bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Sales of Vaping Products and Cigarettes Associated With the New York State Flavored Vaping Product Sales Restriction
Authors: Brown Elizabeth M , Rogers Todd , Spinks James G , Gammon Doris , Nonnemaker James , Farrelly Matthew C
Published: September 2023

Introduction

New York (NY) implemented a statewide restriction on the retail sale of flavored vaping products to reduce availability of vaping products having youth-appealing flavors in 2020. We assessed the intended effects of the NY law on sales of flavored vaping products and explored whether policy implementation had unintended effects on consumer behavior by evaluating policy-associated changes in sales of combusted cigarettes, which could serve as more harmful substitute products for NY consumers of flavored vaping products.

Aims and Methods

We analyzed custom product-level weekly retail tobacco sales scanner data for NY and a comparison state (California [CA]) for convenience stores and other outlets from June 2018 through June 2021. We categorized flavor descriptors for vaping products as flavored or as tobacco or unflavored and categorized cigarettes as menthol or non-menthol. We used a difference-in-difference model to assess the effect of the sales restriction on unit sales of flavored and unflavored vaping products and menthol and non-menthol cigarettes in NY compared with CA.

Results

Following NY policy implementation, flavored and total vaping product sales decreased in NY relative to CA. Unflavored vaping product sales increased in NY, while menthol cigarette sales did not change significantly relative to CA sales.

Conclusions

The NY flavored vaping product policy was associated with fewer sales of flavored and total vaping products. The increase in sales of unflavored vaping products did not suggest complete substitution, and sales data suggest that consumers did not turn to cigarettes after flavored vaping products became unavailable.

Implications

This study provides evidence that NY’s flavored vaping product policy is associated with reduced flavored vaping product access and sales. Our analyses of potential unintended consequences indicate that some consumers switched from flavored to unflavored vaping products, but that cigarette sales did not change concurrent with the policy which means that decreased availability of flavored vaping products did not result in vapers switching to cigarettes. NY’s policy had its intended effect with limited unintended consequences.
Does Taxing Business Owners Affect Employees? Evidence From A Change in the Top Marginal Tax Rate
Authors: Risch Max
Published: September 2023

Debates about the taxation of business owners often center on the distributional effects of these taxes, particularly the degree to which they affect workers. Drawing on a new linked owner-firm-worker data set created from U.S. administrative tax records, I analyze how an increase in the top marginal tax rate faced by business owners affected the earnings of their employees. I use panel difference-in-differences methods to compare the earnings of workers in similar firms but whose owners were differentially exposed to the tax increase. I estimate that 11–18 cents per dollar of new business income tax liability was passed through to employee earnings. I find no change in employment in response to the tax increase. The responses were generally associated with lower earnings growth, not changes in workforce composition. The burden was not borne equally by all workers. Essentially all of the workers’ share of the burden was borne by those in the top 30% of the earnings distribution, highlighting that the ultimate distributional effects of the policy depend not only on the share of the burden borne by workers but on the shares borne by different types of workers. Furthermore, since the owners bore the majority of the burden, the policy resulted in a decrease in after-tax earnings inequality between top-bracket owners and lower-bracket workers. I discuss the implications of the findings for the mediating labor market mechanisms and for welfare analyses of income taxation using a marginal value of public funds framework.
Effects of endoplasmic reticulum stress on erectile function in rats with cavernous nerve injury
Authors: Guo Shanjie , Zhao Danfeng , Zang Zhenjie , Shao Dingchang , Zhang Keqin , Fu Qiang
Published: September 2023

Background

Erectile dysfunction (ED) occurs in an increasing number of patients after radical prostatectomy and cystectomy, and the phenotypic modulation of corpus cavernosum smooth muscle cells is closely related to ED.

Aim

To determine whether endoplasmic reticulum stress (ERS) is implicated in the phenotypic modulation of ED induced by bilateral cavernous nerve injury (BCNI).

Methods

In total, 36 Sprague-Dawley rats were randomly divided into 3 groups: sham, in which rats received sham surgery with bilateral cavernous nerve exposure plus phosphate-buffered saline; control, in which rats received BCNI plus phosphate-buffered saline; and experimental, in which rats received BCNI plus 4-phenylbutyric acid. Analysis of variance and a Bonferroni multiple-comparison test were utilized to evaluate differences among groups.

Outcomes

Erectile function, smooth muscle/collagen ratios, and the expression levels of phenotypic modulation and ERS were measured.

Results

Two ratios—maximum intracavernosal pressure/mean arterial pressure and smooth muscle/collagen—were decreased in the control group as compared with the sham group. In penile tissue, there was increased expression of GRP78 (78-kDa glucose-regulated protein), p-PERK/PERK (phosphorylated protein kinase R–like endoplasmic reticulum kinase/protein kinase R–like endoplasmic reticulum kinase), caspase 3, CHOP (C/EBP homologous protein), and OPN (osteopontin) but decreased expression of nNOS (neuronal nitric oxide synthase) and α-SMA (α–smooth muscle actin). As compared with the control group, erectile function was improved and pathologic changes were partially recovered in the experimental group.

Clinical Translation

The present study demonstrated that ERS is involved in ED caused by cavernous nerve injury, thereby providing a new target and theoretical basis for clinical treatment.

