bluuebunny/crossref_metadata_2025 huggingface dataset:
De Novo Long-Read Genome Assembly and Annotation of the Luna Moth (Actias luna) Fully Resolves Repeat-Rich Silk Genes
Authors: Markee Amanda , Godfrey Rebekah Keating , Frandsen Paul B , Weng Yi-Ming , Triant Deborah A , Kawahara Akito Y
Published: July 2024

We present the first long-read de novo assembly and annotation of the luna moth (Actias luna) and provide the full characterization of heavy chain fibroin (h-fibroin), a long and highly repetitive gene (>20 kb) essential in silk fiber production. There are >160,000 described species of moths and butterflies (Lepidoptera), but only within the last 5 years have we begun to recover high-quality annotated whole genomes across the order that capture h-fibroin. Using PacBio HiFi reads, we produce the first high-quality long-read reference genome for this species. The assembled genome has a length of 532 Mb, a contig N50 of 16.8 Mb, an L50 of 14 contigs, and 99.4% completeness (BUSCO). Our annotation using Bombyx mori protein and A. luna RNAseq evidence captured a total of 20,866 genes at 98.9% completeness with 10,267 functionally annotated proteins and a full-length h-fibroin annotation of 2,679 amino acid residues.
Comparing Unmet Service Needs Between Rural and Urban Family Caregivers of People Living With Alzheimer’s Disease and Related Dementias: A Multisite Study
Authors: Miyawaki Christina E , McClellan Angela , Russell David , Bouldin Erin D
Published: July 2024

Background and Objectives

The scarcity of resources and available caregiving services in rural areas in the United States has been well documented. However, less research has compared unmet service needs between caregivers of people with Alzheimer’s disease and related dementias (ADRD) in rural versus urban areas.

Research Design and Methods

Using semistructured interviews guided by theories of health service use and dependent care, we interviewed 20 family caregivers residing in rural areas of Western North Carolina and 18 caregivers within the urban setting of Houston, Texas, and compared their unmet service needs and contextual factors that facilitate their service use.

Results

Thematic analyses revealed similar unmet service needs among rural and urban caregivers; however, the ways they approached and solved their challenges differed. Caregivers in rural areas wished for more information and caregiver support whereas urban caregivers looked for information they needed until they found the answers. Rural caregivers expressed guilt about using services because they felt they were limited and zero-sum whereas urban caregivers shared available resources so that other caregivers could use them as well. Unmet service needs for urban caregivers included more racially and ethnically specific services for people with ADRD in their ethnic-specific languages and foods while rural caregivers’ cultural needs were not racially and ethnically specific but for more place-specific services.

Discussion and Implications

Recommendations for rural caregivers included utilizing online and virtual opportunities and expanding their reach across the United States. For urban caregivers, increasing culturally tailored service options would likely increase access and use.
A geometric integration approach to smooth optimization: foundations of the discrete gradient method
Authors: Ehrhardt Matthias J , Riis Erlend S , Ringholm Torbjørn , Schönlieb Carola-Bibiane
Published: July 2024

Discrete gradient methods are geometric integration techniques that can preserve the dissipative structure of gradient flows. Due to the monotonic decay of the function values, they are well suited for general convex and nonconvex optimization problems. Both zero- and first-order algorithms can be derived from the discrete gradient method by selecting different discrete gradients. In this paper, we present a thorough analysis of the discrete gradient method for optimization that provides a solid theoretical foundation. We show that the discrete gradient method is well-posed by proving the existence of iterates for any positive time step, as well as uniqueness in some cases, and propose an efficient method for solving the associated discrete gradient equation. Moreover, we establish an $\text{O}(1/k)$ convergence rate for convex objectives and prove linear convergence if instead the Polyak–Łojasiewicz inequality is satisfied. The analysis is carried out for three discrete gradients—the Gonzalez discrete gradient, the mean value discrete gradient, and the Itoh–Abe discrete gradient—as well as for a randomised Itoh–Abe method. Our theoretical results are illustrated with a variety of numerical experiments, and we furthermore demonstrate that the methods are robust with respect to stiffness.
LncRNA PCAT6 promotes the occurrence of laryngeal squamous cell carcinoma via modulation of the miR-4731-5p/NOTCH3 axis
Authors: Bai Jianye , Yao Fen , Fu Yeyun , Kang Ningxin , Wen Guohua
Published: July 2024

Laryngeal squamous cell carcinoma (LSCC) is one of the most aggressive cancers that affect the head and neck region. Recent researches have confirmed that long non-coding RNAs (lncRNAs) present an emerging role in diversiform diseases including cancers. Prostate cancer-associated ncRNA transcript 6 (PCAT6) is an oncogene in lung cancer, cervical cancer, colon cancer and gastric cancer, but its role in LSCC is still unknown. In the current study, we attempted to figure out the role of PCAT6 in LSCC. RT-qPCR was to analyze PCAT6 expression in LSCC cells. Functional assays were to uncover the role of PCAT6 in LSCC. Mechanism assays were to explore the regulatory mechanism behind PCAT6 in LSCC. PCAT6 exhibited higher expression in LSCC cells and PCAT6 strengthened cell proliferation and inhibited cell apoptosis. Furthermore, lncRNA PCAT6 modulated notch receptor 3 expression and activated NOTCH signaling pathway via serving as a sponge for miR-4731-5p. Taken together, lncRNA PCAT6 was identified as an oncogene in LSCC, which revealed that PCAT6 might be used as potential therapeutic target for LSCC.
Comprehensive study on pharmacognostic, pharmacological, and toxicological features of Ficus racemosa in Alzheimer’s disease using GC–MS and molecular docking analyses
Authors: Rani Anu , Sharma Pritam Babu , Bhatia Saurabh , Sharma Arun K
Published: July 2024

Background

Alzheimer's disease (AD) presents as a widespread neurodegenerative condition impacting over 55 million individuals globally, with an annual rise of 10 million new cases. Despite its staggering prevalence, the absence of a definitive cure establishes the need for a revisit.

