bluuebunny/crossref_metadata_2025 huggingface dataset:
Complexities of autonomy in military medical ethics: A brief report
Authors: Applewhite Megan K. , Girton Joshua , Bader Christine , Kaniaru Anthony , Martin Matthew , Holcomb John B. , Gurney Jennifer M. , Yelon Jay , Lough Frederick
Published: July 2024

The first Fallen Surgeons Military Educational Symposium was convened in conjunction with the the American Association for the Surgery of Trauma (AAST) 23 meeting, under the guidance of the AAST Military Liaison Committee. The daylong session included a 1.5-hour segment on military medical ethics in combat and its unique challenges. Medical ethical issues arise frequently within the military across a range of varied circumstances, from the day-to-day operations of stateside forces to the complexities of deployed troops in theaters of conflict. Given the scope of these circumstances, preparation and advanced planning are the key to addressing and resolving the ethical issues that occur. The goal of this session was to present illustrative cases, not to prescribe solutions, and to make the attendees aware of some of the challenges they may encounter when deployed.
Transcranial magnetic stimulation and transcranial direct current stimulation in reducing depressive symptoms during the peripartum period
Authors: Ganho-Ávila Ana , Sobral Mónica , Berg Mijke Lambregtse-van den
Published: July 2024

Purpose of review

To present the latest data on the efficacy, safety, and acceptability of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) in peripartum depression (PPD), complemented by notes emerging from our clinical and research experience.

Recent findings

TMS and tDCS show promising results to manage mild to moderate depressive symptoms in the peripartum period. Evidence of TMS efficacy during pregnancy and the postpartum comes from two small randomized controlled trials (RCTs) with encouraging but still inconsistent results. Evidence of tDCS efficacy during pregnancy comes from one small RCT and in the postpartum the first RCT is just now being conducted and results are highly expected. The safety profile (with transient mild adverse effect to women and no known risk to the foetus/newborn) and acceptability by women seems overall good. However, the perspectives from health professionals and managers are unclear.

Whereas TMS accelerated protocols (e.g., more than one session/day) and shorter sessions (e.g., theta burst stimulation) could address the need for fast results in PPD, home-based tDCS systems could address accessibility issues. Currently, the evidence on the efficacy of TMS and tDCS in PPD is limited warranting further research to support stronger evidence-based clinical guidelines.
Aquibaculum arenosum gen. nov., sp. nov., a novel member of the family Rhodovibrionaceae, isolated from sea sand
Authors: Ahn Soyeon , Choi David Hyung-Sun , Weerawongwiwat Veeraya , Kim Jong-Hwa , Sukhoom Ampaitip , Kim Wonyong
Published: July 2024

A Gram-negative, non-motile, and creamy-white coloured bacterium, designated CAU 1616T, was isolated from sea sand collected at Ayajin Beach, Goseong-gun, Republic of Korea. The bacterium was found to grow optimally at 37 °C, pH 8.0–8.5, and with 1–5 % (w/v) NaCl. Phylogenetic analyses based on the 16S rRNA gene sequences placed strain CAU 1616T within the order Rhodospirillales. The highest 16S rRNA gene sequence similarity was to Fodinicurvata fenggangensis YIM D812T (94.1 %), Fodinicurvata sediminis YIM D82T (93.7 %), Fodinicurvata halophila BA45ALT (93.6 %) and Algihabitans albus HHTR 118T (92.3 %). Comparing strain CAU 1616T with closely related species (Fodinicurvata fenggangensis YIM D812T and Fodinicurvata sediminis YIM D82T), the average nucleotide identity based on blast+ values were 69.7–69.8 %, the average amino acid identity values were 61.3–61.4 %, and the digital DNA–DNA hybridization values were 18.4–18.5 %. The assembled draft genome of strain CAU 1616T had 29 contigs with an N50 value of 385.8 kbp, a total length of 3 490 371 bp, and a DNA G+C content of 65.1 mol%. The predominant cellular fatty acids were C18 : 1 2−OH, C19 : 0 cyclo ω8c, and summed feature 8 (C18 : 1
 ω6c and/or C18 : 1
 ω7c). The major respiratory quinone was Q-10. Based on phenotypic, phylogenetic, and chemotaxonomic evidence, strain CAU 1616T represents a novel genus in the family Rhodovibrionaceae, for which the name Aquibaculum arenosum gen. nov., sp. nov. is proposed. The type strain is CAU 1616T (=KCTC 82428T=MCCC 1K06089T).
High-speed three-dimensional random access scanning with SPARCLS
Authors: Berlage Caroline , Böhm Urs L. , Moreno Ana Sanchez , Ledderose Julia , Gidon Albert , Larkum Matthew E. , Plested Andrew , Judkewitz Benjamin
Published: July 2024