Strengths and Limitations

The present study demonstrated for the first time that ERS is related to ED caused by cavernous nerve injury. Inhibition of ERS reverses phenotypic modulation and improves erectile function in rats with BCNI. Additional in vitro studies should be performed to verify these conclusions and explore the specific mechanism of phenotypic modulation.

Conclusion

The present study demonstrated that inhibiting ERS reverses phenotypic modulation and enhances erectile function in rats with BCNI.
Establishing the acute physiological and sleep disruption characteristics of wind farm versus road traffic noise disturbances in sleep: a randomized controlled trial protocol
Authors: Micic Gorica , Zajamsek Branko , Lechat Bastien , Hansen Kristy , Scott Hannah , Toson Barbara , Liebich Tessa , Dunbar Claire , Nguyen Duc Phuc , Decup Felix , Vakulin Andrew , Lovato Nicole , Lack Leon , Hansen Colin , Bruck Dorothy , Chai-Coetzer Ching Li , Mercer Jeremy , Doolan Con , Catcheside Peter
Published: September 2023

Study Objectives

Despite the global expansion of wind farms, effects of wind farm noise (WFN) on sleep remain poorly understood. This protocol details a randomized controlled trial designed to compare the sleep disruption characteristics of WFN versus road traffic noise (RTN).

Methods

This study was a prospective, seven night within-subjects randomized controlled in-laboratory polysomnography-based trial. Four groups of adults were recruited from; <10 km away from a wind farm, including those with, and another group without, noise-related complaints; an urban RTN exposed group; and a group from a quiet rural area. Following an acclimation night, participants were exposed, in random order, to two separate nights with 20-s or 3-min duration WFN and RTN noise samples reproduced at multiple sound pressure levels during established sleep. Four other nights tested for continuous WFN exposure during wake and/or sleep on sleep outcomes.

Results

The primary analyses will assess changes in electroencephalography (EEG) assessed as micro-arousals (EEG shifts to faster frequencies lasting 3–15 s) and awakenings (>15 s events) from sleep by each noise type with acute (20-s) and more sustained (3-min) noise exposures. Secondary analyses will compare dose–response effects of sound pressure level and noise type on EEG K-complex probabilities and quantitative EEG measures, and cardiovascular activation responses. Group effects, self-reported noise sensitivity, and wake versus sleep noise exposure effects will also be examined.

Conclusions

This study will help to clarify if wind farm noise has different sleep disruption characteristics compared to road traffic noise.
Effects of reduced-protein diets with protease supplementation on growth, carcass yield, intestinal morphology, organ development, nutrient digestibility, and blood biochemical of broiler chickens
Authors: Song X , Anas M A , Kurniawati A , Hanim C , Muhlisin  , Aprianto M A , Madani A M A , Wang Q , Chen H
Published: September 2023

This study was conducted to evaluate growth performance, carcass yield, intestinal morphology, organ development, nutrient digestibility, and blood biochemical parameters of broiler fed 1% reduced-protein diets with /without protease supplementation. A total of 1120 one-day male broiler chickens with average initial body weight (BW), 46.45±0.49g, divided into 5 groups with 7 replications and 32 birds per replication. The treatment varied according to the protein and protease enzyme levels: positive control (PC), negative control (NC, PC with reduction of 1% protein), PC supplemented with 50g/t protease (PC+50), NC supplemented with 50g/t protease (NC+50), and NC supplemented with 100g/t protease (NC+100). The results showed that there was no significant effect of 1% reduced-protein diets, with or without protease on feed intake, final body weight (FBW), average daily gain (ADG), feed conversion ratio (FCR), and nutrient digestibility. The changes in dietary protein level and supplementation of protease did not affect carcass yield, but significantly affected abdominal fat content, PC+50 group had significantly lower abdominal fat content than NC based diet including NC, NC+50, NC+100. Reduced-protein with protease supplementation strongly affected organ weight, especially on day 21: the pancreas was heavier in PC and NC+50 group than other groups, spleen was heaver in NC group than in NC+100 group, thymus was heavier in NC+50 group than in PC, NC and NC+100 group, small intestine was heavier in NC+50 and NC+100 group than in PC group, and large intestine was also heavier in NC+50 group than in NC group. Villus height sampled at 35-day was significantly increased with protease supplement, and which was significantly higher in NC+100 group than NC group. Regarding on blood metabolites, only urea and uric acid were affected by the reduction of dietary protein, broiler fed PC diet had higher urea and uric acid content than fed NC diet. In conclusion, supplementation of 50g/t protease in 1% reduced-protein diets does not negatively affect on growth, nutrient digestibility, carcass yield, organ development and blood metabolites. Moreover, supplementation of protease in low-protein diet could effectively promote organ development and benefit intestine morphology.
Role of ferroptosis in fibrosis: From mechanism to potential therapy
Authors: Qiu Xuemeng , Bi Qing , Wu Jiyue , Sun Zejia , Wang Wei
Published: September 2023