Methods

We explore the alternative strategies, focusing on the potential therapeutic efficacy of ethanolic extracts derived from the fruit and leaf of Ficus racemosa Linn.

Results

The investigation comprehensively explores pharmacognostic, phytochemical, toxicological, and pharmacological characteristics. In addition to pharmacognostic and physicochemical analyses, toxicological evaluations conducted on experimental animals demonstrated the innocuous nature of the ethanolic extracts (from both fruit and leaf) of F. racemosa, as evidenced by assessments of hemocompatibility, oxidative parameters, and vital organ histology. Phytochemical profiling via GC-MS identified 48 and 80 phytoconstituents in the fruit and leaf extracts, respectively. These constituents were screened for bioactive potential using the “Lipinski Rule of Five,” resulting in the selection of 25 and 33 constituents from fruit and leaf extracts, respectively. Subsequent molecular docking studies against the AChE enzyme revealed promising interactions of the selected phytoconstituents. Furthermore, the top-scoring phytoconstituents were subjected to in silico screening to assess their interactions with β- and γ-secretase enzymes, in addition to the AChE enzyme. The cumulative findings substantiate the therapeutic utility of the plant extracts, particularly in the context of AD.

Conclusion

In conclusion, our investigation highlights the promising therapeutic potential of selected phytoconstituents derived from ethanolic extracts of F. racemosa in mitigating AD pathology by targeting key enzyme sites such as AChE, β-, and γ-secretase.
Diversification over deep and shallow temporal scales in the Holarctic genus Perpolita (Gastropoda: Gastrodontidae)
Authors: Saito Takumi , Nekola Jeffrey C , Nováková Markéta , Líznarová Eva , Hirano Takahiro , Horsáková Veronika , Horsák Michal
Published: July 2024

The Holarctic land snail genus Perpolita was used to explore the influence of past and current biogeography on diversification. The number of empirically-supported species was determined using a consensus between mtDNA sequence, nDNA sequence, conchology, and geographic and ecological range with five valid temperate-boreal species (Perpolita binneyana, Perpolita electrina, Perpolita hammonis, Perpolita petronella, and Perpolita radiatella) being recognized. Only P. petronella was unchanged in both nomenclature and diagnostic characteristics with the remainder requiring alterations. Perhaps the most important of these was elevation of P. radiatella to a valid species, with its populations having been previously lumped either under European P. hammonis or North American P. electrina. Divergence times of 18.7–10.0 Mya were suggested through genome-wide SNPs in combination with the fossil record, indicating a pre-Pleistocene origin for all Perpolita species. Using genetically-confirmed diagnostic shell characters, we accumulated > 2000 valid occurrences and used these to estimate appropriate modern and Last Glacial Maximum climate extents for all species. These models suggest that modern intra-specific gene pool diversity may generally reflect Pleistocene palaeoclimatology.
What Are We Teaching Medical Students and Physician Learners About the Social Determinants of Health? A Scoping Review
Authors: Solomon Loel S. , Nocon Robert S. , Jimenez Jazmin , Johnson Robert E. , Lupi Carla , Xu Jacqueline , Doobay-Persaud Ashti A. , Gallegos Abraham , Cohen Caleb
Published: July 2024

Purpose

Curricula about social determinants (drivers) of health (SDOH) are becoming more common in medical education, reflecting increasing expectations from payers and accreditors that health care systems do more to address health-related social needs and close pervasive health equity gaps. Few previous reviews have addressed the content of SDOH-related curricula. This review examines the scope and focus of medical education on SDOH and adjacent concepts.

Method

The authors screened 2,442 articles describing curricula delivered in undergraduate, graduate, and continuing medical education settings between 2010 and 2023 using PubMed and 2 field-specific databases, yielding 289 articles. Data on course duration, pedagogic approach, assessment methods, and curricular content were extracted and analyzed. Curricular content was categorized using the National Academies of Science, Engineering, and Medicine’s (NASEM’s) 5As framework, which recommends 5 key activities health care can undertake to mitigate social risk (awareness, adjustment, assistance, alignment, and advocacy).

Results

A total of 289 articles were included in this review. Curricula covering SDOH-related concepts have increased over time. Of the included articles, 190 (65.7%) referenced at least 1 of NASEM’s 5 key activities. Training on social risk screening and other awareness activities were noted most frequently [123 (42.6%)], followed by curricula on helping patients get social care [assistance; 86 (29.8%)] and providing social risk-adjusted health care [adjustment; 81 (28.0%)]. Curricula on system- and policy-level activities, including alignment of health care and social care organizations (alignment), and advocacy (advocacy) were described less frequently [43 (14.9%) and 49 (17.0%), respectively]. Ninety-four articles (32.5%) referenced only general information about SDOH without describing specific actions to adjust care or reduce social adversity.

