bluuebunny/crossref_metadata_2025 huggingface dataset:
Gibberellin transport affects (lateral) root growth through HY5 during Far-Red light enrichment.
Authors: van Gelderen Kasper van , van der Velde Kyra , Kang Chia-Kai , Hollander Jessy , Petropoulos Orfeas , Akyuz Tugba , Pierik Ronald
Published: April 2023

Plants compete for light by growing taller than their nearest competitors. This is part of the shade avoidance syndrome and is a response to an increase of Far-Red light (FR) reflected from neighboring leaves. The root responds to this shoot-sensed FR cue by reducing lateral root emergence. It is well-established that the plant hormone Gibberellic Acid (GA) is involved in supplemental FR-induced shoot elongation. Although GA is also transported from shoot to root, its role in regulating lateral root growth is unclear. We show via GA manipulations, both chemical and genetic, that GA modulates the lateral root reduction induced by shoot-sensed FR enrichment. Using the FRET-based GA biosensor GPS1, we observed detailed GA changes in the root upon shoot exposure to FR enrichment and when GA was supplied to the shoot. Supplying GA to the shoot also mitigated the FR-enrichment root phenotype, indicating a functional link between GA and changes in root development in response to shoot-sensed FR. The regulatory role of GA in root growth appears to be partially dependent upon the role of ELONGATED HYPOCOTYL 5 (HY5), a light-responsive transcription factor that regulates root growth. Shoot-to-root transported GA4 led to an increase in HY5 protein levels in the lateral root primordia. HY5 then repressed auxin signaling to repress lateral root growth. Our data unveil a novel way in which hormone and light signaling coordinate development across spatial scales by adjusting (lateral) root growth from above-ground FR light signals.
Astrocyte-Derived Exosomes Regulate Sperm miR-34c Levels to Mediate the Transgenerational Effects of Paternal Chronic Social Instability Stress
Authors: Champroux Alexandre , Sadat-Shirazi Mitra , Chen Xuan , Hacker Jonathan , Yang Yongjie , Feig Larry A.
Published: April 2023

The effects of chronically stressing male mice can be transmitted across generations by stress-specific changes in their sperm miRNA content that induce stress-specific phenotypes in their offspring. But how each stress paradigm alters the levels of distinct sets of sperm miRNAs is not known. We showed previously that exposure of male mice to chronic social instability (CSI) stress results in elevated anxiety and reduced sociability specifically in their female offspring across multiple generations because it reduces miR-34c levels in sperm of stressed males and their unstressed male offspring. Here we describe evidence thatastrocyte-derivedexosomes (A-Exos) carrying miR-34c mediate how CSI stress has this transgenerational effect on sperm. We found that CSI stress decreases miR-34c carried by A-Exos in the prefrontal cortex and amygdala, as well as in the blood of males. Importantly, miR-34c A-Exos levels are also reduced in these tissues in their F1 male offspring, who despite not being exposed to stress exhibit reduced sperm miR-34c levels and transmit the same stress-associated traits to their male and female offspring. Furthermore, restoring A-Exos miR-34c content in the blood of CSI-stressed males by intravenous injection of miR-34c-containing A-Exos restores miR-34c levels in their sperm. These findings reveal an unexpected role for A-Exos in maintaining sperm miR-34c levels by a process that when suppressed by CSI stress mediates this example of transgenerational epigenetic inheritance.
CNC Knitting Micro-Resolution Mosquito Bite Blocking Textiles
Authors: Holt Bryan , Oswalt Kyle , England Alexa , Murphy Richard , Owens Isabella , Finney Micaela , Wong Natalie , Adhikari Sushil , McCann James , Beckmann John
Published: April 2023

Mosquitoes and other biting arthropods transmit diseases worldwide, causing over 700,000 deaths each year, and costing about 3 billion annually forAedesspecies alone. These insects also pose a significant threat to agricultural animals. While clothing could provide a simple solution to vector-borne diseases, modern textiles do not effectively block mosquito bites. To address this issue, we have designed three micro-resolution knitted structures, with five adjustable parameters, that can block bites. These designs were integrated into a computer numerical control knitting robot for mass production of bite-blocking garments with minimal human labor. We then quantified the comfort of blocking garments. Our knits enable individuals to protect themselves from insects amidst their day-to-day activities without impacting the environment.

One Sentence Summary

We create micro-resolution mosquito bite blocking knits produced by robotic manufacturing to protect humans against vector-borne disease.
Phylogeny, morphology, virulence, ecology, and host range ofOrdospora pajunii(Ordosporidae), a microsporidian symbiont ofDaphniaspp
Authors: Dziuba Marcin K. , McIntire Kristina M. , Seto Kensuke , Davenport Elizabeth S. , Rogalski Mary A. , Gowler Camden D. , Baird Emma , Vaandrager Megan , Huerta Cristian , Jaye Riley , Corcoran Fiona E. , Withrow Alicia , Ahrendt Steven , Salamov Asaf , Nolan Matt , Tejomurthula Sravanthi , Barry Kerrie , Grigoriev Igor V. , James Timothy Y. , Duffy Meghan A.
Published: April 2023