Fibrosis, which is a manifestation of the physiological response to injury characterized by excessive accumulation of extracellular matrix components, is a ubiquitous outcome of the repair process. However, in cases of repetitive or severe injury, fibrosis may become dysregulated, leading to a pathological state and organ failure. In recent years, a novel form of regulated cell death, referred to as ferroptosis, has been identified as a possible contributor to fibrosis; it is characterized by iron-mediated lipid peroxidation. It has garnered attention due to the growing body of evidence linking ferroptosis and fibrogenesis, which is believed to be driven by underlying inflammation and immune responses. Despite the increasing interest in the relationship between ferroptosis and fibrosis, a comprehensive understanding of the precise role that ferroptosis plays in the formation of fibrotic tissue remains limited. This review seeks to synthesize previous research related to the topic. We categorized the different direct and indirect mechanisms by which ferroptosis may contribute to fibrosis into three categories: (1) iron overload toxicity; (2) ferroptosis-evoked necroinflammation, with a focus on ferroptosis and macrophage interplay; and (3) ferroptosis-associated pro-fibrotic factors and pathways. Furthermore, the review considers the potential implications of these findings and highlights the utilization of ferroptosis-targeted therapies as a promising strategy for mitigating the progression of fibrosis. In conclusion, novel anti-fibrotic treatments targeting ferroptosis could be an effective treatment for fibrosis.
Adapted Kaizen: Multi-Organizational Complex Process Redesign for Adapting Clinical Guidelines for the Digital Age
Authors: Michaels Maria , Hangsleben Mindy , Sherwood Amy , Skapik Julia , Larsen Kevin
Published: September 2023

The need for a method to examine complex, multidisciplinary processes involving many diverse organizations initially led multiple US federal agencies to adopt the traditional Kaizen, a Lean process improvement method typically used within a single organization, to encompass multiple organizations each with its own leadership and priorities. First, the Centers for Medicare and Medicaid Services and the Office of the National Coordinator for Health Information Technology adapted Kaizen to federal agency processes for the development of electronic clinical quality measures. Later, the Centers for Disease Control and Prevention (CDC) further modified this adapted Kaizen during its Adapting Clinical Guidelines for the Digital Age (ACG) initiative, which aimed to improve the broader scope of guideline development and implementation. This is a methods article to document the adapted Kaizen method for future use in similar complex processes, illustrating how to apply the adapted Kaizen through CDC’s ACG initiative and showing the reach achieved by using the adapted Kaizen method. The adapted Kaizen includes pre-Kaizen planning, a Kaizen event, and post-Kaizen implementation that accommodate multidisciplinary and multi-organizational participation. ACG included 5 workgroups that each developed products to support their respective scope: Guideline Creation, Informatics Framework, Translation and Implementation, Communication and Dissemination, and Evaluation. Despite challenges gathering diverse perspectives and balancing the competing priorities of multiple organizations, the ACG participants produced interrelated standards, processes, and tools—further described in separate publications—that programs and partners have leveraged. Use of a siloed approach may not have supported the development and dissemination of these products.
Correlation Among Workplace Burnout, Resilience, and Well-Being in Nursing Staff: A Cross-Sectional Study in Taiwan
Authors: TZENG Shau-Tion , SU Bei-Yi , CHEN Hsiao-Mei
Published: September 2023

Background

Because nurses often work in medical environments characterized by high workloads and high levels of stress and pressure, they are particularly vulnerable to workplace burnout and their well-being may suffer. Related studies on burnout, resilience, and well-being have focused primarily on teachers, social workers, and students, with few studies addressing the situation faced by nursing staff. It is important to understand the factors affecting the well-being of nursing staff.

Purpose

This study explores the status quo and correlations among nursing-staff demographic characteristics, workplace burnout, well-being-related resilience, and the predictive factors of well-being in nurses.

Methods

A cross-sectional, descriptive, correlational research design and purposive sampling were used in this study. Nursing staff who had worked for more than 6 months at a medical center in central Taiwan were recruited as participants, with data from 289 participants collected. A structured questionnaire was used to collect data on demographic characteristics, workplace burnout, resilience, and well-being.

Results

The average scores for workplace burnout, resilience, and well-being were 40.40/(0- to 100-point scale), 26.79/(10- to 50-point scale), and 43.25/(24- to 96-point scale), respectively. The result of the regression analysis explained about 51.6% of the variance in well-being. Furthermore, resilience (28.4%), self-perceived health (14.3%), workplace burnout (4.5%), exercise frequency (1.8%), job title (1.2%), interpersonal pressure relief resilience (0.9%), and marital status (0.5%) were other important predictive factors of well-being in the participants.

Conclusions/Implications for Practice

Medical institutions should provide appropriate resilience-enhancing countermeasures to reduce workplace burnout as well as pay greater attention to the exercise frequency, self-perceived health, job title, and marital status of their nurses to help them achieve physical, mental, and overall well-being.
Dermatologic care of patients with differences of sex development
Authors: Gold Sarah , Huang Christina , Radi Rakan , Gupta Pranav , Felner Eric I. , Haw Jeehea Sonya , Childress Krista , Sokkary Nancy , Tangpricha Vin , Goodman Michael , Yeung Howa
Published: September 2023

Background:

Differences of sex development (DSD or disorders of sex development) are uncommon congenital conditions, characterized by atypical development of chromosomal, gonadal, or anatomic sex.

Objective:

Dermatologic care is an important component of the multidisciplinary care needed for individuals with DSD. This article discusses the most common primary dermatologic manifestations of DSD in addition to the cutaneous manifestations of hormonal and surgical therapies in individuals with DSD.

Data sources:

Published articles including case series and case reports on PubMed.

Study selections:

Selection was conducted by examining existing literature with a team of multidisciplinary specialists.