Conclusions

NASEM’s 5As framework provides a useful construct for characterizing SDOH-related curricula. Medical educators should teach not only the prevalence and pathophysiology of SDOH but also what physicians can do to address these factors.
Risk Factors of Failed Conservative Treatment for Adjacent Vertebral Fractures Following Percutaneous Vertebroplasty
Authors: Huang Po-Hao , Chen Chih-Wei , Hu Ming-Hsiao , Yang Shu-Hua , Huang Chuan-Ching
Published: July 2024

Study Design.

A retrospective, single-center, observational study.

Objective.

This study investigated the risk factors associated with the failure of conservative treatment for adjacent vertebral fractures (AVFs).

Summary of Background Data.

Adjacent vertebral fractures following vertebroplasty for osteoporotic vertebral compression fractures are not uncommon. Presently, there is a lack of consensus regarding the management of adjacent vertebral fractures.

Methods.

We included patients who developed adjacent vertebral fractures within 2 years post single-level vertebroplasty between January 2013 and December 2020. All patients initially underwent 6 weeks of conservative treatment, including pain medications, bracing, and physical therapy. Surgical intervention was offered to those with intractable back pain due to AVFs. Baseline demographics, AVF characteristics, and radiologic measurements were systematically collected, and sequential univariable and multivariable logistic regression analyses were conducted to explore the risk factors.

Results.

Of the 114 patients with a mean age of 78.6 years, 2-thirds (76 patients) tolerated conservative treatment well, whereas 38 required surgical interventions for adjacent vertebral fractures. Both groups demonstrated similar baseline demographics and radiologic parameters regarding AVFs (P>0.05). The multivariable logistic regression analyses revealed that the development of AVFs later than 6 months post-vertebroplasty and their caudal location to the index vertebroplasty were the independent risk factors of unsuccessful conservative treatment, with odds ratios of 3.57 (95% confidence interval [CI]: 1.14–11.1, P=0.029) and 2.50 (95% CI, 1.09–5.88, P=0.032), respectively.

Conclusion.

Adjacent vertebral fractures following percutaneous vertebroplasty generally have favorable outcomes under conservative treatment. However, the timing and the relative anatomical location of adjacent vertebral fractures are associated with treatment efficacy. Adjacent vertebral fractures occurring later than 6 months following the initial vertebroplasty or situated in the caudal location to the index vertebroplasty may exhibit reduced responsiveness to conservative treatment. These patients might benefit from a more aggressive therapeutic approach.

Level of Evidence.

3
Benefits and Harms of Procalcitonin- or C-Reactive Protein-Guided Antimicrobial Discontinuation in Critically Ill Adults With Sepsis: A Systematic Review and Network Meta-Analysis*
Authors: Kubo Kenji , Sakuraya Masaaki , Sugimoto Hiroshi , Takahashi Nozomi , Kano Ken-ichi , Yoshimura Jumpei , Egi Moritoki , Kondo Yutaka
Published: July 2024

OBJECTIVES:

In sepsis treatment, antibiotics are crucial, but overuse risks development of antibiotic resistance. Recent guidelines recommended the use of procalcitonin to guide antibiotic cessation, but solid evidence is insufficient. Recently, concerns were raised that this strategy would increase recurrence. Additionally, optimal protocol or difference from the commonly used C-reactive protein (CRP) are uncertain. We aimed to compare the effectiveness and safety of procalcitonin- or CRP-guided antibiotic cessation strategies with standard of care in sepsis.

DATA SOURCES:

A systematic search of PubMed, Embase, CENTRAL, Igaku Chuo Zasshi, ClinicalTrials.gov, and World Health Organization International Clinical Trials Platform.

STUDY SELECTION:

Randomized controlled trials involving adults with sepsis in intensive care.

DATA EXTRACTION:

A systematic review with network meta-analyses was performed. The Grading of Recommendations, Assessments, Developments, and Evaluation method was used to assess certainty.

DATA SYNTHESIS:

Eighteen studies involving 5023 participants were included. Procalcitonin-guided and CRP-guided strategies shortened antibiotic treatment (–1.89 days [95% CI, –2.30 to –1.47], –2.56 days [95% CI, –4.21 to –0.91]) with low- to moderate-certainty evidence. In procalcitonin-guided strategies, this benefit was consistent even in subsets with shorter baseline antimicrobial duration (7–10 d) or in Sepsis-3, and more pronounced in procalcitonin cutoff of “0.5 μg/L and 80% reduction.” No benefit was observed when monitoring frequency was less than half of the initial 10 days. Procalcitonin-guided strategies lowered mortality (–27 per 1000 participants [95% CI, –45 to –7]) and this was pronounced in Sepsis-3, but CRP-guided strategies led to no difference in mortality. Recurrence did not increase significantly with either strategy (very low to low certainty).