Impacts of microsporidia on host individuals are frequently subtle and can be context dependent. A key example of the latter comes from a recently discovered microsporidian symbiont ofDaphnia,the net impact of which was found to shift from negative to positive based on environmental context. Given this, we hypothesized low baseline virulence of the microsporidian; here, we investigated the impact of infection on hosts in controlled conditions and the absence of other stressors. We also investigated its phylogenetic position, ecology and host range. The genetic data indicates that the symbiont isOrdospora pajunii, a newly described microsporidian parasite ofDaphnia. We show thatO. pajuniiinfection damages the gut, causing infected epithelial cells to lose microvilli and then rupture. The prevalence of this microsporidian could be high (up to 100% in the lab and 77% of adults in the field). Its overall virulence was low in most cases, but some genotypes suffered reduced survival and/or reproduction. Susceptibility and virulence were strongly host-genotype dependent. We found that North AmericanO. pajuniiwere able to infect multipleDaphniaspecies, including the European speciesD. longispina, as well asCeriodaphnia spp. Given the low, often undetectable virulence of this microsporidian, and potentially far reaching consequences of infections for the host when interacting with other pathogens or food, thisDaphnia-O. pajuniisymbiosis emerges as a valuable system for studying the mechanisms of context-dependent shifts between mutualism and parasitism, as well as for understanding how symbionts might alter host interactions with resources.

Importance

The net outcome of symbiosis depends on the costs and benefits to each partner. Those can be context dependent, driving the potential for an interaction to change between parasitism and mutualism. Understanding the baseline fitness impact in an interaction can help us understand those shifts; for an organism that is generally parasitic, it should be easier for it to become a mutualist if its baseline virulence is relatively low. Recently, a microsporidian was found to become beneficial to itsDaphniahosts in certain ecological contexts, but little was known about the symbiont (including its species identity). Here, we identify it as the microsporidiumOrdospora pajunii. Despite the parasitic nature of microsporidia, we foundO. pajuniito be, at most, mildly virulent; this helps explain why it can shift towards mutualism in certain ecological contexts and helps establishO. pajuniiis a valuable model for investigating shifts along the mutualism-parasitism continuum.
Evaluating Large Language Models on Medical Evidence Summarization
Authors: Tang Liyan , Sun Zhaoyi , Idnay Betina , Nestor Jordan G , Soroush Ali , Elias Pierre A. , Xu Ziyang , Ding Ying , Durrett Greg , Rousseau Justin , Weng Chunhua , Peng Yifan
Published: April 2023

Recent advances in large language models (LLMs) have demonstrated remarkable successes in zero- and few-shot performance on various downstream tasks, paving the way for applications in high-stakes domains. In this study, we systematically examine the capabilities and limitations of LLMs, specifically GPT-3.5 and ChatGPT, in performing zero-shot medical evidence summarization across six clinical domains. We conduct both automatic and human evaluations, covering several dimensions of summary quality. Our study has demonstrated that automatic metrics often do not strongly correlate with the quality of summaries. Furthermore, informed by our human evaluations, we define a terminology of error types for medical evidence summarization. Our findings reveal that LLMs could be susceptible to generating factually inconsistent summaries and making overly convincing or uncertain statements, leading to potential harm due to misinformation. Moreover, we find that models struggle to identify the salient information and are more error-prone when summarizing over longer textual contexts.
ESCRT disruption provides evidence against signaling functions for synaptic exosomes
Authors: Dresselhaus Erica C , Harris Kathryn P , Blanchette Cassandra R R , Koles Kate , Del Signore Steven J , Pescosolido Matthew F , Ermanoska Biljana , Rozencwaig Mark , Soslowsky Rebecca C , Parisi Michael J , Stewart Bryan A , Mosca Timothy J , Rodal Avital Adah
Published: April 2023

Extracellular vesicles (EVs) are released by many cell types including neurons, carrying cargoes involved in signaling and disease. It is unclear whether EVs promote intercellular signaling or serve primarily to dispose of unwanted materials. We show that loss of multivesicular endosome-generating ESCRT (endosomal sorting complex required for transport) machinery disrupts release of EV cargoes from Drosophila motor neurons. Surprisingly, ESCRT depletion does not affect the signaling activities of the EV cargo Synaptotagmin-4 (Syt4) and disrupts only some signaling activities of the EV cargo Evenness Interrupted (Evi). Thus, these cargoes may not require intercellular transfer via EVs, and instead may be conventionally secreted or function cell autonomously in the neuron. We find that EVs are phagocytosed by glia and muscles, and that ESCRT disruption causes compensatory autophagy in presynaptic neurons, suggesting that EVs are one of several redundant mechanisms to remove cargoes from synapses. Our results suggest that synaptic EV release serves primarily as a proteostatic mechanism for certain cargoes.
CDK7 is a Novel Therapeutic Vulnerability in Fibrolamellar Carcinoma
Authors: Nukaya Manabu , Cafferty Crystal , Zahed Katerina , Yun Isabelle , Al-Adra David P. , Kazim Noor A. , Farghli Alaa R. , Chan Marina , Kratz Jeremy D. , Berres Mark E. , Yen Andrew , Gujral Taranjit S. , Sethupathy Praveen , Bradfield Christopher A. , Ronnekleiv-Kelly Sean M.
Published: April 2023