Methods:

Narrative review.

Limitations:

This article was not conducted as a systematic review.

Results:

In Klinefelter syndrome, refractory leg ulcers and incontinentia pigmenti have been described. Turner syndrome is associated with lymphatic malformations, halo nevi, dermatitis, and psoriasis. Virilization can be seen in some forms of congenital adrenal hyperplasia, where acne and hirsutism are common.

Conclusion:

Dermatologists should consider teratogenic risk for treatments of skin conditions in DSD depending on pregnancy potential. Testosterone replacement, commonly used for Klinefelter syndrome, androgen insensitivity syndrome, 5-alpha reductase deficiency, gonadal dysgenesis, or ovotesticular DSD, may cause acne.
Uncoupled redox stress: how a temporal misalignment of redox-regulated processes and circadian rhythmicity exacerbates the stressed state
Authors: Clark Anna D. , Cumpstey Andrew F. , Santolini Jérôme , Jackson Alan A. , Feelisch Martin
Published: September 2023

Diurnal and seasonal rhythmicity, entrained by environmental and nutritional cues, is a vital part of all life on Earth operating at every level of organization; from individual cells, to multicellular organisms, whole ecosystems and societies. Redox processes are intrinsic to physiological function and circadian regulation, but how they are integrated with other regulatory processes at the whole-body level is poorly understood. Circadian misalignment triggered by a major stressor (e.g. viral infection with SARS-CoV-2) or recurring stressors of lesser magnitude such as shift work elicit a complex stress response that leads to desynchronization of metabolic processes. This in turn challenges the system's ability to achieve redox balance due to alterations in metabolic fluxes (redox rewiring). We infer that the emerging ‘alternative redox states' do not always revert readily to their evolved natural states; ‘Long COVID’ and other complex disorders of unknown aetiology are the clinical manifestations of such rearrangements. To better support and successfully manage bodily resilience to major stress and other redox challenges needs a clear perspective on the pattern of the hysteretic response for the interaction between the redox system and the circadian clock. Characterization of this system requires repeated (ideally continuous) recording of relevant clinical measures of the stress responses and whole-body redox state (temporal redox phenotyping). The human/animal body is a complex ‘system of systems’ with multi-level buffering capabilities, and it requires consideration of the wider dynamic context to identify a limited number of stress-markers suitable for routine clinical decision making. Systematically mapping the patterns and dynamics of redox biomarkers along the stressor/disease trajectory will provide an operational model of whole-body redox regulation/balance that can serve as basis for the identification of effective interventions which promote health by enhancing resilience.
Weld map tomography for determining local grain orientations from ultrasound
Authors: Kalkowski Michał K. , Lowe Michael J. S. , Samaitis Vykintas , Schreyer Fabian , Robert Sébastien
Published: September 2023

The complex structure of inhomogeneous welds poses a long-standing challenge in ultrasonic non-destructive testing. Elongated grains with spatially varying dominant orientations can distort and split the ultrasonic beam, hindering inspection data interpretation. One way to tackle this problem is to include material information in imaging and signal analysis; however, such information is often only gathered using destructive methods. This paper reports the development of a physics-based weld inversion strategy determining grain orientations using a ray tomography principle. The considered approach does not rely on a macroscopic weld description but may incorporate it to facilitate inversion. Hence, it is more general than other available approaches. The methodology is demonstrated in both numerical and experimental examples. The experimental work focuses on mock-up samples from the nuclear industry and a sample manufactured during this research. The ‘ground truth’ for the latter comes from an EBSD evaluation—the most accurate (yet destructive) examination technique available. Across the considered specimens, our methodology yielded orientation maps with average errors well below

20

∘

, leading to time-of-flight errors below

0.05

 

μ

s

. Applying the result from inversion to ultrasonic imaging offered between 5 and 14 dB signal-to-noise ratio improvement for defect signatures.
Can a border collision bifurcation of a chaotic attractor lead to its expansion?
Authors: Avrutin Viktor , Panchuk Anastasiia , Sushko Iryna
Published: September 2023

Recently, we reported that a chaotic attractor in a discontinuous one-dimensional map may undergo a so-called exterior border collision bifurcation, which causes additional bands of the attractor to appear. In the present paper, we suppose that the chaotic attractor’s basin boundary contains a chaotic repeller, and discuss a bifurcation pattern consisting of an exterior border collision bifurcation and an expansion bifurcation (interior crisis). In the generic case, where neither the border point the chaotic attractor collides with, nor any of its images belong to the chaotic repeller, the exterior border collision bifurcation is followed by the expansion bifurcation, and the distance between both bifurcations may be arbitrarily small but positive. In the non-generic (codimension-2) case, these bifurcations occur simultaneously, so that a border collision bifurcation of a chaotic attractor leads directly to its expansion.
Nonlinear realization approach to topologically massive supergravity
Authors: Kuzenko Sergei M. , Stirling Jake C.
Published: September 2023

We develop a nonlinear realization approach to topologically massive supergravity in three dimensions, with and without a cosmological term. It is a natural generalization of a similar construction for