CONCLUSIONS:

In sepsis, procalcitonin- or CRP-guided antibiotic discontinuation strategies may be beneficial and safe. In particular, the usefulness of procalcitonin guidance for current Sepsis-3, where antimicrobials are used for more than 7 days, was supported. Well-designed studies are needed focusing on monitoring protocol and recurrence.
Campbell's 1953 Book on “Manic-Depressive Disease”
Authors: Kendler Kenneth S.
Published: July 2024

The DSM-III symptomatic criteria for major depression (MD) were derived from those proposed by Feighner and colleagues in 1972, which closely resembled those published by Cassidy in 1957. I here present a counter-factual history in which Feighner carefully read a key reference in Cassidy, a large 1953 follow-up study by Campbell of depressed patients with detailed tables of depressive signs and symptoms. In this alternative timeline, the Feighner criteria for MD were modified by Campbell's results, which then changed DSM-III and subsequent MD criteria sets. The historical pathway to the current DSM MD criteria was contingent on a range of historical events and could easily have been different. This story is not meant to criticize DSM MD criteria that perform well. Rather, it suggests that these criteria represent a useful but fallible set of symptoms/signs that index but do not constitute MD and therefore are not to be reified.
The Importance of Knowledge on Dementia Risk Factors in the General Public
Authors: Meng Xiangfei , Dong Yueyang , Gao Tianbao , Su Jianping , Zhao Yanjie , Zhu Xiangning , He Meng , Zhang Tingmeng , Sun Jiao
Published: July 2024

The purpose of this study was to determine the influence of knowledge and beliefs on beneficial behaviors and dementia risk scores. A online survey was conducted among Chinese community residents over 18 years old. Multivariate logistic regression was used to identify the impact of knowledge and beliefs on dementia risk scores and beneficial behaviors. The respondents were 760 adults (mean age = 47.6 years, 60.8% female). Knowledge and beliefs were associated with cognitive activities (knowledge, odds ratio [OR] = 1.04; beliefs, OR = 1.17) and dementia risk scores (knowledge, OR = 0.95; beliefs, OR = 0.82). Additionally, lower perceived susceptibility (OR = 1.68; 95% CI, 1.04 to 2.72) and higher perceived benefits (OR = 0.68; 95% CI, 0.57 to 0.80) were associated with lower dementia risk scores. Knowledge and beliefs can promote beneficial behaviors and reduce dementia risk. In particular, perceptions of dementia susceptibility and benefits should be enhanced, which will greatly reduce dementia risk in the general public.
Association between hip joint function and urinary incontinence for patients with end-stage hip osteoarthritis
Authors: Bai Daisuke , Tamai Katsuya , Motomura Kaho , Tokuda Mitsunori , Tanaka Yasuhito
Published: July 2024

Purpose:

This study aims to investigate the correlation between hip joint muscle strength and symptoms of urinary incontinence (UI) among patients with end-stage hip osteoarthritis (OA) before undergoing total hip arthroplasty (THA).

Materials and methods:

A total of 32 patients with end-stage hip OA, preparing for THA, were included in this research. We assessed hip muscle strength, including hip extension, hip adduction, and hip external rotation, along with the Japanese Orthopaedic Association hip score. Patients were categorized into either an incontinence or nonincontinence group based on results from the International Consultation on Incontinence Questionnaire-Short Form. Incontinence was indicated by a score of ≥1 for the question, “How often do you leak urine?”

Results:

Of the 32 patients, 16 (50%) in the pre-THA stage were identified with UI (incontinence group), whereas the remaining 16 (50%) patients showed no UI symptoms (nonincontinence group). Significantly better hip adduction muscle strength and Japanese Orthopaedic Association hip total score were shown in the nonincontinence group compared with the incontinence group (P < 0.05). Nevertheless, no substantial difference in muscle strength during hip extension or external rotation was detected between the 2 groups.

Conclusion:

This study revealed a connection between pelvic floor function and hip joint function. The findings suggest a potential association between the strength of the hip adductor muscle and UI symptoms. As a part of preparing patients with end-stage hip OA for THA, physical therapists should consider incorporating exercises to enhance hip adductor muscle strength, which could assist in identifying and addressing UI symptoms.
Genomic analysis of Oceanotoga teriensis strain UFV_LIMV02, a multidrug-resistant thermophilic bacterium isolated from an offshore oil reservoir
Authors: Santos Adriele Jéssica do Carmo , Dias Roberto Sousa , Silva Carlos Henrique Martins da , Vidigal Pedro Marcus Pereira , Sousa Maira Paula de , Silva Cynthia Canedo da , Paula Sergio Oliveira de
Published: July 2024

Bacteria of the species Oceanotoga teriensis belong to the Family Petrotogaceae, are Gram-negative bacilli, moderately thermophilic, and are included in the group of thiosulfate-reducing bacteria (TRB), being capable of significantly accelerating corrosion in metallic structures. However, no in-depth study on the genome, antibiotic resistance, and mobile elements has been carried out so far. In this work, the isolation, phenotypic and genotypic characterization of the multi-resistant O. teriensis UFV_LIMV02 strain was carried out, from water samples from an offshore oil extraction platform in Rio de Janeiro (Brazil). We determined that the isolate has a genome 2,812,778 bp in size, with 26% GC content, organized into 34 contigs. Genomic annotation using RAST revealed the presence of genes related to resistance to antibiotics and heavy metals. By evaluating the antimicrobial resistance of the isolate using the disk diffusion technique, resistance was verified for the classes of antibiotics, beta-lactams, fluoroquinolones, aminoglycosides, sulfonamides, lincosamides, and rifamycins, a total of 14 antibiotics. The search for genomic islands, prophages, and defense systems against phage infection revealed the presence of 5 genomic islands in its genome, containing genes related to resistance to heavy metals and antibiotics, most of which are efflux pumps and several transposases. No prophage was found in its genome, however, 9 different defense systems against phage infection were detected. When analyzing the CRISPR systems four CRISPR arrays, classified as types I-B and III-B, with 272 spacers, can provide the strain with immunity to different mobile genetic elements and bacteriophage infection. The results found in this study show that the isolate UFV_LIVM02 is an environmental bacterium, resistant to different classes of antibiotics and that the proteins encoded by the predicted genomic islands may be associated with the development of greater resistance to antibiotics and heavy metals. They provide evidence that environmental bacteria found in offshore oil exploration residues may pose a risk for the spread of ARGs. More comprehensive studies on the microbial community present in oil waste are needed to assess the risks of horizontal gene transfer.
Learning from imagined experiences via an endogenous prediction error
Authors: Dabas Aroma , Bruckner Rasmus , Schultz Heidrun , Benoit Roland G.
Published: July 2024

