again and again to get better and better results for our residents. Pull your chair up to the edge of the stage for a good read in the glow of the spotlight.




tim

Improving Crop Water-Use Efficiency Requires Optimizing the Circadian Clock




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Forced oscillation technique for optimising PEEP in ventilated extremely preterm infants

Ventilatory settings are critical in mechanically ventilated extremely preterm newborn infants due to the risk of ventilation-induced lung injury (VILI) and the subsequent development of bronchopulmonary dysplasia (BPD) [1]. Positive end-expiratory pressure (PEEP) settings usually rely on blood gases, oxygen requirement, lung auscultation, evaluation of chest radiograph and assessment of the pressure/volume curves provided by ventilators. Studies of optimal PEEP settings in the surfactant-treated preterm infant in need of mechanical ventilation are limited and evidence-based clinical guidelines are sparse [2, 3]. A bedside method identifying the PEEP value that comprises maximal lung volume recruitment and minimising tissue overdistension could improve real-time optimisation of PEEP and potentially minimise the risk of VILI and BPD [4, 5].




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Optimizing Resources in Childrens Surgical Care: An Update on the American College of Surgeons' Verification Program

Surgical procedures are performed in the United States in a wide variety of clinical settings and with variation in clinical outcomes. In May 2012, the Task Force for Children’s Surgical Care, an ad hoc multidisciplinary group comprising physicians representing specialties relevant to pediatric perioperative care, was convened to generate recommendations to optimize the delivery of children’s surgical care. This group generated a white paper detailing the consensus opinions of the involved experts. Following these initial recommendations, the American College of Surgeons (ACS), Children’s Hospital Association, and Task Force for Children’s Surgical Care, with input from all related perioperative specialties, developed and published specific and detailed resource and quality standards designed to improve children’s surgical care (https://www.facs.org/quality-programs/childrens-surgery/childrens-surgery-verification). In 2015, with the endorsement of the American Academy of Pediatrics (https://pediatrics.aappublications.org/content/135/6/e1538), the ACS established a pilot verification program. In January 2017, after completion of the pilot program, the ACS Children’s Surgery Verification Quality Improvement Program was officially launched. Verified sites are listed on the program Web site at https://www.facs.org/quality-programs/childrens-surgery/childrens-surgery-verification/centers, and more than 150 are interested in verification. This report provides an update on the ACS Children’s Surgery Verification Quality Improvement Program as it continues to evolve.




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The Time Is Now: Standardized Sedation Training for Pediatric Hospitalists




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Exploring Early Childhood Factors as an Avenue to Address Chronic Peer Victimization




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Optimizing Human Papillomavirus Immunization: The Role of Centralized Reminder and Recall Systems




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Early Childhood Factors Associated With Peer Victimization Trajectories From 6 to 17 Years of Age

OBJECTIVES:

To describe (1) the developmental trajectories of peer victimization from 6 to 17 years of age and (2) the early childhood behaviors and family characteristics associated with the trajectories.

METHODS:

We used data from 1760 children enrolled in the Quebec Longitudinal Study of Child Development, a population-based birth cohort. Participants self-reported peer victimization at ages 6, 7, 8, 10, 12, 13, 15, and 17 years. Participants’ behavior and family characteristics were measured repeatedly between ages 5 months and 5 years.

RESULTS:

We identified 4 trajectories of peer victimization from 6 to 17 years of age: low (32.9%), moderate-emerging (29.8%), childhood-limited (26.2%), and high-chronic (11.1%). Compared with children in the low peer victimization trajectory, children in the other 3 trajectories were more likely to exhibit externalizing behaviors in early childhood, and those in the high-chronic and moderate-emerging trajectories were more likely to be male. Paternal history of antisocial behavior was associated with moderate-emerging (odds ratio [OR] = 1.54; 95% confidence interval [CI] = 1.09–2.19) and high-chronic (OR = 1.93; 95% CI = 1.25–2.99) relative to low peer victimization. Living in a nonintact family in early childhood was associated with childhood-limited (OR = 1.48; 95% CI = 1.11–1.97) and high-chronic (OR = 1.59; 95% CI = 1.09–2.31) relative to low peer victimization.

CONCLUSIONS:

Early childhood externalizing behaviors and family vulnerabilities were associated with the development of peer victimization. Some children entered the cascade of persistent peer victimization at the beginning of primary school. Support to these children and their families early in life should be an important component of peer victimization preventive interventions.