High-speed volumetric imaging is crucial for observing fast and distributed processes such as neuronal activity. Multiphoton microscopy helps to mitigate scattering effects inside tissue, but the standard raster scanning approach limits achievable volume rates. Random-access scanning can lead to a considerable speed-up by sampling only pre-selected locations, but existing techniques based on acousto-optic deflectors are still limited to a point rate of up to ∼50 kHz. This limits the number of parallel targets at the high acquisition rates necessary, for example, in voltage imaging or imaging of fast synaptic events.

Here we introduce SPARCLS, a method for 3D random-access scanning at up to 340 kHz point rate using a single 1D phase modulator. We show the potential of this method by imaging synaptic events with fluorescent glutamate sensors in mammalian organotypic slices as well as in zebrafish larvae.
Dynamic control of neural manifolds
Authors: Lehr Andrew B. , Kumar Arvind , Tetzlaff Christian
Published: July 2024

In the central nervous system, sequences of neural activity form trajectories on low dimensional neural manifolds. The neural computation underlying flexible cognition and behavior relies on dynamic control of these structures. For example different tasks or behaviors are represented on different subspaces, requiring fast timescale subspace rotation to move from one behavior to the next. For flexibility in a particular behavior, the neural trajectory must be dynamically controllable within that behaviorally determined subspace. To understand how dynamic control of neural trajectories and their underlying subspaces may be implemented in neural circuits, we first characterized the relationship between features of neural activity sequences and aspects of the low dimensional projection. Based on this, we propose neural mechanisms that can act within local circuits to modulate activity sequences thereby controlling neural trajectories in low dimensional subspaces. In particular, we show that gain modulation and transient synaptic currents control the speed and path of neural trajectories and clustered inhibition determines manifold orientation. Together, these neural mechanisms may enable a substrate for fast timescale computation on neural manifolds.
Quantifying the massive pleiotropy of microRNA: a human microRNA-disease causal association database generated with ChatGPT
Authors: Rowan Wang K. , Hecker Julian , McGeachie Michael J.
Published: July 2024

MicroRNAs (miRNAs) are recognized as key regulatory factors in numerous human diseases, with the same miRNA often involved in several diseases simultaneously or being identified as a biomarker for dozens of separate diseases. While of evident biological importance, miRNA pleiotropy remains poorly understood, and quantifying this could greatly aid in understanding the broader role miRNAs play in health and disease. To this end, we introduce miRAIDD (miRNA Artificial Intelligence Disease Database), a comprehensive database of human miRNA-disease causal associations constructed using large language models (LLM). Through this endeavor, we provide two entirely novel contributions: 1) we systematically quantify miRNA pleiotropy, a property of evident translational importance; and 2) describe biological and bioinformatic characteristics of miRNAs which lead to increased pleiotropy. Further, we provide our code, database, and experience using AI LLMs to the broader research community.
Mechanosensitive PIEZO2 channels shape coronary artery development
Authors: Pampols-Perez Mireia , Fürst Carina , Sánchez-Carranza Oscar , Cano Elena , Raimundo Sandra , Lindberg Eric L. , Taube Martin , Heuser Arnd , Sporbert Anje , Hübner Norbert , Gerhardt Holger , Lewin Gary R. , Hammes Annette
Published: July 2024