Experiences shape preferences. This is particularly the case when they deviate from our expectations and thus elicit prediction errors. Here we show that prediction errors do not only occur in response to actual events – they also arise endogenously in response to merely imagined events. Specifically, we show that people acquire a preference for acquaintances as they imagine interacting with them in unexpectedly pleasant situations. This learning can best be accounted for by a computational model that calculates prediction errors based on these rewarding experiences. Using functional MRI, we show that the prediction error is mediated via striatal activity. This activity, in turn, seems to update preferences about the individuals by updating their cortical representations. Our findings demonstrate that imaginings can violate our own expectations and thus drive endogenous learning by coopting a neural system that implements reinforcement learning. They reveal fundamental principles how we acquire knowledge devoid of actual experiences.
Multi-dimensional oscillatory activity of mouse GnRH neurons in vivo
Authors: Han Su Young , Yeo Shel-Hwa , Kim Jae-Chang , Zhou Ziyue , Herbison Allan E.
Published: July 2024

The gonadotropin-releasing hormone (GnRH) neurons represent the key output cells of the neural network controlling mammalian fertility. We used GCaMP fiber photometry to record the population activity of the GnRH neuron distal projections in the ventral arcuate nucleus where they merge before entering the median eminence to release GnRH into the portal vasculature. Recordings in freely behaving intact male and female mice revealed abrupt ∼8-min duration increases in activity that correlated perfectly with the appearance of a subsequent pulse of luteinizing hormone (LH). The GnRH neuron dendrons also exhibited a low level of unchanging clustered, rapidly fluctuating baseline activity in males and throughout the estrous cycle in females. In female mice, a gradual increase in basal activity that exhibited ∼80-min oscillations began in the afternoon of proestrus and lasted for 12 h. This was associated with the onset of the LH surge that ended several hours before the fall in GCaMP signal. Abrupt 8-min duration episodes of GCaMP activity continued to occur on top of the rising surge baseline before ceasing in estrus. These observations provide the first description of GnRH neuron activity in freely behaving animals. They demonstrate that three distinct patterns of oscillatory activity occur in GnRH neurons. These are comprised of low-level rapid baseline activity, abrupt 8-min duration oscillations that drive pulsatile gonadotropin secretion and, in females, a gradual and very prolonged oscillating increase in activity responsible for the preovulatory LH surge.
VICR: A Novel Software for Unbiased Video and Image Analysis in Scientific Research
Authors: Kihn Kyle , Thomas Clementine A.D. , Brelidze Tinatin I.
Published: July 2024

In scientific research, objectivity and unbiased data analysis is crucial for the validity and reproducibility of outcomes. This is particularly important for studies involving video or image categorization. A common approach of decreasing the bias is delegating data analysis to researchers unfamiliar with the experimental settings. However, this requires additional personnel and is prone to cognitive biases. Here we describe the Video & Image Cutter & Randomizer (VICR) software (https://github.com/kkihnphd/VICR), designed for unbiased analysis by segmenting and then randomizing videos or still images. VICR allows a single researcher to conduct and analyze studies in a blinded manner, eliminating the bias in analysis and streamlining the research process. We describe the features of the VICR software and demonstrate its capabilities using zebrafish behavior studies. To our knowledge, VICR is the only software for the randomization of video and image segments capable of eliminating bias in data analysis in a variety of research fields.
Gut-to-brain regulation ofDrosophilaaging through neuropeptide F, insulin and juvenile hormone
Authors: Chen Jiangtian , Nouzova Marcela , Noriega Fernando G. , Tatar Marc
Published: July 2024

Dietary restriction slows aging in many animals, while in some cases the sensory signals from diet alone are sufficient to retard or accelerate lifespan. The digestive tract is a candidate location to sense nutrients, where neuropeptides secreted by enteroendocrine cells (EEC) produce systemic signals in response to food. Here we measure howDrosophilaneuropeptide F (NPF) is secreted into adult circulation by enteroendocrine cells and find that specific enteroendocrine cells differentially respond to dietary sugar and yeast. Lifespan is increased when gut NPF is genetically depleted, and this manipulation is sufficient to blunt the longevity benefit conferred by dietary restriction. Depletion of NPF receptors at insulin producing neurons of the brain also increases lifespan, consistent with observations where loss of gut NPF decreases neuronal insulin secretion. The longevity conferred by repressing gut NPF and brain NPF receptors is reversed by treating adults with a juvenile hormone (JH) analog. JH is produced by the adultcorpora allata, and inhibition of the insulin receptor at this tissue decreases JH titer and extends lifespan, while this longevity is restored to wild type by treating adults with a JH analog. Overall, enteroendocrine cells of the gut modulate Drosophila aging through interorgan communication mediated by a gut- brain-corpora allataaxis, and insulin produced in the brain impacts lifespan through its control of JH titer. These data suggest that we should consider how human incretins and their analogs, which are used to treat obesity and diabetes, may impact aging.