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Rif1 Functions in a Tissue-Specific Manner To Control Replication Timing Through Its PP1-Binding Motif [Genome Integrity and Transmission]

Replication initiation in eukaryotic cells occurs asynchronously throughout S phase, yielding early- and late-replicating regions of the genome, a process known as replication timing (RT). RT changes during development to ensure accurate genome duplication and maintain genome stability. To understand the relative contributions that cell lineage, cell cycle, and replication initiation regulators have on RT, we utilized the powerful developmental systems available in Drosophila melanogaster. We generated and compared RT profiles from mitotic cells of different tissues and from mitotic and endocycling cells of the same tissue. Our results demonstrate that cell lineage has the largest effect on RT, whereas switching from a mitotic to an endoreplicative cell cycle has little to no effect on RT. Additionally, we demonstrate that the RT differences we observed in all cases are largely independent of transcriptional differences. We also employed a genetic approach in these same cell types to understand the relative contribution the eukaryotic RT control factor, Rif1, has on RT control. Our results demonstrate that Rif1 can function in a tissue-specific manner to control RT. Importantly, the Protein Phosphatase 1 (PP1) binding motif of Rif1 is essential for Rif1 to regulate RT. Together, our data support a model in which the RT program is primarily driven by cell lineage and is further refined by Rif1/PP1 to ultimately generate tissue-specific RT programs.




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Topoisomerases Modulate the Timing of Meiotic DNA Breakage and Chromosome Morphogenesis in Saccharomyces cerevisiae [Genome Integrity and Transmission]

During meiotic prophase, concurrent transcription, recombination, and chromosome synapsis place substantial topological strain on chromosomal DNA, but the role of topoisomerases in this context remains poorly defined. Here, we analyzed the roles of topoisomerases I and II (Top1 and Top2) during meiotic prophase in Saccharomyces cerevisiae. We show that both topoisomerases accumulate primarily in promoter-containing intergenic regions of actively transcribing genes, including many meiotic double-strand break (DSB) hotspots. Despite the comparable binding patterns, top1 and top2 mutations have different effects on meiotic recombination. TOP1 disruption delays DSB induction and shortens the window of DSB accumulation by an unknown mechanism. By contrast, temperature-sensitive top2-1 mutants exhibit a marked delay in meiotic chromosome remodeling and elevated DSB signals on synapsed chromosomes. The problems in chromosome remodeling were linked to altered Top2 binding patterns rather than a loss of Top2 catalytic activity, and stemmed from a defect in recruiting the chromosome remodeler Pch2/TRIP13 to synapsed chromosomes. No chromosomal defects were observed in the absence of TOP1. Our results imply independent roles for Top1 and Top2 in modulating meiotic chromosome structure and recombination.




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Development of IFN-Stimulated Gene Expression from Embryogenesis through Adulthood, with and without Constitutive MDA5 Pathway Activation [INNATE IMMUNITY AND INFLAMMATION]

Key Points

  • The augmented ISG profile of RdRP mice develops largely postnatally.

  • Elevated ISG expression is then maintained through adulthood.

  • The ISG signature in adults requires persistent type I IFN signaling.




    tim

    Differential Outcomes following Optimization of Simian-Human Immunodeficiency Viruses from Clades AE, B, and C [Pathogenesis and Immunity]

    Simian-human immunodeficiency virus (SHIV) infection of rhesus monkeys is an important preclinical model for human immunodeficiency virus type 1 (HIV-1) vaccines, therapeutics, and cure strategies. SHIVs have been optimized by incorporating HIV-1 Env residue 375 mutations that mimic the bulky or hydrophobic residues typically found in simian immunodeficiency virus (SIV) Env to improve rhesus CD4 binding. We applied this strategy to three SHIV challenge stocks (SHIV-SF162p3, SHIV-AE16, and SHIV-325c) and observed three distinct outcomes. We constructed six Env375 variants (M, H, W, Y, F, and S) for each SHIV, and we performed a pool competition study in rhesus monkeys to define the optimal variant for each SHIV prior to generating large-scale challenge stocks. We identified SHIV-SF162p3S/wild type, SHIV-AE16W, and SHIV-325cH as the optimal variants. SHIV-SF162p3S could not be improved, as it already contained the optimal Env375 residue. SHIV-AE16W exhibited a similar replicative capacity to the parental SHIV-AE16 stock. In contrast, SHIV-325cH demonstrated a 2.6-log higher peak and 1.6-log higher setpoint viral loads than the parental SHIV-325c stock. These data demonstrate the diversity of potential outcomes following Env375 modification in SHIVs. Moreover, the clade C SHIV-325cH challenge stock may prove useful for evaluating prophylactic or therapeutic interventions against clade C HIV-1.