Fibrolamellar carcinoma (FLC) is a rare and lethal cancer that afflicts young individuals. The tumor arises in the background of a healthy liver, and patients typically present with advanced cancer at the time of diagnosis. Unfortunately, for these patients with advanced or recurrent cancer, no proven systemic therapies exist resulting in only 30-45% of patients surviving to 5 years. Investigations into the molecular underpinning of FLC have revealed a unique gene fusion between heat shock protein 40 (DNAJB1) and the catalytic subunit alpha of protein kinase A (PRKACA), leading to the formation of an oncoprotein (DNAJ-PKAc) that retains kinase activity and is a proven tumor-causing event in FLC. To uncover potential therapeutic targets, we engineered an FLC cell line by introducing theDNAJB1-PRKACAoncogene rearrangement into human hepatocellular cells using CRISPR/Cas9. We identified aberrant cell cycle progression, and follow-up molecular analysis revealed evidence of enhanced cyclin dependent kinase 7 (CDK7) activation in theDNAJB1-PRKACAexpressing FLC cells. These findings were confirmed in human samples of FLC. In turn, targeting CDK7 with selective inhibitors demonstrated efficacy in several patient-derived models of FLC, with minimal toxicity to normal liver. Collectively, this work uncovers a novel candidate therapeutic vulnerability in FLC.
Facilitators and Barriers for Telemedicine Systems in India from Multiple Stakeholder Perspectives and Settings
Authors: Venkataraman Aparna , Fatma Najiya , Edirippulige Sisira , Ramamohan Varun
Published: April 2023

Telemedicine is viewed as a crucial tool for addressing the challenges of limited medical resources at healthcare facilities. However, its adoption in healthcare is not entirely realised due to perceived barriers. This systematic review outlines the critical facilitators and barriers that influence the implementation of telemedicine in the Indian healthcare system, observed at the infrastructural, socio-cultural, regulatory and financial levels, from the perspectives of healthcare providers, patients, patient caregivers, society, health organisations and the government. This review complies with the current PRISMA-P protocol. 1200 peer-reviewed studies published from December 2016 to December 2021 in the PubMed, Cochrane, Scopus, Web of Science, CINAHL, MEDLINE and PsycInfo databases were considered for the title and abstract screening, after which 157 articles were chosen for the full-text review. In the end, 26 studies were selected for data synthesis. Data privacy and security concerns, doctor and patient resistance to information and communications technology (ICT), poor infrastructure, and lack of ICT training were considered significant barriers to implementing telemedicine. However, reduced healthcare delivery costs, improved patient access to healthcare in remote areas, and reduced patient waiting times all helped promote telemedicine implementation. The review outcomes also revealed that the barriers and facilitators at the regulatory and financial level largely influenced the adoption of telemedicine systems in India, with 59% (n=20) articles citing a reduction in healthcare delivery costs as the critical facilitator and 59% citing fear of violation of patient privacy and security as the significant barrier.
Temporally correlated active forces drive segregation and enhanced dynamics in chromosome polymers
Authors: Brahmachari Sumitabha , Markovich Tomer , MacKintosh Fred C. , Onuchic José N.
Published: April 2023

Understanding the mechanisms governing the structure and dynamics of flexible polymers like chromosomes, especially, the signatures of motor-driven active processes is of great interest in genome biology. We study chromosomes as a coarse-grained polymer model where microscopic motor activity is captured via an additive temporally persistent noise. The active steady state is characterized by two parameters: active force, controlling the persistent-noise amplitude, and correlation time, the decay time of active noise. We find that activity drives correlated motion over long distances and a regime of dynamic compaction into a globally collapsed entangled globule. Diminished topological constraints destabilize the entangled globule, and the active segments trapped in the globule move toward the periphery, resulting in an enriched active monomer density near the periphery. We also show that heterogeneous activity leads to the segregation of the highly dynamic species from the less dynamic one, suggesting a role of activity in chromosome compartmental segregation. Adding activity to experimental-data-derived structures, we find active loci may mechanically perturb and switch compartments established via epigenetics-driven passive self-association. The key distinguishing signatures of activity are enhanced apparent diffusivity, exploration of all the dynamic regimes (sub-diffusion, effective diffusion, and super-diffusion) at various lag times, and a broadened distribution of observables like the dynamic exponents.
Screening non-conventional yeasts for organic acid tolerance and engineeringPichia occidentalisfor production ofcis,cis-muconic acid
Authors: Pyne Michael E. , Bagley James A. , Narcross Lauren , Kevvai Kaspar , Exley Kealan , Davies Meghan , Wang Qingzhao , Whiteway Malcolm , Martin Vincent J.J.
Published: April 2023