N

=
1

supergravity in four dimensions, which was recently proposed by one of us. At the heart of both formulations is the nonlinear realization approach to gravity which was given by Volkov and Soroka 50 years ago in the context of spontaneously broken local supersymmetry. In our setting, the action for cosmological topologically massive supergravity is invariant under two different local supersymmetries. One of them acts on the Goldstino, while the other supersymmetry leaves the Goldstino invariant. The former can be used to gauge away the Goldstino, and then the resulting action coincides with that given in the literature.
DNA hypomethylation promotes the expression of CASPASE-4 which exacerbates neuroinflammation and amyloid-β deposition in Alzheimer’s disease The Ohio State University College of Medicine
Authors: Daily Kylene P. , Badr Asmaa , Eltobgy Mostafa , Estfanous Shady , Whitham Owen , Tan Michelle H. , Carafice Cierra , Krause Kathrin , McNamara Andrew , Hamilton Kaitlin , Houle Samuel , Gupta Spandan , Gupta Gauruv A. , Madhu Shruthi , Fitzgerald Julie , Saadey Abbey A. , Laster Brooke , Yan Pearlly , Webb Amy , Zhang Xiaoli , Pietrzak Maciej , Kokiko-Cochran Olga N. , Ghoneim Hazem E. , Amer Amal O.
Published: September 2023

Alzheimer’s Disease (AD) is the 6th leading cause of death in the US. It is established that neuroinflammation contributes to the synaptic loss, neuronal death, and symptomatic decline of AD patients. Accumulating evidence suggests a critical role for microglia, innate immune phagocytes of the brain. For instance, microglia release pro-inflammatory products such as IL-1β which is highly implicated in AD pathobiology. The mechanisms underlying the transition of microglia to proinflammatory promoters of AD remain largely unknown. To address this gap, we performed Reduced Representation Bisulfite Sequencing (RRBS) to profile global DNA methylation changes in human AD brains compared to no disease controls. We identified differential DNA methylation of CASPASE-4 (CASP4), which when expressed, can be involved in generation of IL-1β and is predominantly expressed in immune cells. DNA upstream of the CASP4 transcription start site was hypomethylated in human AD brains, which was correlated with increased expression of CASP4. Furthermore, microglia from a mouse model of AD (5xFAD) express increased levels of CASP4 compared to wild-type (WT) mice. To study the role of CASP4 in AD, we developed a novel mouse model of AD lacking the mouse ortholog of CASP4, CASP11, which is encoded by mouseCaspase-4(5xFAD/Casp4-/-). The expression of CASP11 was associated with increased accumulation of pathologic protein aggregate amyloid-β (Aβ) and increased microglial production of IL-1β in 5xFAD mice. Utilizing RNA sequencing, we determined that CASP11 promotes unique transcriptomic phenotypes in 5xFAD mouse brains, including alterations of neuroinflammatory and chemokine signaling pathways. Notably,in vitro, CASP11 promoted generation of IL-1β from macrophages in response to cytosolic Aβ through cleavage of downstream effector Gasdermin D (G SDMD). We describe a role for CASP11 and GSDMD in the generation of IL-1β in response to Aβ and the progression of pathologic inflammation in AD. Overall, our results demonstrate that overexpression of CASP4 due to differential methylation in AD microglia contributes to the progression of AD pathobiology, thus identifying CASP4 as a potential target for immunotherapies for the treatment of AD.
Natural genomic variation in rice blast genomes is associated with specific heterochromatin modifications
Authors: Rowe David , Huang Jun , Zhang Wei , Mishra Divya , Jordan Katherine , Valent Barbara , Liu Sanzhen , Cook David E.
Published: September 2023

Genome organization in eukaryotes exhibits non-random patterns tied to transcription, replication, and chromatin. However, the driving forces across these processes, and their impacts on genome evolution remain unclear. To address this, we analyzed sequence data from 86Magnaporthe oryzaeisolates, a globally important plant pathogenic fungus, alongside new reference genomes, to investigate DNA sequence variation and the epigenome. Histone modification profiles were obtained through genome-wide chromatin immunoprecipitation-sequencing of the four new reference strains, which revealed that repressive histone marks (H3K27me3, H3K9me3) were associated with SNP and INDEL frequency. Densely grouped SNPs were found to reside in heterochromatin, often outside transposable elements, highlighting the link between heterochromatin and DNA variation. Even when controlling for selection, silent SNP frequency/kb was higher in H3K27me3-associated genes. Effector genes, key to pathogenicity, also displayed this trend. Comparing the reference strains, euchromatic regions were often syntenic, while heterochromatic regions trended towards non-syntenic. Heterochromatin emerged as a major factor associated with diverse DNA variations inM. oryzaepopulations, even when accounting for selective pressure. This underscores heterochromatin’s pivotal role in shaping genetic diversity in these mainly asexually reproducing fungi.
Early life adversity has sex-dependent effects on survival across the lifespan in rhesus macaques
Authors: Patterson Sam K. , Andonov Ella , Arre Alyssa M. , Martínez Melween I. , Negron-Del Valle Josué E. , Petersen Rachel M. , Phillips Daniel , Rahman Ahaylee , Ruiz-Lambides Angelina , Villanueva Isabella , Lea Amanda J. , Snyder-Mackler Noah , Brent Lauren J.N. , Higham James P.
Published: September 2023