    IMPORTANCE We sought to enhance the infectivity of three SHIV stocks by optimization of a key residue in human immunodeficiency virus type 1 (HIV-1) Env (Env375). We developed the following three new simian-human immunodeficiency virus (SHIV) stocks: SHIV-SF162p3S/wild type, SHIV-AE16W, and SHIV-325cH. SHIV-SF162p3S could not be optimized, SHIV-AE16W proved comparable to the parental virus, and SHIV-325cH demonstrated markedly enhanced replicative capacity compared with the parental virus.




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    Detecting electronic coherences by time-domain high-harmonic spectroscopy [Physics]

    Ultrafast spectroscopy is capable of monitoring electronic and vibrational states. For electronic states a few eV apart, an X-ray laser source is required. We propose an alternative method based on the time-domain high-order harmonic spectroscopy where a coherent superposition of the electronic states is first prepared by the strong optical...




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    Inner Workings: Molecular biologists offer “wartime service” in the effort to test for COVID-19 [Medical Sciences]

    As the novel coronavirus spreads, communities across the United States are struggling to offer public testing. The need is urgent. Testing got off to a delayed start in the United States as a result of technical missteps and a slow response from government officials. Now cities across the country are...




    tim

    Starvation and antimetabolic therapy promote cytokine release and recruitment of immune cells [Immunology and Inflammation]

    Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell...




    tim

    Aerosol-photolysis interaction reduces particulate matter during wintertime haze events [Earth, Atmospheric, and Planetary Sciences]

    Aerosol–radiation interaction (ARI) plays a significant role in the accumulation of fine particulate matter (PM2.5) by stabilizing the planetary boundary layer and thus deteriorating air quality during haze events. However, modification of photolysis by aerosol scattering or absorbing solar radiation (aerosol–photolysis interaction or API) alters the atmospheric oxidizing capacity, decreases...




    tim

    Optimizing Rhizobium-legume symbioses by simultaneous measurement of rhizobial competitiveness and N2 fixation in nodules [Agricultural Sciences]

    Legumes tend to be nodulated by competitive rhizobia that do not maximize nitrogen (N2) fixation, resulting in suboptimal yields. Rhizobial nodulation competitiveness and effectiveness at N2 fixation are independent traits, making their measurement extremely time-consuming with low experimental throughput. To transform the experimental assessment of rhizobial competitiveness and effectiveness, we...




    tim

    Seasonal timing adaptation across the geographic range of Arabidopsis thaliana [Evolution]

    The most fundamental genetic program of an annual plant defines when to grow and reproduce and when to remain dormant in the soil as a seed. With the right timing, plants can even live in hostile regions with only a few months of growth-favorable abundant rains and mild temperatures. To...




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    Habituation of the cardiovascular response to restraint stress is inhibited by exposure to other stressor stimuli and exercise training [RESEARCH ARTICLE]

    Ricardo Benini, Leandro A. Oliveira, Lucas Gomes-de-Souza, Bruno Rodrigues, and Carlos C. Crestani

    This study evaluated the effect of exposure to either a chronic variable stress (CVS) protocol or social isolation, as well as treadmill exercise training, in the habituation of the cardiovascular response upon repeated exposure to restraint stress in rats. The habituation of the corticosterone response to repeated restraint stress was also evaluated. For this, animals were subjected to either acute or 10 daily sessions of 60 min of restraint stress. CVS and social isolation protocols lasted for 10 consecutive days, whereas treadmill training was performed for 1 h per day, 5 days per week for 8 weeks. We observed that the increase in serum corticosterone was reduced during both the stress and the recovery period of the 10th session of restraint. Habituation of the cardiovascular response was identified in terms of a faster return of heart rate to baseline values during the recovery period of the 10th session of restraint. The increase in blood pressure and the decrease in tail skin temperature were similar at the 1st and 10th session of restraint. Exposure to CVS, social isolation or treadmill exercise training inhibited the habituation of the restraint-evoked tachycardia. Additionally, CVS increased the blood pressure response at the 10th session of restraint, whereas social isolation enhanced both the tachycardia during the first session and the drop in skin temperature at the 10th session of restraint. Taken together, these findings provide new evidence that pathologies evoked by stress might be related to impairment in the habituation process to homotypic stressors.