Saccharomyces cerevisiae is a workhorse of industrial biotechnology owing to the organism’s prominence in alcohol fermentation and the suite of sophisticated genetic tools available to manipulate its metabolism. However, S. cerevisiae is not suited to overproduce many bulk bioproducts, as toxicity constrains production at high titers. Here we employ a high-throughput assay to screen 108 publicly accessible yeast strains for tolerance to 20 g L−1adipic acid (AA), a nylon precursor. We identify 15 tolerant yeasts and select Pichia occidentalis for production of cis,cis-muconic acid (CCM), a precursor to AA. By developing a genome editing toolkit for P. occidentalis, we demonstrate fed-batch production of CCM with a maximum titer (38.8 g L−1), yield (0.134 g g−1glucose) and productivity (0.511 g L−1h−1) that surpasses all metrics achieved using S. cerevisiae. This work brings us closer to the industrial bioproduction of AA and underscores the importance of host selection in bioprocessing.
Cortical cellular encoding of thermotactile integration
Authors: Schnepel Philipp , Paricio-Montesinos Ricardo , Ezquerra-Romano Ivan , Haggard Patrick , Poulet James FA
Published: April 2023

Recent evidence suggests that primary sensory cortical regions play a role in the integration of information from multiple sensory modalities. How primary cortical neurons integrate multisensory information is unclear, partly because multisensory interactions in the cortex are typically weak or modulatory. To address this question, we take advantage of the robust representation of thermal (cooling) and tactile stimuli in mouse forepaw primary somatosensory cortex (fS1). Using a thermotactile detection task, we show that the perception of threshold level cool or tactile information is enhanced when they are presented simultaneously compared to presentation alone. To investigate the cortical correlates of thermotactile integration, we performed in vivo extracellular recordings from fS1 during unimodal and bimodal stimulation of the forepaw. Unimodal stimulation evoked thermal- or tactile- specific excitatory and inhibitory responses of fS1 neurons. The most prominent features of bimodal, thermotactile stimulation are the recruitment of unimodally silent fS1 neurons, non-linear integration features and a change in the response dynamics to favor longer response durations. Together, we identify quantitative and qualitative changes in cortical encoding that may underlie the improvement in perception of multisensory, thermotactile surfaces during haptic exploration.
Early embryogenesis in CHDFIDD mouse model reveals facial clefts and altered craniofacial neurogenesis
Authors: Hampl M , Jandova N , Luskova D , Novakova M , Prochazka J , Kohoutek J , Buchtova M
Published: April 2023

Congenital heart defects, facial dysmorphism and intellectual development disorder (CHDFIDD) is associated with mutations inCDK13gene which encodes a transcription regulating Cyclin-dependent kinase 13 (CDK13). Here we analyzed early embryonic stages of CHDFIDD mouse models with hypomorphic mutation inCdk13gene with very similar phenotypic manifestations plus cleft lip/palate and knockout ofCdk13which exhibits robust phenotype with midfacial cleft.Cdk13is strongly expressed in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme.In vitro,CDK13 protein is located not only in nuclear region but also in the cellular protrusions in cultured mesenchymal cells and cells isolated from dorsal root ganglia. InCdk13-deficient embryos, we found hypoplastic branches of the trigeminal nerve including maxillary branch and additionally we detected significant gene expression changes of molecules involved in neurogenesis (Mef2c,Pou4f1,Sod1,Cdk5rap2,Nrcam) within the developing palatal shelves. Key palate-associated molecules (Msx1andMeis2) were downregulated during early craniofacial development in mutant embryos. These results demonstrate the role of CDK13 in regulation of facial morphogenesis and also growth of craniofacial peripheral nerves.
Alpha Synuclein Modulates Mitochondrial Ca2+Uptake from ER During Cell Stimulation and Under Stress Conditions
Authors: Ramezani Meraj , Wagenknecht-Wiesner Alice , Wang Tong , Holowka David A. , Eliezer David , Baird Barbara A.
Published: April 2023

Alpha synuclein (a-syn) is an intrinsically disordered protein prevalent in neurons, and aggregated forms are associated with synucleinopathies including Parkinson’ disease (PD). Despite the biomedical importance and extensive studies, the physiological role of a-syn and its participation in etiology of PD remain uncertain. We showed previously in model RBL cells that a-syn colocalizes with mitochondrial membranes, depending on formation of N-terminal helices and increasing with mitochondrial stress.1We have now characterized this colocalization and functional correlates in RBL, HEK293, and N2a cells. We find that expression of a-syn enhances stimulated mitochondrial uptake of Ca2+from the ER, depending on formation of its N-terminal helices but not on its disordered C-terminal tail. Our results are consistent with a-syn acting as a tether between mitochondria and ER, and we show increased contacts between these two organelles using structured illumination microscopy. We tested mitochondrial stress caused by toxins related to PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) and carbonyl cyanide m-chlorophenyl hydrazone (CCCP), and found that a-syn prevents recovery of stimulated mitochondrial Ca2+uptake. The C-terminal tail, and not N-terminal helices, is involved in this inhibitory activity, which is abrogated when phosphorylation site serine-129 is mutated (S129A). Correspondingly, we find that MPTP/MPP+ and CCCP stress is accompanied by both phosphorylation (pS129) and aggregation of a-syn. Overall, our results indicate that a-syn can participate as a tethering protein to modulate Ca2+flux between ER and mitochondria, with potential physiological significance. A-syn can also prevent cellular recovery from toxin-induced mitochondrial dysfunction, which may represent a pathological role of a-syn in the etiology of PD.
Stacked regressions and structured variance partitioning for interpretable brain maps
Authors: Lin Ruogu , Naselaris Thomas , Kay Kendrick , Wehbe Leila
Published: April 2023