The coronary arteries develop under substantial mechanical loads. However, the role of mechanosensitive ion channels has barely been addressed in this system. Here we demonstrate the expression of the mechanosensitive ion channel PIEZO2 in specific coronary endothelial cell populations during a crucial phase of vascular modeling.Piezo2positive coronary endothelial cells display distinct transcriptional profiles and have mechanically activated ionic currents. Strikingly,Piezo2-/-mouse embryos and mice with human pathogenic variants ofPIEZO2display coronary vessel malformations and left ventricular hyperplasia. We conclude that an optimal balance of PIEZO2 channel function is indispensable for coronary vessel formation, integrity, and remodeling and likely for proper cardiac function.
Disentangling the Roles of Distinct Cell Classes with Cell-Type Dynamical Systems
Authors: Jha Aditi , Gupta Diksha , Brody Carlos D. , Pillow Jonathan W.
Published: July 2024

Latent dynamical systems have been widely used to characterize the dynamics of neural population activity in the brain. However, these models typically ignore the fact that the brain contains multiple cell types. This limits their ability to capture the functional roles of distinct cell classes, and to predict the effects of cell-specific perturbations on neural activity or behavior. To overcome these limitations, we introduce the “cell-type dynamical systems” (CTDS) model. This model extends latent linear dynamical systems to contain distinct latent variables for each cell class, with biologically inspired constraints on both dynamics and emissions. To illustrate our approach, we consider neural recordings with distinct excitatory (E) and inhibitory (I) populations. The CTDS model defines separate latents for both cell types, and constrains the dynamics so that E (I) latents have a strictly positive (negative) effects on other latents. We applied CTDS to recordings from rat frontal orienting fields (FOF) and anterior dorsal striatum (ADS) during an auditory decision-making task. The model achieved higher accuracy than a standard linear dynamical system (LDS), and revealed that the animal’s choice can be decoded from both E and I latents and thus is not restricted to a single cell-class. We also performed in-silico optogenetic perturbation experiments in the FOF and ADS, and found that CTDS was able to replicate the experimentally observed effects of different perturbations on behavior, whereas a standard LDS model—which does not differentiate between cell types—did not. Crucially, our model allowed us to understand the effects of these perturbations by revealing the dynamics of different cell-specific latents. Finally, CTDS can also be used to identify cell types for neurons whose class labels are unknown in electrophysiological recordings. These results illustrate the power of the CTDS model to provide more accurate and more biologically interpretable descriptions of neural population dynamics and their relationship to behavior.
Optimizing murine sample sizes for RNA-seq studies revealed from large-scale comparative analysis
Authors: Halasz Gabor , Schmahl Jennifer , Negron Nicole , Ni Min , Atwal Gurinder S. , Glass David J.
Published: July 2024

Determining the appropriate sample size (N) for comparative biological experiments is critical for obtaining reliable results. In order to determine the N, the usual approach is to perform a power calculation, which involves understanding the variability between samples and the expected effect size. Here, we focused on bulk RNA-seq experiments, which have become ubiquitous in biology, but which have many unknown or difficult to estimate parameters, and so the required analyses to determine the minimum N is typically lacking. We therefore performed two N=30 profiling studies between wild-type mice and mice in which one copy of a gene had been deleted, to determine how many mice would be required to minimize false positives and to maximize true discoveries found in the N of 30 experiment. Results from experiments with N=4 or less are shown to be highly misleading, given the substantial false positive rate, and the lack of discovery of genes later found with higher N. For a cut-off of 2-fold expression differences, we found that an N of 6-7 mice was required to consistently decrease the false positive rate to below 50%, and that “more is always better” when it came to discovery rates - an N of 8-12 is significantly better in lowering the false positive rate.