Exposure to adversity during early life is linked to lasting detrimental effects on evolutionary fitness across many taxa. However, due to the challenges of collecting longitudinal data, especially in species where one sex disperses, direct evidence from long-lived species remains relatively scarce. Here we test the effects of early life adversity on male and female longevity in a free-ranging population of rhesus macaques (Macaca mulatta) at Cayo Santiago, Puerto Rico. We leveraged six decades of data to quantify the relative importance of ten forms of early life adversity for 6,599 macaques (3,230 male, 3,369 female), with a smaller sample size (N=299) for one form of adversity (maternal social isolation) which required high-resolution behavioral data. We found that individuals who experienced more early life adversity died earlier than those who experienced less adversity. Mortality risk was highest during early life, defined as birth to four years old, suggesting acute survival effects of adversity, but heightened mortality risk was also present in macaques who survived to adulthood. Females and males were affected differently by some forms of adversity, and these differences might be driven by varying energetic demands, female philopatry, and male dispersal. By leveraging data on thousands of macaques collected over decades, our results show that the fitness consequences of early life adversity are not uniform across individuals but vary as a function of the type of adversity, timing, and social context, and thus contribute to our limited but growing understanding of the evolution of early life sensitivities in long-lived species.

Significance Statement

Exposure to early life adversity, even when conditions subsequently improve, can have profound and persistent consequences for human health. Negative effects of early life adversity appear widespread across the animal kingdom. To date, however, direct evidence from long-lived species is relatively scarce due to the difficulties of collecting data from early life till death. We leverage six decades of observations on thousands of free-ranging male and female rhesus macaques to examine the complex ways early life adversity impacts survival. Our results suggest that the type of adversity and life history factors intersect to impact immediate and downstream survival. By studying early life adversity across environments, cultures, contexts, and species, we can better understand the evolutionary underpinnings of early life sensitivities.
Sleep pressure modulates single-neuron synapse dynamics in zebrafish
Authors: Suppermpool Anya , Lyons Declan G. , Broom Elizabeth , Rihel Jason
Published: September 2023

Sleep is a nearly universal behaviour with unclear functions1. The Synaptic Homeostasis Hypothesis (SHY) proposes that sleep is required to renormalize the increases in synaptic number and strength that occur during wakefulness2. Some studies examining either large neuronal populations3or small patches of dendrites4have found evidence consistent with SHY, but whether sleep merely serves as a permissive state or actively promotes synaptic downregulation at the scale of whole neurons is unknown. Here, by repeatedly imaging all excitatory synapses on single neurons across sleep/wake states of zebrafish larvae, we show that synapses are gained during periods of wake (either spontaneous or forced) and lost during sleep in a neuron-subtype dependent manner. However, synapse loss is greatest during sleep associated with high sleep pressure following prolonged wakefulness and low in the latter half of the night. Conversely, sleep induced pharmacologically during periods of low sleep pressure is insufficient to trigger synapse loss unless adenosine levels are boosted while noradrenergic tone is inhibited. We conclude that sleep-dependent synapse loss is regulated by sleep pressure at the level of the single neuron and that not all sleep periods are equally capable of fulfilling the functions of synaptic homeostasis.
Heterotypic stressors unmask behavioral influences of PMAT deficiency in mice
Authors: Weber Brady L , Nicodemus Marissa M , Hite Allianna K , Spalding Isabella R , Beaver Jasmin N , Scrimshaw Lauren R , Kassis Sarah K , Reichert Julie M , Ford Matthew T , Russell Cameron N , Hallal Elayna M , Gilman T Lee
Published: September 2023

Certain life stressors having enduring physiological and behavioral consequences, in part by eliciting dramatic signaling shifts in monoamine neurotransmitters. High monoamine levels can overwhelm selective transporters like the serotonin transporter. This is when polyspecific transporters like plasma membrane monoamine transporter (PMAT, Slc29a4) are hypothesized to contribute most to monoaminergic signaling regulation. Here, we employed two distinct counterbalanced stressors – fear conditioning, and swim stress – in mice to systematically determine how reductions in PMAT function affect heterotypic stressor responsivity. We hypothesized male heterozygotes would exhibit augmented stressor responses relative to female heterozygotes. Decreased PMAT function enhanced context fear expression, an effect unexpectedly obscured by a sham stress condition. Impaired cued fear extinction retention and enhanced context fear expression in males were conversely unmasked by a sham swim condition. Abrogated corticosterone levels in male heterozygotes that underwent swim stress after context fear conditioning did not map on to any measured behaviors. In sum, male heterozygous mouse fear behaviors proved malleable in response to preceding stressor or sham stress exposure. Combined, these data indicate reduced male PMAT function elicits a form of stress-responsive plasticity. Future studies should assess how PMAT is differentially affected across sexes and identify downstream consequences of the stress-shifted corticosterone dynamics.
Exploring the Conformational Landscape of Cryo-EM Using Energy-Aware Pathfinding Algorithm
Authors: Lin Teng-Yu , Chung Szu-Chi
Published: September 2023