Significance Statement

Neuropeptide F (NPF) produced in theDrosophilagut is an insulin-regulatory hormone (incretin) that is secreted into adult circulation in response to feeding and diet. Suppression of gut NPF extendsDrosophilalongevity, as does knockdown of Neuropeptide F receptors at the insulin-producing medial neurosecretory cells in the brain that control the titer of juvenile hormone. Gut hormones and brain insulin regulate lifespan because they control juvenile hormone titer, which itself is the master endocrine regulator ofDrosophilaaging. Gut NPF modulates Drosophila aging through the integration of nutrient sensing, insulin signaling and juvenile hormone. Given the role of incretin-mimetic drugs to treat diabetes and obesity, it may be time to consider how incretin analogs could impact human aging.
Impact of dosing schedules on performance of rotavirus vaccines in Ghana
Authors: Asare Ernest O. , Al-Mamun Mohammad A. , Armah George E. , Lopman Benjamin A. , Pitzer Virginia E.
Published: July 2024

Background

Available live-oral rotavirus vaccines are associated with low to moderate performance in low- and middle-income settings. There is limited evidence relating to how the vaccine dosing schedule might be adjusted to improve vaccine performance in these settings.

Methods

We used mathematical models fitted to rotavirus surveillance data for children <5 years of age from three different hospitals in Ghana (Korle-Bu Teaching Hospital in Accra, Komfo Anokye Teaching Hospital in Kumasi and War Memorial Hospital in Navrongo) to project the impact of rotavirus vaccination over a 10-year period (April 2012-March 2022). We quantified and compared the impact of the previous vaccination program in Ghana to the model-predicted impact for other vaccine dosing schedules across the three hospitals and the entire country, under different assumptions about vaccine protection. To project the rotavirus vaccine impact over Ghana, we sampled from the range of model parameters for Accra and Navrongo, assuming that these two settings represent the “extremes” of rotavirus epidemiology within Ghana.

Results

For the previously implemented 6/10-week monovalent Rotarix vaccine (RV1) schedule, the model-estimated average annual incidence of moderate-to-severe rotavirus-associated gastroenteritis (RVGE) ranged between 1,151 and 3,002 per 100,000 people per year over the 10-year period for the three sites. Compared to no vaccination, the model-estimated median percentage reductions in RVGE ranged from 28-85% and 12-71% among children <1 year and <5 years of age respectively, with the highest and lowest percentage reductions predicted using model parameters estimated for Accra and Navrongo, respectively. The median predicted reductions in RVGE for the whole country ranged from 57-66% and 35-45% among children <1 year and <5 years of age, respectively. The 1/6/10- and 6/10/14-week schedules provided the best and comparable reductions in RVGE compared to the original 6/10-week schedule, whereas there was no improvement in impact for the 10/14-week schedule.

Conclusions

We found that administering an additional dose of RV1 might be an effective strategy to improve rotavirus vaccine impact, particularly in settings with low vaccine effectiveness. The results could be extrapolated to other countries using a 2-dose vaccine schedule with low to moderate vaccine performance.
Crk mediates Csk-Hippo signaling independently of Yap tyrosine phosphorylation to induce cell extrusion
Authors: Hannan Abdul , Wang Qian , Wu Yihua , Makrides Neoklis , Qu Xiuxia , Mao Junhao , Que Jianwen , Cardoso Wellington , Zhang Xin
Published: July 2024

Src family kinases (SFKs), including Src, Fyn and Yes, play important roles in development and cancer. Despite being first discovered as theYes-associatedprotein, the regulation of Yap by SFKs remains poorly understood. Here, through single-cell analysis and genetic lineage tracing, we show that the pan-epithelial ablation of C-terminal Src kinase (Csk) in the lacrimal gland unleashes broad Src signaling but specifically causes extrusion and apoptosis of acinar progenitors at a time when they are shielded by myoepithelial cells from the basement membrane.Cskmutants can be phenocopied by constitutively activeYapand rescued by deletingYaporTaz, indicating a significant functional overlap between Src and Yap signaling. Although Src-induced tyrosine phosphorylation has long been believed to regulate Yap activity, we find that mutating these tyrosine residues in bothYapandTazfails to perturb mouse development or alleviate theCsklacrimal gland phenotype. In contrast, Yap loses Hippo signaling-dependent serine phosphorylation and translocates into the nucleus inCskmutants. Further chemical genetics studies demonstrate that acute inhibition of Csk enhances Crk/CrkL phosphorylation and Rac1 activity, whereas removingCrk/CrkLorRac1/Rap1ameliorates theCskmutant phenotype. These results show that Src controls Hippo-Yap signaling through the Crk/CrkL-Rac/Rap axis to promote cell extrusion.
B cell receptor dependent enhancement of dengue virus infection
Authors: Gebo Chad , Hardy Celine Suzanne Colombe , McElvany Benjamin D , Graham Nancy R , Lu Joseph , Moradpour Shima , Currier Jeffrey R , Friberg Heather , Gromowski Gregory D , Thomas Stephen J , Chan Gary J , Diehl Sean A , Waickman Adam Tully
Published: July 2024