A common method to reduce false discovery rate in underpowered experiments is to raise the fold cutoff or increase the stringency of the P-value and include only highly perturbed, highly significant genes. We show that while this strategy is no substitute for increasing the N of the experiment, because it results in consistently inflated effect sizes and a substantial drop in sensitivity. These data should be helpful to others in choosing their Ns, since it’s often not practical to do such large studies for every mouse model.
The impact of Library Size and Scale of Testing on Virtual Screening
Authors: Liu Fangyu , Mailhot Olivier , Glenn Isabella S. , Vigneron Seth F. , Bassim Violla , Xu Xinyu , Fonseca-Valencia Karla , Smith Matthew S. , Radchenko Dmytro S. , Fraser James S. , Moroz Yurii S. , Irwin John J. , Shoichet Brian K.
Published: July 2024

Virtual libraries for ligand discovery have recently increased 10,000-fold, and this is thought to have improved hit rates and potencies from library docking. This idea has not, however, been experimentally tested in direct comparisons of larger-vs-smaller libraries. Meanwhile, though libraries have exploded, the scale of experimental testing has little changed, with often only dozens of high-ranked molecules investigated, making interpretation of hit rates and affinities uncertain. Accordingly, we docked a 1.7 billion molecule virtual library against the model enzyme AmpC β-lactamase, testing 1,521 new molecules and comparing the results to the same screen with a library of 99 million molecules, where only 44 molecules were tested. Encouragingly, the larger screen outperformed the smaller one: hit rates improved by two-fold, more new scaffolds were discovered, and potency improved. Overall, 50-fold more inhibitors were found, supporting the idea that there are many more compounds to be discovered than are being tested. With so many compounds evaluated, we could ask how the results vary with number tested, sampling smaller sets at random from the 1521. Hit rates and affinities were highly variable when we only sampled dozens of molecules, and it was only when we included several hundred molecules that results converged. As docking scores improved, so too did the likelihood of a molecule binding; hit rates improved steadily with docking score, as did affinities. This also appeared true on re-analysis of large-scale results against the σ2 and dopamine D4 receptors. It may be that as the scale of both the virtual libraries and their testing grows, not only are better ligands found but so too does our ability to rank them.
Hypersensitivity of the vimentin cytoskeleton to net-charge states and Coulomb repulsion
Authors: Unger Bret A. , Wu Chun Ying , Choi Alexander A. , He Changdong , Xu Ke
Published: July 2024

As with most intermediate filament systems, the hierarchical self-assembly of vimentin into nonpolar filaments requires no nucleators or energy input. Utilizing a set of live-cell, single-molecule, and super-resolution microscopy tools, here we show that in mammalian cells, the assembly and disassembly of the vimentin cytoskeleton is highly sensitive to the protein net charge state. Starting with the intriguing observation that the vimentin cytoskeleton fully disassembles under hypotonic stress yet reassembles within seconds upon osmotic pressure recovery, we pinpoint ionic strength as its underlying driving factor. Further modulating the pH and expressing differently charged constructs, we converge on a model in which the vimentin cytoskeleton is destabilized by Coulomb repulsion when its mass-accumulated negative charges (-18 per vimentin protein) along the filament are less screened or otherwise intensified, and stabilized when the charges are better screened or otherwise reduced. Generalizing this model to other intermediate filaments, we further show that whereas the negatively charged GFAP cytoskeleton is similarly subject to fast disassembly under hypotonic stress, the cytokeratin, as a copolymer of negatively and positively charged subunits, does not exhibit this behavior. Thus, in cells containing both vimentin and keratin cytoskeletons, hypotonic stress disassembles the former but not the latter. Together, our results both provide new handles for modulating cell behavior and call for new attention to the effects of net charges in intracellular protein interactions.
Development of a DSM test battery to determine depression-like marmoset
Authors: Yamanaka Hajime , Ishibashi Hidetoshi , Nakamura Katsuki
Published: July 2024