Relating brain activity associated with a complex stimulus to different properties of that stimulus is a powerful approach for constructing functional brain maps. However, when stimuli are naturalistic, their properties are often correlated (e.g., visual and semantic features of natural images, or different layers of a convolutional neural network that are used as features of images). Correlated properties can act as confounders for each other and complicate the interpretability of brain maps, and can impact the robustness of statistical estimators. Here, we present an approach for brain mapping based on two proposed methods:stackingdifferent encoding models andstructured variance partitioning. Our stacking algorithm combines encoding models that each use as input a feature space that describes a different stimulus attribute. The algorithm learns to predict the activity of a voxel as a linear combination of the outputs of different encoding models. We show that the resulting combined model can predict held-out brain activity better or at least as well as the individual encoding models. Further, the weights of the linear combination are readily interpretable; they show the importance of each feature space for predicting a voxel. We then build on our stacking models to introduce structured variance partitioning, a new type of variance partitioning that takes into account the known relationships between features. Our approach constrains the size of the hypothesis space and allows us to ask targeted questions about the similarity between feature spaces and brain regions even in the presence of correlations between the feature spaces. We validate our approach in simulation, showcase its brain mapping potential on fMRI data, and release a Python package. Our methods can be useful for researchers interested in aligning brain activity with different layers of a neural network, or with other types of correlated feature spaces.
Force tuning explains changes in phasic dopamine signaling during stimulus-reward learning
Authors: Bakhurin Konstantin , Hughes Ryan N. , Jiang Qiaochu , Hossain Meghdoot , Gutkin Boris , Fallon Isabella P. , Yin Henry H.
Published: April 2023

According to a popular hypothesis, phasic dopamine (DA) activity encodes a reward prediction error (RPE) necessary for reinforcement learning. However, recent work showed that DA neurons are necessary for performance rather than learning. One limitation of previous work on phasic DA signaling and RPE is the limited behavioral measures. Here, we measured subtle force exertion while recording and manipulating DA activity in the ventral tegmental area (VTA) during stimulus-reward learning. We found two major populations of DA neurons that increased firing before forward and backward force exertion. Force tuning is the same regardless of learning, reward predictability, or outcome valence. Changes in the pattern of force exertion can explain results traditionally used to support the RPE hypothesis, such as modulation by reward magnitude, probability, and unpredicted reward delivery or omission. Thus VTA DA neurons are not used to signal RPE but to regulate force exertion during motivated behavior.
Codon affinity in mitochondrial DNA shapes evolutionary and somatic fitness
Authors: Lareau Caleb A. , Yin Yajie , Gutierrez Jacob C. , Dhindsa Ryan S. , Gribling-Burrer Anne-Sophie , Hsieh Yu-Hsin , Nitsch Lena , Buquicchio Frank A. , Abay Tsion , Zielinski Sebastian , Stickels Robert R. , Ulirsch Jacob C. , Yan Patrick , Wang Fangyi , Miao Zhuang , Sandor Katalin , Daniel Bence , Liu Vincent , Wang Quanli , Hu Fengyuan , Smith Katherine R. , Deevi Sri V.V. , Maschmeyer Patrick , Petrovski Slavé , Smyth Redmond P. , Greenleaf William J. , Kundaje Anshul , Munschauer Mathias , Ludwig Leif S. , Satpathy Ansuman T.
Published: April 2023

Summary Paragraph

Somatic variation contributes to biological heterogeneity by modulating cellular proclivity to differentiate, expand, adapt, or die. While large-scale sequencing efforts have revealed the foundational role of somatic variants to drive human tumor evolution, our understanding of the contribution of mutations to modulate cellular fitness in non-malignant contexts remains understudied. Here, we identify a mosaic synonymous variant (m.7076A>G) in the mitochondrial DNA (mtDNA) encoded cytochrome c-oxidase subunit 1 gene (MT-CO1, p.Gly391=), which was present at homoplasmy in 47% of immune cells from a healthy donor. Using single-cell multi-omics, we discover highly specific selection against the m.7076G mutant allele in the CD8+effector memory T cell compartmentin vivo, reminiscent of selection observed for pathogenic mtDNA alleles1, 2and indicative of lineage-specific metabolic requirements. While the wildtype m.7076A allele is translated via Watson-Crick-Franklin base-pairing, the anticodon diversity of the mitochondrial transfer RNA pool is limited, requiring wobble-dependent translation of the m.7076G mutant allele. Notably, mitochondrial ribosome profiling revealed altered codon-anticodon affinity at the wobble position as evidenced by stalled translation of the synonymous m.7076G mutant allele encoding for glycine. Generalizing this observation, we provide a new ontogeny of the 8,482 synonymous variants in the human mitochondrial genome that enables interpretation of functional mtDNA variation. Specifically, via inter- and intra-species evolutionary analyses, population-level complex trait associations, and the occurrence of germline and somatic mtDNA mutations from large-scale sequencing studies, we demonstrate that synonymous variation impacting codon:anticodon affinity is actively evolving across the entire mitochondrial genome and has broad functional and phenotypic effects. In summary, our results introduce a new ontogeny for mitochondrial genetic variation and support a model where organismal principles can be discerned from somatic evolution via single-cell genomics.
Rapid quantitative assessment of small molecule leakage from microdroplets by flow cytometry and improvement of fluorophore retention in biochemical assays
Authors: Zinchenko Anastasia , Devenish Sean R. A. , Hollfelder Florian
Published: April 2023