Dengue virus (DENV) is the causative agent of dengue, a mosquito-borne disease that represents a significant and growing public health burden around the world. A unique pathophysiological feature of dengue is immune-mediated enhancement, wherein preexisting immunity elicited by a primary infection can enhance the severity of a subsequent infection by a heterologous DENV serotype. A leading mechanistic explanation for this phenomenon is antibody dependent enhancement (ADE), where sub-neutralizing concentrations of DENV-specific IgG antibodies facilitate entry of DENV into FcγR expressing cells such as monocytes, macrophages, and dendritic cells. Accordingly, this model posits that phagocytic mononuclear cells are the primary reservoir of DENV. However, analysis of samples from individuals experiencing acute DENV infection reveals that B cells are the largest reservoir of infected circulating cells, representing a disconnect in our understanding of immune-mediated DENV tropism. In this study, we demonstrate that the expression of a DENV-specific B cell receptor (BCR) renders cells highly susceptible to DENV infection, with the infection-enhancing activity of the membrane-restricted BCR correlating with the ADE potential of the IgG version of the antibody. In addition, we observed that the frequency of DENV-infectable B cells increases in previously flavivirus-naive volunteers after a primary DENV infection. These findings suggest that BCR-dependent infection of B cells is a novel mechanism immune-mediated enhancement of DENV-infection.
Upregulation of Inhibitor of DNA Binding 1 and 3 is Important for Efficient Thermogenic Response in Human Adipocytes
Authors: Arianti Rini , Vinnai Boglárka Ágnes , Alrifai Rahaf , Karadsheh Gyath , Al-Khafaji Yousif Qais , Póliska Szilárd , Győry Ferenc , Fésüs László , Kristóf Endre
Published: July 2024

Brown and beige adipocytes can be activated by β-adrenergic agonist via cAMP-dependent signaling. Performing RNA-sequencing analysis in human cervical area-derived adipocytes, we found that dibutyryl-cAMP, which can mimicin vivostimulation of browning and thermogenesis, enhanced the expression of browning and batokine genes and upregulated several signaling pathway genes linked to thermogenesis. We observed that the expression of ‘Inhibitor of DNA binding and cell differentiation’ (ID) 1 and particularly ID3 was strongly induced by the adrenergic stimulation. The degradation of ID1 and ID3 elicited by the ID antagonist AGX51 during thermogenic activation prevented the induction of proton leak respiration that reflects thermogenesis and abrogated cAMP analogue-stimulated upregulation of thermogenic genes and mitochondrial complex I, II, and IV subunits. The presented data suggests that ID proteins contribute to efficient thermogenic response of adipocytes during adrenergic stimulation.

Graphical abstract
Read Length Dominates Phylogenetic Placement Accuracy of Ancient DNA Reads
Authors: Bettisworth Ben , Psonis Nikolaos , Poulakakis Nikos , Pavlidis Pavlos , Stamatakis Alexandros
Published: July 2024

A common problem when analyzing ancient DNA (aDNA) data is to identify the species which corresponds to the recovered aDNA sequence(s). The standard approach is to deploy sequence similarity based tools such as BLAST. However, as aDNA reads may frequently either stem from unsampled taxa due to extinction, it is likely that there is no exact match in any database. As a consequence, these tools may not be able to accurately place such reads in a phylogenetic context. Phylogenetic placement is a technique where a read is placed onto a specific branch of a phylogenetic reference tree, which allows for a substantially finer resolution when identifying reads. Prior applications of phylogenetic placement has deployed only on data from extant sources. Therefore, it is unclear how the aDNA damage affects phylogenetic placement’s applicability to aDNA data. To investigate how aDNA damage affects placement accuracy, we re-implemented a statistical model of aDNA damage. We deploy this model, along with a modified version of the existing assessment pipeline PEWO, to 7 empirical datasets with 4 leading tools: APPLES, EPA-ng, pplacer, and RAPPAS. We explore the aDNA damage parameter space via a grid search in order to identify the aDNA damage factors that exhibit the largest impact on placement accuracy. We find that the frequency of DNA backbone nicks (and consequently read length) has the by far largest impact on aDNA read placement accuracy, and that other factors, such as misincorporations, have a negligible effect on overall placement accuracy.
Temporal changes in sleep parameters and body mass index after using the Pokémon Sleep app
Authors: Iwagami Masao , Seol Jaehoon , Yanagisawa Masashi
Published: July 2024

Pokémon Sleep is a new sleep-tracking game app released in July 2023. We examined whether sleep parameters would improve with the use of the Pokémon Sleep app, and whether participants’ improvement status was associated with changes in their body mass index (BMI). We analyzed data from 2,063 volunteer Japanese participants (mean age 38.3 ± 10.7 years, female 82.1%) who used both the Pokémon Sleep and Asken (a commonly-used app in Japan to record daily BMI) for ≥90 days. During the 90 days, improvement was seen in total sleep time (TST) for 44.8% of participants, sleep latency for 18.1%, and percentage of wakefulness after sleep onset for 24.4%. BMI tended to decrease faster in participants with improved TST and sleep latency. In conclusion, the Pokémon Sleep app can improve some sleep parameters, and by association, lead to improvement in BMI.
Can ChatGPT-4o really pass medical science exams? A pragmatic analysis using novel questions
Authors: Newton Philip M. , Summers Christopher J. , Zaheer Uzman , Xiromeriti Maira , Stokes Jemima R. , Bhangu Jaskaran Singh , Roome Elis G. , Roberts-Phillips Alanna , Mazaheri-Asadi Darius , Jones Cameron D. , Hughes Stuart , Gilbert Dominic , Jones Ewan , Essex Keioni , Ellis Emily C. , Davey Ross , Cox Adrienne A. , Bassett Jessica A.
Published: July 2024