Depression is a serious and high-incidence mental disorder that can lead to suicide. Despite much depression research using humans and rodents to date, it has been difficult to completely overcome depression and elucidate its etiology. Marmoset monkeys have been utilized to study neuropsychiatric disorders in recent years. Since the clinical diagnostic criteria for psychiatric disorders are mainly based on multiple behavioral changes, test battery systems, a multifaceted and comprehensive strategy, are applied to depression research. Here, we devised a test battery with six tests to investigate depression-like symptoms corresponding to clinical criteria and set criteria for a test indicator-based judgment. We did a usability confirmation experiment using a drug and judged three of nine marmosets as depression-like. This rate is comparable with the incidence rate of human patients; i.e., 10-30% of patients who received reserpine treatment suffer from depression. Thus, we propose the test battery we constructed in this study will contribute to the study of depression.
Amino acids trigger MDC-dependent mitochondrial remodeling by altering mitochondrial function
Authors: Raghuram Nidhi , Hughes Adam
Published: July 2024

Cells utilize numerous pathways to maintain mitochondrial homeostasis, including a recently identified mechanism that adjusts the content of the outer mitochondrial membrane (OMM) through formation of OMM-derived multilamellar domains called mitochondrial-derived compartments, or MDCs. MDCs are triggered by perturbations in mitochondrial lipid and protein content, as well as increases in intracellular amino acids. Here, we sought to understand how amino acids trigger MDCs. We show that amino acid-activation of MDCs is dependent on the functional state of mitochondria. While amino acid excess triggers MDC formation when cells are grown on fermentable carbon sources, stimulating mitochondrial biogenesis blocks MDC formation. Moreover, amino acid elevation depletes TCA cycle metabolites in yeast, and preventing consumption of TCA cycle intermediates for amino acid catabolism suppresses MDC formation. Finally, we show that directly impairing the TCA cycle is sufficient to trigger MDC formation in the absence of amino acid stress. These results demonstrate that amino acids stimulate MDC formation by perturbing mitochondrial metabolism.
L-type calcium channel blockade with verapamil prevents noise induced neuronal dys-synchrony
Authors: Yalcinoglu Selin , Braun Rod D. , Wattoo Ammaar , Apawu Aaron K. , Alrayashi Rasheed , Holt Avril Genene
Published: July 2024

Previous studies have established the protective effects of calcium channel blockade on the peripheral auditory system in response to noise exposure. While these studies implicate L-type calcium channels (LTCCs) in noise generated dysfunction in the auditory periphery, contributions of LTCCs to noise-induced central dysfunction remains unclear. To begin to elucidate the roles of LTCCs in hearing, peripheral and central auditory function were assessed longitudinally after LTCC blockade. Neuronal synchrony and activity were assessed by analyzing wave I (peripheral) and wave V (central) auditory brainstem responses (ABRs). Just prior to a noise exposure resulting in a temporary shift in hearing thresholds, rats were administered verapamil (LTCC blocker) or saline. Verapamil administration prevented the noise-induced decrease in ABR wave I and V amplitudes. Interestingly, when non-noise exposed animals were administered verapamil, wave V amplitude decreased, suggesting that LTCCs are critical for neuronal synchrony in the inferior colliculus. The inferior colliculus mediates inhibition of the acoustic startle reflex (giASR). Following noise exposure giASR was enhanced, but the enhancement was not prevented by LTCC blockade. These results suggest that while LTCCs are necessary for auditory-related synchronous activity, these channels do not contribute to noise-induced hyperactivity in the inferior colliculus.
Translatome analysis reveals cellular network in DLK-dependent hippocampal glutamatergic neuron degeneration
Authors: Ritchie Erin M , Acar Dilan , Zhong Siming , Pu Qianyi , Li Yunbo , Zheng Binhai , Jin Yishi
Published: July 2024