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    Temperature has a causal and plastic effect on timing of breeding in a small songbird [RESEARCH ARTICLE]

    Irene Verhagen, Barbara M. Tomotani, Phillip Gienapp, and Marcel E. Visser

    Phenotypic plasticity is an important mechanism by which an individual can adapt its seasonal timing to predictable, short-term environmental changes by using predictive cues. Identification of these cues is crucial to forecast the response of species to long-term environmental change and to study their potential to adapt. Individual great tits (Parus major) start reproduction early under warmer conditions in the wild, but whether this effect is causal is not well known. We housed 36 pairs of great tits in climate-controlled aviaries and 40 pairs in outdoor aviaries, where they bred under artificial contrasting temperature treatments or in semi-natural conditions, respectively, for two consecutive years, using birds from lines selected for early and late egg laying. We thus obtained laying dates in two different thermal environments for each female. Females bred earlier under warmer conditions in climate-controlled aviaries, but not in outdoor aviaries. The latter was inconsistent with laying dates from our wild population. Further, early selection line females initiated egg laying consistently ~9 days earlier than late selection line females in outdoor aviaries, but we found no difference in the degree of plasticity (i.e. the sensitivity to temperature) in laying date between selection lines. Because we found that temperature causally affects laying date, climate change will lead to earlier laying. This advancement is, however, unlikely to be sufficient, thereby leading to selection for earlier laying. Our results suggest that natural selection may lead to a change in mean phenotype, but not to a change in the sensitivity of laying dates to temperature.




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    The effect of vertical extent of stimuli on cockroach optomotor response [RESEARCH ARTICLE]

    Juha Nuutila, Anna E. Honkanen, Kyösti Heimonen, and Matti Weckström

    Using tethered American cockroaches walking on a trackball in a spherical virtual reality environment, we tested optomotor responses to horizontally moving black-and-white gratings of different vertical extent under six different light intensities. We found that shortening the vertical extent of the wide-field stimulus grating within a light level weakened response strength, reduced average velocity, and decreased angular walking distance. Optomotor responses with the vertically shortened stimuli persisted down to light intensity levels of 0.05 lx. Response latency seems to be independent of both the height of the stimulus and light intensity. The optomotor response started saturating at the light intensity of 5 lx, where the shortest behaviourally significant stimulus was 1°. This indicates that the number of vertical ommatidial rows needed to elicit an optomotor response at 5 lx and above is in the single digits, maybe even just one. Our behavioural results encourage further inquiry into the interplay of light intensity and stimulus size in insect dim-light vision.




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    Responses of activity rhythms to temperature cues evolve in Drosophila populations selected for divergent timing of eclosion [RESEARCH ARTICLE]

    Lakshman Abhilash, Arshad Kalliyil, and Vasu Sheeba

    Even though the rhythm in adult emergence and rhythm in locomotor activity are two different rhythmic phenomena that occur at distinct life-stages of the fly life cycle, previous studies have hinted at similarities in certain aspects of the organisation of the circadian clock driving these two rhythms. For instance, the period gene plays an important regulatory role in both rhythms. In an earlier study, we have shown that selection on timing of adult emergence behaviour in populations of Drosophila melanogaster leads to the co-evolution of temperature sensitivity of circadian clocks driving eclosion. In this study, we were interested in asking if temperature sensitivity of the locomotor activity rhythm has evolved in our populations with divergent timing of adult emergence rhythm, with the goal of understanding the extent of similarity (or lack of it) in circadian organisation between the two rhythms. We found that in response to simulated jetlag with temperature cycles, late chronotypes (populations selected for predominant emergence during dusk) indeed re-entrain faster than early chronotypes (populations selected for predominant emergence during dawn) to 6-h phase-delays, thereby indicating enhanced sensitivity of the activity/rest clock to temperature cues in these stocks (entrainment is the synchronisation of internal rhythms to cyclic environmental time-cues). Additionally, we found that late chronotypes show higher plasticity of phases across regimes, day-to-day stability in phases and amplitude of entrainment, all indicative of enhanced temperature sensitive activity/rest rhythms. Our results highlight remarkably similar organisation principles between emergence and activity/rest rhythms.




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    Finding Best PEEP: A Little at a Time