ChatGPT apparently shows excellent performance on high level professional exams such as those involved in medical assessment and licensing. This has raised concerns that ChatGPT could be used for academic misconduct, especially in unproctored online exams. However, ChatGPT has also shown weaker performance on questions with pictures, and there have been concerns that ChatGPT’s performance may be artificially inflated by the public nature of the sample questions tested, meaning they likely formed part of the training materials for ChatGPT. This led to suggestions that cheating could be mitigated by using novel questions for every sitting of an exam and making extensive use of picture-based questions. These approaches remain untested.

Here we tested the performance of ChatGPT-4o on existing medical licensing exams in the UK and USA, and on novel questions based on those exams.

ChatGPT-4o scored 94% on the United Kingdom Medical Licensing Exam Applied Knowledge Test, and 89.9% on the United States Medical Licensing Exam Step 1. Performance was not diminished when the questions were rewritten into novel versions, or on completely novel questions which were not based on any existing questions. ChatGPT did show a slightly reduced performance on questions containing images, particularly when the answer options were added to an image as text labels.

These data demonstrate that the performance of ChatGPT continues to improve and that online unproctored exams are an invalid form of assessment of the foundational knowledge needed for higher order learning.
Integrator dynamics in the cortico-basal ganglia loop underlie flexible motor timing
Authors: Yang Zidan , Inagaki Miho , Gerfen Charles R. , Fontolan Lorenzo , Inagaki Hidehiko K.
Published: July 2024

Flexible control of motor timing is crucial for behavior. Before volitional movement begins, the frontal cortex and striatum exhibit ramping spiking activity, with variable ramp slopes anticipating movement onsets. This activity in the cortico-basal ganglia loop may function as an adjustable ‘timer,’ triggering actions at the desired timing. However, because the frontal cortex and striatum share similar ramping dynamics and are both necessary for timing behaviors, distinguishing their individual roles in this timer function remains challenging. To address this, we conducted perturbation experiments combined with multi-regional electrophysiology in mice performing a flexible lick-timing task. Following transient silencing of the frontal cortex, cortical and striatal activity swiftly returned to pre-silencing levels and resumed ramping, leading to a shift in lick timing close to the silencing duration. Conversely, briefly inhibiting the striatum caused a gradual decrease in ramping activity in both regions, with ramping resuming from post-inhibition levels, shifting lick timing beyond the inhibition duration. Thus, inhibiting the frontal cortex and striatum effectively paused and rewound the timer, respectively. These findings suggest the striatum is a part of the network that temporally integrates input from the frontal cortex and generates ramping activity that regulates motor timing.
Break-induced replication is activated to repair R-loop-associated double-strand breaks in SETX-deficient cells
Authors: Wu Tong , Li Youhang , Shi Linda Z. , Wu Xiaohua
Published: July 2024

The primary role of break-induced replication (BIR) is to repair single-ended double strand breaks (seDSBs) generated at broken replication forks and eroding telomeres. In this study, we demonstrated that when senataxin (SETX), an RNA/DNA helicase, is defective, hyperrecombination using the BIR mechanism is induced at R-loops/hybrids-accumulated double-ended DNA double strand breaks (deDSBs), suggesting a potential role of BIR in repair of R-loops/hybrids-associated deDSBs. Intriguingly, while loss of SETX initiates a non-canonical hyper end resection pathway requiring RAD52 and XPF, it also causes collisions of DNA repair synthesis with R-loops/hybrids, leading to ubiquitination of PCNA and recruitment of PIF1 to establish BIR at R-loops/hybrids-associated deDSBs. Strikingly, SETX-deficiency does not only induce hyper BIR but also leads to a drastic increase in template switching during BIR, uncovering an important mechanism causing genome instability through replicative chromosomal rearrangements due to SETX deficiency. Furthermore, SETX is synthetic lethal with PIF1, RAD52 and XPF. Collectively, our study sheds light on how R- loops/hybrids influence the utilization and fidelity of DSB repair pathways and offers new strategies for targeted treatment of SETX-deficient tumors.

Significance statement

R-loops are widespread, occupying 5-10 % of the human genome, and thus understanding the DSB repair mechanisms associated with R-loops is of great importance. Defect in senataxin (SETX), an RNA-DNA helicase, is associated with neurodegenerative disorders and tumorigenesis. Our study reveals that R-loop accumulation at DNA double strand breaks (DSBs) due to SETX deficiency triggers hyperrecombination through break-induced replication (BIR), accompanied by a drastic increase in template switching during BIR. This uncovers a significant source of replication-associated complex genome rearrangements (CGRs) linked to prevalent R-loops, providing new insights into cancer-associated genome instability. Furthermore, this work not only uncovers the repair mechanisms utilized at DSBs in the context of dynamic R-loop formation, but also opens new therapeutic opportunities for targeting SETX-deficient tumors.