The conserved MAP3K12/Dual Leucine Zipper Kinase (DLK) plays versatile roles in neuronal development, axon injury and stress responses, and neurodegeneration, depending on cell-type and cellular contexts. Emerging evidence implicates abnormal DLK signaling in several neurodegenerative diseases. However, our understanding of the DLK-dependent gene network in the central nervous system remains limited. Here, we investigated the roles of DLK in hippocampal glutamatergic neurons using conditional knockout and induced overexpression mice. We found that dorsal CA1 and dentate gyrus neurons are vulnerable to elevated expression of DLK, while CA3 neurons appear less vulnerable. We identified the DLK-dependent translatome that includes conserved molecular signatures and displays cell-type specificity. Increasing DLK signaling is associated with disruptions to microtubules, potentially involving STMN4. Additionally, primary cultured hippocampal neurons expressing different levels of DLK show altered neurite outgrowth, axon specification, and synapse formation. The identification of translational targets of DLK in hippocampal glutamatergic neurons has relevance to our understanding of selective neuron vulnerability under stress and pathological conditions.
Sleep induced by mechanosensory stimulation provides cognitive and health benefits inDrosophila
Authors: Inami Sho , Koh Kyunghee
Published: July 2024

Study Objectives

Sleep is a complex phenomenon regulated by various factors, including sensory input. Anecdotal observations have suggested that gentle rocking helps babies fall asleep, and experimental studies have verified that rocking promotes sleep in both humans and mice. Recent studies have expanded this understanding, demonstrating that gentle vibration also induces sleep inDrosophila. Natural sleep serves multiple functions, including learning and memory, synaptic downscaling, and clearance of harmful substances associated with neurodegenerative diseases. Here, we investigated whether vibration-induced sleep provides similar cognitive and health benefits inDrosophila.

Methods

We administered gentle vibration to flies that slept very little due to a forced activation of wake-promoting neurons and investigated how the vibration influenced learning and memory in the courtship conditioning paradigm. Additionally, we examined the effects of VIS on synaptic downscaling by counting synapse numbers of select neurons. Finally, we determined whether vibration could induce sleep inDrosophilamodels of Alzheimer’s disease (AD) and promote the clearance of Amyloid β (Aβ) and Tubulin Associated Unit (TAU).

Results

Vibration-induced sleep enhanced performance in a courtship conditioning paradigm and reduced the number of synapses in select neurons. Moreover, vibration improved sleep inDrosophilamodels of AD, promoting the clearance of Aβ and TAU.

Conclusions

Mechanosensory stimulation offers a promising non-invasive avenue for enhancing sleep, potentially providing associated cognitive and health benefits.

Significance Statement

Sleep is critical for a healthy mind and body, and sleep disturbances are commonly associated with neurodegenerative diseases such as Alzheimer’s disease. Sleep is influenced by sensory input, and mechanical stimulation, such as gentle rocking and vibration, has been shown to promote sleep in various species, including humans, mice, and fruit flies. This study demonstrates that gentle vibration not only helps flies sleep better but also improves their performance in a learning and memory task and makes their brains more efficient in clearing harmful substances. Notably, vibration can facilitate the clearance of Amyloid β and the TAU proteins, which accumulate in Alzheimer’s disease. These results highlight the potential for gentle mechanosensory stimulation to promote sleep and cognitive health.
Association study of Plasmodium falciparum Acetyl-CoA Synthetase Mutations S868G and V949I with antimalarial drugs
Authors: Zhao Wei , Xiang Zheng , Zeng Weilin , Qin Yucheng , Pan Maohua , Wu Yanrui , Duan Mengxi , Mou Ye , Liang Tao , Zhang Yanmei , Liu Cheng , Tang Xiuya , Huang Yaming , Yang Gongchao , Cui Liwang , Yang Zhaoqing
Published: July 2024

Plasmodium falciparum acetyl-CoA synthetase (PfACAS) protein is an important source of acetyl-CoA. We detected the mutations S868G and V949I in PfACAS by whole-genome sequencing analysis in some recrudescent parasites after antimalarial treatment with artesunate and dihydroartemisinin-piperaquine, suggesting that they may confer drug resistance. Using CRISPR/Cas9 technology, we engineered parasite lines carrying the PfACAS S868G and V949I mutations in two genetic backgrounds and evaluated their susceptibility to antimalarial drugs in vitro. The results demonstrated that PfACAS S868G and V949I mutations alone or in combination were not enough to provide resistance to antimalarial drugs.
Single-cell RNA-sequencing identifies unique cell-specific gene expression profiles in high-grade cardiac allograft vasculopathy
Authors: Amancherla Kaushik , Schlendorf Kelly H. , Chow Nelson , Sheng Quanhu , Freedman Jane E. , Rathmell Jeffrey C.
Published: July 2024