Microdroplets are compartments made in the laboratory that allow the miniaturisation of chemical and biological experiments to the femto- to picolitre scale, replacing the classical test tube with a droplet. Ideally containment of the contents of individual droplets would be perfect, but in reality this situation rarely occurs. Instead the leaking of molecules even from intact droplets presents a challenge to the success of miniaturisation and must be assessed on a case-by-case basis. We now present a new method for quantitative determination of leakage: a sheath fluid-free flow cytometer (Guava EasyCyte) is used to directly determine the fluorescence of water-in-oil droplets as a function of time. We validate this method by demonstrating that this assessment of leakage provides a framework for experimental improvements that reduce the leakage of two widely used fluorophores. A 40-fold better retention compared to current protocols is achieved for resorufin with an optimized mix (oil: FC-70, surfactant: 0.1% w/w AZ900C, additive: 1% BSA) to maintain useful retention for up to 130 hours. Likewise leakage of the fluorophore methylumbelliferone is reduced by 75-fold. The availability of a method to quantitate leakage quickly for a variety of experimental conditions will facilitate future applications of droplet-based experiments (e.g. in directed evolution or diagnostics), aid miniaturisation of lab-scale assays into this format, and improve the degrees of freedom in setting up such ultrahigh-throughput experiments.
XIAP-mediated targeting of endolysosomes to stressed mitochondria occurs in a switch-like, global manner and results in autophagy-independent, sub-organelle level mitochondrial degradation
Authors: Wang Tim Sen , Coppens Isabelle , Brady Nathan Ryan , Hamacher-Brady Anne
Published: April 2023

Damaged mitochondria can be subject to lysosomal degradation via mitophagy. However, whole-organelle degradation exhibits relatively slow kinetics and thus its impact may be limited in response to acute, fast-acting cellular stress. We previously reported that in Parkin-deficient cells endolysosomes directly target mitochondria when subjected to bioenergetic stress. Here, using high-resolutionlivecell imaging we reveal a striking level of dynamic targeting of Rab5+ early endosomes to stressed mitochondria, culminating in a switch-like accumulation in the entire mitochondrial population, independently of canonical autophagy. This process of rapid, largescale Rab5+ vesicle trafficking to mitochondria coincides with, and is mediated by, XIAP E3 ligase activated mitochondrial ubiquitylation and results in ultrastructural changes to, and degradation of, intra-mitochondrial components. Mitochondria-targeting vesicles include early endosomal subpopulations marked by Rab5 effector APPL1 and ubiquitin-binding endocytic adaptors OPTN, TAX1BP1 and Tollip, and Rab7-positive late endosomes/lysosomes. In Parkin expressing cells, XIAP- and Parkin-dependent mitochondrial targeting and resulting processing modes are competitively regulated. Together, our data suggest that XIAP-mediated targeting of endolysosomes to mitochondria functions as a stress-responsive, sub-organelle level mitochondrial processing mode that is distinct from, and competitive to, Parkin-mediated mitophagy.
Does a probiotic (L. reuteri) lozenge taken twice daily over 3-4 weeks reduce probing pocket depth in patients with chronic periodontitis after 3 months? A systematic review of clinical trials (Protocol)
Authors: Mickenautsch Steffen , Rupf Stefan , Yengopal Veerasamy
Published: April 2023

Introduction

Chronic periodontitis is a slow progressing, multifactorial inflammatory disease of the periodontium that may lead to its destruction, which is detectable as increasing probing pocket depth (PPD), subsequent tooth mobility and tooth loss. The purpose of this systematic review is to update and appraise the current trial evidence to the question do probiotic (L. reuteri) lozenge taken twice daily over 3-4 weeks reduce probing pocket depth in patients with chronic periodontitis after 3 months.

Methods and analysis

We will conduct reference checks of previous systematic review and trial reports to the topic. PubMed, Scopus, Cochrane library and the Directory of Open Access Journals (DOAJ) will be searched. All selected trial reports will be independently appraised by two reviewers, using the CQS-2B trial appraisal tool. Meta-analysis will be conducted using a random effect model with inverse variance method, stratified according to CQS-2B corroboration levels (C1 – 4). The I2– test with 95% Confidence Interval will be used to establish whether any statistical heterogeneity between datasets exist. Sensitivity analysis will be conducted for meta-analysis results of trials that were rated with 1-score at all four CQS-2B appraisal criteria, by excluding trials in which: Patients were smokers; Patients were Type II diabetics; Adjunctive antibiotic therapy was provided. For meta-analyses including data of at least four trials, which have been rated with a 1-score for all four appraisal criteria, the results will be further statistically tested for possible selection bias. Publication bias risk will be quantitatively assessed by use of Egger’s regression.