Cryo-electron microscopy (cryo-EM) is a powerful technique for studying macromolecules and holds the potential for identifying kinetically preferred transition sequences between conformational states. Typically, these sequences are explored within two-dimensional energy landscapes. However, due to the complexity of biomolecules, representing conformational changes in two dimensions can be challenging. Recent advancements in reconstruction models have successfully extracted structural heterogeneity from cryo-EM images using higher-dimension latent space. Nonetheless, creating high-dimensional conformational landscapes in the latent space and then searching for preferred paths continues to be a formidable task. This study introduces an innovative framework for identifying preferred trajectories within high-dimensional conformational landscapes. Our method encompasses the search for the shortest path in the graph, where edge weights are determined based on the energy estimation at each node using local density. The effectiveness of this approach is demonstrated by identifying accurate transition states in both synthetic and real-world datasets featuring continuous conformational changes.
HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells
Authors: Wu Hao , Zhao Xiufeng , Hochrein Sophia M. , Eckstein Miriam , Gubert Gabriela F. , Knöpper Konrad , Mansilla Ana Maria , Öner Arman , Doucet-Ladevèze Remi , Schmitz Werner , Ghesquière Bart , Theurich Sebastian , Dudek Jan , Gasteiger Georg , Zernecke-Madsen Alma , Kobold Sebastian , Kastenmüller Wolfgang , Vaeth Martin
Published: September 2023

Functional exhaustion of T cells in cancer and persistent infections is characterized by the upregulation of inhibitory receptors, the progressive decline in cytokine secretion and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex) with phenotypic features of memory T cells and a stem-like capacity to self-renew. However, the metabolic principles of Tpex maintenance and the regulatory circuits that control the exhaustion of their progeny remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics and metabolomic analyses, we here show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the T cell exhaustion program. At the molecular level, we found that diminished mitochondrial respiration and metabolic remodeling cause oxidative stress, which inhibits the proteasomal degradation ofhypoxia inducible factor 1 alpha(HIF-1α) in Tpex cells. HIF-1α mediates the transcriptional-glycolytic reprogramming of Tpex cells as an initial step towards terminal differentiation and functional exhaustion. Finally, we show that enhancing respiration by limiting the glycolytic activity of CAR T cells is a feasible metabolic intervention strategy to preserve the stemness of Tpex cells during chronic viral infection and cancer immunotherapy.
Belt and braces: two escape ways to maintain the cassette reservoir of large chromosomal integrons
Authors: Richard Egill , Darracq Baptiste , Littner Eloi , Millot Gael , Conte Valentin , Cokelaer Thomas , Engelstädter Jan , Rocha Eduardo P.C. , Mazel Didier , Loot Céline
Published: September 2023

Integrons are adaptive devices that capture, stockpile, shuffle and express gene cassettes thereby sampling combinatorial phenotypic diversity. Some integrons called sedentary chromosomal integrons (SCIs) can be massive structures containing hundreds of cassettes. Since most of these cassettes are non-expressed, it is not clear how they remain stable over long evolutionary timescales. Recently, it was found that the experimental inversion of the SCI ofVibrio choleraeled to a dramatic increase of the cassette excision rate associated to a fitness defect. Here, we question the evolutionary sustainability of this apparently counter selected genetic context through experimental evolution. We find that the integrase is rapidly inactivated and that the inverted SCI can recover its original orientation by homologous recombination between two insertion sequences (ISs) present in the array. These two outcomes of SCI inversion restore the normal growth and prevent the loss of cassettes, enabling SCIs to retain their roles as reservoirs of functions. These results illustrate an interesting interplay between gene orientation, genome rearrangement, bacterial fitness and demonstrate how integrons can benefit from their embedded ISs.
Identification and copy number variant analysis of enhancer regions of genes causing spinocerebellar ataxia
Authors: Ghorbani Fatemeh , de Boer Eddy N. , Fokkens Michiel R. , de Boer-Bergsma Jelkje , Verschuuren-Bemelmans Corien C. , Wierenga Elles , Kasaei Hamidreza , Noordermeer Daan , Verbeek Dineke S. , Westers Helga , van Diemen Cleo C.
Published: September 2023

Currently, routine diagnostics for spinocerebellar ataxia (SCA) consist of analyses that look for polyQ repeat expansions and conventional variations affecting the proteins encoded by known SCA genes. Despite all the effort, ∼40% of the patients still remain without a genetic diagnosis after routine tests. Increasing evidence suggests that variations in the enhancer regions of genes involved in neurodegenerative disorders can also be disease-causing. Since the enhancers of SCA genes are not yet known, it remains to be determined whether variations in these regions are a cause of SCA. In this pilot project, we aimed to identify the enhancers of the SCA genesATXN1, ATXN3, TBPandITPR1in human cerebellum using 4C-seq experiments, publicly available datasets, reciprocal 4C-seq and luciferase assays. We then screened these enhancers for copy number variants (CNVs) in a cohort of genetically undiagnosed SCA patients. We identified two active enhancers for each of the four SCA genes in human cerebellar tissue. In addition, forTBPandITPR1, we observed interactions between the putative enhancers of each gene. CNV analysis did not reveal any CNVs in the active enhancers of the four SCA genes in any of the genetically undiagnosed SCA patients. However, in one patient, we noted a CNV deletion with unknown clinical significance near one of the active enhancers ofITPR1. These results not only reveal elements involved in regulation of SCA genes, they can also lead to the discovery of novel SCA-causing genetic variants. As enhancer variations are increasingly recognized to cause brain disorders, screening the enhancers ofATXN1, ATXN3, TBPandITPR1for variations other than CNVs and identifying and screening enhancers of other SCA genes might elucidate the genetic cause in genetically undiagnosed patients.
Profiling plasma extracellular vesicle-derived microRNAs for noninvasive diagnosis of alpha-1 antitrypsin deficiency associated liver disease
Authors: Oshins Regina , Huo Zhiguang , Poole Brittney , Clark Virginia , Zhou Huiping , West Jesse , Wheeler Matthew , Aghaee Mahya , He Mei , Brantly Mark , Khodayari Nazli
Published: September 2023