Background

Cardiac allograft vasculopathy (CAV), a diffuse thickening of the intima of the coronary arteries and microvasculature, is the leading cause of late graft failure and mortality after heart transplantation (HT). Diagnosis involves invasive coronary angiography, which carries substantial risk, and minimally-invasive approaches to CAV diagnosis are urgently needed. Using single-cell RNA-sequencing in peripheral blood mononuclear cells (PBMCs), we sought to identify cell-specific gene expression profiles in CAV.

Methods

Whole blood was collected from 22 HT recipients with angiographically-confirmed CAV and 18 HT recipients without CAV. PBMCs were isolated and subjected to single-cell RNA-sequencing using a 10X Genomics microfluidic platform. Downstream analyses focused on differential expression of genes, cell compositional changes, and T cell receptor repertoire analyses.

Results

Across 40 PBMC samples, we isolated 134,984 cells spanning 8 major clusters and 31 subclusters of cell types. Compositional analyses showed subtle, but significant increases in CD4+ T central memory cells, and CD14+ and CD16+ monocytes in high-grade CAV (CAV-2 and CAV-3) as compared to low-grade or absent CAV. After adjusting for age, gender, and prednisone use, 745 genes were differentially expressed in a cell-specific manner in high-grade CAV. Weighted gene co-expression network analyses showed enrichment for putative pathways involved in inflammation and angiogenesis. There were no significant differences in T cell clonality or diversity with increasing CAV severity.

Conclusions

Unbiased whole transcriptomic analyses at single-cell resolution identify unique, cell-specific gene expression patterns in CAV, suggesting the potential utility of peripheral gene expression biomarkers in diagnosing CAV.
Risk of Delayed Percutaneous Coronary Intervention for STEMI in the Southeast United States
Authors: Messinger Maxwell C. , Ashburn Nicklaus P. , Chait Joshua S. , Snavely Anna C. , Hapig-Ward Siena , Stopyra Jason P. , Mahler Simon A.
Published: July 2024

Background

Emergent reperfusion by percutaneous coronary intervention (PCI) within 90 minutes of first medical contact (FMC) is indicated in patients with ST-segment elevation myocardial infarction (STEMI). However, long transport times in rural areas in the Southeast US make meeting this goal difficult. The objective of this study was to determine the number of Southeast US residents with prolonged transport times to the nearest 24/7 primary PCI (PPCI) center.

Methods

A cross-sectional study of residents in the Southeastern US was conducted based on geographical and 2022 5-Year American Community Survey data. The geographic information system (GIS) ArcGIS Pro was used to estimate Emergency Medical Services (EMS) transport times for Southeast US residents to the nearest PPCI center. All 24/7 PPCI centers in North Carolina, South Carolina, Georgia, Florida, Mississippi, Alabama, and Tennessee were included in the analysis, as well as nearby PPCI centers in surrounding states. To identify those at risk of delayed FMC-to-device time, the primary outcome was defined as a >30-minute transport time, beyond which most patients would not have PCI within 90 minutes. A secondary outcome was defined as transport >60 minutes, the point at which FMC-to-device time would be >120 minutes most of the time. These cutoffs are based on national median EMS scene times and door-to-device times.

Results

Within the Southeast US, we identified 62,880,528 residents and 350 PPCI centers. Nearly 11 million people living in the Southeast US reside greater than 30 minutes from a PPCI center (17.3%, 10,866,710, +/- 58,143), with 2% (1,271,522 +/- 51,858) living greater than 60 minutes from a PPCI hospital. However, most patients reside in short transport zones; 82.7% (52,013,818 +/- 98,741). Within the Southeast region, 8.4% (52/616) of counties have more than 50% of their population in a long transport zone and 42.3% (22/52) of those have more than 90% of their population in long transport areas.