Ethics and dissemination

Ethical approval is not required for literature-based studies. The results will be disseminated as a prior preprint version and subsequent peer-reviewed publication.
Early-life socioeconomic circumstances and the comorbidity of depression and overweight in adolescence and young adulthood: a longitudinal study
Authors: Kilpi Fanny , Howe Laura D
Published: April 2023

Background

Depression and overweight both often emerge early in life and have been found to be associated, but few studies examine depression-overweight comorbidity and its social patterning early in the life course. This study investigates how different aspects of early-life socioeconomic circumstances are associated with depression-overweight comorbidity from adolescence to young adulthood exploring any differences by age and sex.

Methods

Drawing on data from 4,948 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort from the UK, we estimated how parental education, social class and financial difficulties reported in pregnancy were associated with depression and overweight, and their comorbidity at approximately the ages 17 and 24 in males and females.

Results

The results from multinomial logistic regression models showed that all three socioeconomic markers were associated with depression-overweight comorbidity and results were similar across age. Lower parental education (relative risk ratio (RRR) and 95% confidence interval (CI) of low education v high education: 3.61 (2.30-5.67) in females and 1.54 (1.14-2.07) in males) and social class (class IV/I v class I: 5.67 (2.48-12.94) in females and 3.11 (0.70-13.91) in males) had strong associations with comorbidity at age 17 relative to having neither depression or overweight. Financial difficulties were also a risk factor in females, with less clear results in males.

Conclusion

The findings indicate that early socioeconomic circumstances are linked with the accumulation of mental and physical health problems already in adolescence, which has implications for life-long health inequalities.
Resistance and prevalence implications of doxycycline post-exposure prophylaxis for gonorrhea prevention in men who have sex with men: a modeling study
Authors: Reichert Emily , Grad Yonatan H.
Published: April 2023

Background

Doxycycline post-exposure prophylaxis (DoxyPEP) has demonstrated efficacy for prevention of bacterial sexually transmitted infections. To inform policy decisions on the use of DoxyPEP for gonorrhea prevention, we used a mathematical model to investigate its impact on resistance dynamics and the burden of infection in men who have sex with men (MSM).

Methods and Findings

Using a deterministic compartmental model of gonorrhea transmission in an MSM population, we introduced DoxyPEP at various uptake levels (10-75%) and compared 20-year prevalence and resistance dynamics relative to those at baseline (i.e., no DoxyPEP introduction). Uptake of DoxyPEP resulted in initial drops in the prevalence and incidence of gonorrhea infection, but also accelerated the spread of doxycycline resistance, with increasing DoxyPEP use driving steeper initial declines followed by faster spread of resistance. This resulted in the total loss of DoxyPEP’s clinical efficacy within 1-2 decades in almost all scenarios explored. The magnitude by which DoxyPEP initially reduced the prevalence of infection was constrained by the extent of pre-existing doxycycline resistant strains in the population.De novoemergence of doxycycline resistance did not influence these dynamics. Additionally, the implementation of DoxyPEP had minimal impact on extending the clinically useful lifespan of ceftriaxone monotherapy.

Conclusions

Model findings suggest DoxyPEP can be an effective but short-term solution for reducing the burden of gonorrhea infection, as its selection for doxycycline-resistant strains results in loss of its prophylaxis benefit. Increasing levels of DoxyPEP uptake and higher starting prevalence of doxycycline resistance resulted in faster loss of its efficacy and had little change on extending the clinical lifespan of ceftriaxone for treatment ofN. gonorrhoeaeinfections.
LONG-TERM PHYSICAL AND MENTAL HEALTH IMPACT OF COVID-19 ON ADULTS IN ENGLAND: FOLLOW UP OF A LARGE RANDOM COMMUNITY SAMPLE
Authors: Atchison Christina J , Davies Bethan , Cooper Emily , Lound Adam , Whitaker Matthew , Hampshire Adam , Azor Adriana , Donnelly Christl , Chadeau-Hyam Marc , Cooke Graham S , Ward Helen , Elliott Paul
Published: April 2023

Background

The COVID-19 pandemic is having a lasting impact on health and well-being. We compare current self-reported health, quality of life and symptom profiles for people with ongoing symptoms following COVID-19 to those who have never had COVID-19 or have recovered.

Methods

A cohort study was established with participants from the REACT programme. A sample (N=800,000) of adults were contacted between August and December 2022 to complete a questionnaire about their current health and COVID-19 history. We used logistic regression to identify predictors of persistent symptoms lasting ≥12 weeks following COVID-19. We fitted Accelerated Failure Time models to assess factors associated with rate of recovery from persistent symptoms.