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease characterized by reduced circulating levels of alpha-1 antitrypsin (AAT) due to the retention of misfolded AAT in the hepatocytes. The toxic AAT aggregates in hepatocytes cause liver fibrosis, cirrhosis, and hepatocellular carcinoma. Most patients remain asymptomatic until the final stage in which liver transplantation becomes the only treatment. Timely diagnosis of AATD liver disease plays a critical role in intervention and finding curative solutions. Assessing the prevalence and severity of AATD liver disease remains challenging due to limitations in current methods. Liver biopsy, the gold standard for evaluating the hepatic AAT accumulation, the initiating stage for AATD liver disease, is hindered by invasiveness and sampling errors. To address these limitations, we conducted a study using unique and precious clinical samples. We analyzed plasma extracellular vesicle (EV) derived miRNAs and liver transcriptomes from AATD individuals to develop a sensitive and noninvasive diagnostic approach for AATD liver disease. In the testing stage of our study, we enrolled 17 AATD individuals with different stages of liver disease, as determined by liver biopsy, and 20 controls. We identified differential expression of 178 miRNAs within the AATD group compared to controls by miRNA sequencing. Among those miRNAs, we selected miR-223-3p, miR-23a-3p, miR-15b-5p, let-7a-5p, let-7f-5p, and miR-374a-5p for further validation in an independent cohort of 45 AATD individuals. Using a logistic model that combined three miRNAs, we achieved an AUC of 0.737 for detecting AATD liver disease. Adding a fourth miRNA into this model increased the AUC to 0.751. The changes in EV miRNAs are correlated to dysregulated expression of liver mRNAs in AATD individuals with different stages of liver disease. We propose that plasma-circulating EV exhibit distinct miRNAs in AATD individuals and could serve as clinically significant biomarkers for the early detection of AATD liver disease.
Detecting signals of critical transition in inclusive teaching in biology education: A computational text analysis ofCourseSource
Authors: Mangane Sokona , Zhao Yuhao , Eaton Carrie Diaz
Published: September 2023

We examine every Inclusive Teaching section in articles published by the journalCourseSource- undergraduate biology teaching materials and related essays - from 2014 to 2022 to understand the evolution of inclusive teaching ideas as expressed through language. We find a rapid shift in attention to inclusive teaching occurs between 2018 and 2019, marked by an increase in section length, increased use of inclusive teaching keywords, and an increase in complexity of ideas in the semantic network. This critical transition occurs before many of the recent events in 2020 which have renewed conversation on equity in education. Some effect is associated with Writing Workshop Faculty Mentoring Networks, which provide participants with authoring resources and support. However, this alone is not enough to explain the observed shift, suggesting that many other structures, conversations, and investments were already providing the fertile ground for educational equity in biology education.
Characterization of an EG.5.1 clinical isolatein vitroandin vivo
Authors: Uraki Ryuta , Kiso Maki , Iwatsuki-Horimoto Kiyoko , Yamayoshi Seiya , Ito Mutsumi , Chiba Shiho , Sakai-Tagawa Yuko , Imai Masaki , Kashima Yukie , Koga Michiko , Fuwa Noriko , Okumura Nobumasa , Hojo Masayuki , Iwamoto Noriko , Kato Hideaki , Nakajima Hideaki , Ohmagari Norio , Yotsuyanagi Hiroshi , Suzuki Yutaka , Kawaoka Yoshihiro
Published: September 2023

EG.5.1 is a subvariant of the SARS-CoV-2 Omicron XBB variant that is rapidly increasing in prevalence worldwide. EG.5.1 has additional substitutions in its spike protein (namely, Q52H and F456L) compared with XBB.1.5. However, the pathogenicity, transmissibility, and immune evasion properties of clinical isolates of EG.5.1 are largely unknown.

In this study, we used wild-type Syrian hamsters to investigate the replicative ability, pathogenicity, and transmissibility of a clinical EG.5.1 isolate. Our data show that there are no obvious differences in growth ability and pathogenicity between EG.5.1 and XBB.1.5, and both EG.5.1 and XBB.1.5 are attenuated compared to a Delta variant isolate.

We also found that EG.5.1 is transmitted more efficiently between hamsters compared with XBB.1.5. In addition, unlike XBB.1.5, we detected EG.5.1 virus in the lungs of four of six exposed hamsters, suggesting that the virus tropism of EG.5.1 is different from that of XBB.1.5 after airborne transmission.

Finally, we assessed the neutralizing ability of plasma from convalescent individuals and found that the neutralizing activity against EG.5.1 was slightly, but significantly, lower than that against XBB.1.5 or XBB.1.9.2. This suggests that EG.5.1 effectively evades humoral immunity and that the amino acid differences in the S protein of EG.5.1 compared with that of XBB.1.5 or XBB.1.9.2 (i.e., Q52H, R158G, and F456L) alter the antigenicity of EG.5.1.

Our data suggest that the increased transmissibility and altered antigenicity of EG.5.1 may be driving its increasing prevalence over XBB.1.5 in the human population.