Findings

Overall, 276,840/800,000 (34.6%) of invited participants completed the questionnaire. Median duration of COVID-related symptoms (N=130,251) was 1.3 weeks (inter-quartile range 6 days to 2 weeks), with 7.5% and 5.2% reporting ongoing symptoms ≥12 weeks and ≥52 weeks respectively. Female sex, having ≥1 comorbidity, more severe symptoms at time of COVID-19 and being infected when Wild-type variant was dominant were associated with higher probability of symptoms lasting ≥12 weeks. Longer time to recovery in those with persistent symptoms was found for females, people with comorbidities, living in more deprived areas, current smokers and for Wild-type compared to later variants. Mental health and health-related quality of life were significantly worse among participants with ongoing persistent COVID-19 symptoms compared with those who had never had COVID-19 or had recovered.

Interpretation

Although COVID-19 is usually of short duration, some adults experience persistent and burdensome illness.

Funding

This work is independent research funded by the National Institute for Health and Care Research (NIHR) (REACT Long COVID (REACT-LC) (COV-LT-0040)). This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (UKRI) (MC_PC_20029). The views expressed in this publication are those of the author(s) and not necessarily those of NIHR or UKRI.
Flow characterization of low sweep MULDICON wing at low speed
Authors: Haider Bilal , Mansor Shuhaimi , Mat Shabudin , Nasir Nazri
Published: April 2023

Purpose

The flow topology for multi-disciplinary configuration (MULDICON) wing is very complicated and nonlinear at low to high angle of attack (AOA). This paper aims to provide the correlation between the unsteadiness and uncertainties of the flow topology and aerodynamic forces and moments above MULDICON WING at a medium to a higher AOA.

Design/methodology/approach

The experimental and computational fluid dynamics methods were used to investigate a generic MULDICON wing. During the experiment, the AOA were varied from α = 5° to 30°, whereas yaw angle varies between β = ±20° and Reynolds number between Re = 3.0 × 105 and Re = 4.50 × 105. During the experiments steady-state loading, dynamic loading and flow visualization wind tunnel methods were used.

Findings

The standard deviation quantified the unsteadiness and uncertainties of flow topology and predicted that they significantly affect the pitching moment (Cm) at medium to higher AOA. A strong correlation between flow topology and Cm was exhibited, and the experiment data was well validated by previous numerical work. The aerodynamic center was not fixed and shifted toward the wing apex when AOA is increasing. For a = 10°, the flow becomes more asymmetric. Power spectral densities plots quantify the flow separation (apex vortex, leading-edge vortex and vortex breakdown) over the MULDICON wing.

Originality/value

The application and comparison of steady-state and dynamic loading data to quantify the unsteadiness and uncertainties of flow topology above the MULDICON wing.
Usage of digital library services during COVID-19 pandemic: a study of Indian Institutes of Management (IIMs)
Authors: Ansari Anam Jamal , PM Naushad Ali
Published: April 2023

Purpose

This paper aims to find out the digital services of management libraries provided during the library closure and the challenges and initiatives the libraries have taken up to fulfill the need of their user community during the pandemic crisis.

Design/methodology/approach

To meet the purpose of the study, the investigators have used a survey method. An online questionnaire was devised and administered among the Indian Institutes of Management (IIMs) librarians using Microsoft Forms.

Findings

The study's findings suggested that all the libraries under investigation must avail of various digital library services in the wake of the coronavirus pandemic. Further, the investigators recommend that libraries formulate a disaster preparedness and management plan in the wake of the COVID-19 pandemic so that libraries can prepare themselves for the future.

Originality/value

The pandemic has affected every aspect of life and changed the digital library services scenario. Thus, it is essential to examine the role libraries have played during the COVID-19 pandemic and distinguish the challenges and initiatives libraries have taken to tackle the problems they faced. This study has been conducted on the digital library services that were provided by the libraries of IIMs.
Does digital transformation increase firms' productivity perception? The role of technostress and work engagement
Authors: Picazo Rodríguez Beatriz , Verdú-Jover Antonio Jose , Estrada-Cruz Marina , Gomez-Gras Jose Maria
Published: April 2023

Purpose

To understand how organizations, public or private, must increase their productivity perception (PP), independently of the sector. This article aims to analyze PP in the digital transformation (DT) process to determine how it is affected by technostress (TS) and work engagement (WE), two concepts that seem to be forces opposing PP.

Design/methodology/approach

The authors use data from a questionnaire addressed to personnel in two organizations (public and private). The analysis applies partial least squares technique to the 505 valid responses obtained from these organizations. This analysis is based not on representativeness but on uniqueness.

Findings

The results suggest a positive, significant relationship between DT and PP. This article integrates DT and its effects on aspects of people's health, PP and WE. The model thus includes interactions of technology with human elements. In both business and administrative environments, PP is key to optimizing resources and survival of organizations.

Research limitations/implications

DT processes are different and complex because every organization is different. The authors recommend expanding this study to other sectors in both spheres, public and private. Aligning the objectives of the institutions for aid with DT is also quite complicated.

Practical implications

This study contributes to improving participating organizations. It also provides government institutions with a clear foundation from which to encourage actions that promote the health and WE of their workforce without reducing productivity. In addition, this study adds novelty to the research line.

Originality/value

The authors have deepened this line of research by developing fuller knowledge of the relationships among novel and necessary variables in organizations. The authors provide complementary, different and inspiring value in addressing this line of research.