Conclusions

Nearly 11 million people in the Southeast US do not have access to timely PCI for STEMI care. This disparity may contribute to increased morbidity and mortality.
KIF2A maintains cytokinesis in mouse embryonic stem cells by stabilising intercellular bridge microtubules
Authors: Stockmann Lieke , Kabbech Helene , Kremers Gert-Jan , van Herk Brent , Dille Bas , van den Hout Mirjam , van IJcken Wilfred , Dekkers Dick H.W , Demmers Jeroen AA , Smal Ihor , Huylebroeck Danny , Basu Sreya , Galjart Niels
Published: July 2024

Cytokinesis, the final stage of cell division, serves to physically separate daughter cells while ensuring correct segregation of cellular components. In cultured naive mouse embryonic stem cells cytokinesis lasts unusually long but the underlying mechanisms are not well understood. Here, using cellular and in vitro approaches, we describe a novel function for the kinesin-13 member KIF2A in this process. In genome-engineered mouse embryonic stem cells we find that KIF2A mainly localises to spindle poles during metaphase and regulates spindle length in a manner consistent with its known role as microtubule minus-end depolymerase. By contrast, during cytokinesis we observe tight binding of KIF2A on the lattices of intercellular bridge microtubules. At this stage KIF2A maintains microtubule length and number, and controls microtubule acetylation. Based on in vitro experiments we propose that the conversion of KIF2A from a depolymerase to a stabiliser is driven both by the inhibition of its ATPase activity, which increases affinity for the lattice, and by a preference of KIF2A for compacted lattices. We propose that during cytokinesis KIF2A maintains the compacted microtubule state, thereby dampening acetylation. As KIF2A depletion causes pluripotency problems and affects mRNA homeostasis our results furthermore indicate that KIF2A-mediated microtubule stabilisation prolongs cytokinesis to maintain pluripotency.
Using breathing systems in anaesthesia for up to 7 days instead of 24 hours: a comparative microbial safety study
Authors: Haanappel Cynthia P. , Rieff Elisabeth A. , Pavkovic Lucija , van Holst-Raaphorst Merel N. , de Groot Woutrinus , van der Marel Caroline D. , Voor in ’t holt Anne F. , Severin Juliëtte A.
Published: July 2024

The replacement frequency of mechanical ventilator’s breathing systems used in operating rooms (ORs) currently varies between hospitals. In light of evidence-based decision-making and sustainability efforts, we aim to determine whether 7-day use of breathing systems instead of 24 hours is microbial safe. In this prospective single-centre explorative study, 30mm UniflowTM breathing systems used in eight ORs were included. In four ORs, breathing systems were replaced daily following standard practice. In the remaining four ORs, they were intended for a 7-day use. Breathing systems were sampled daily on three locations of the exterior surface and cultured for the presence of microorganisms. A total of 128 breathing systems were included, 99 from an OR with daily replacement and 29 from an OR with weekly replacement. A total of 604 samples were cultured, of which the majority, 549 (90.9%) cultures were negative. From the 55 (9.1%) positive cultures, the majority (n=49, 70%) were coagulase-negative staphylococci. None of the identified microorganisms were found in consecutive cultures. Cultures from day 2 to 7 did not show a statistically significant increased positivity rate compared to cultures from day 1, respectively 22.9% vs. 24.1%. The weekly replacement regimen, furthermore, decreased the number of breathing systems used with 71%.

Our data indicates that use of breathing systems up to seven days remains microbial safe. Additionally, only a minimal number of pathogenic microorganisms were detected, and these were not persistent on the breathing systems. Transitioning from 24-hours to intended 7-day use could significantly reduce costs and CO2emissions.
Microbial consortia driving lignocellulose transformation in agricultural woodchip bioreactors
Authors: Schiml Valerie , Walter Juline , Hagen Live H. , Várnai Anikó , Bergaust Linda , de León Arturo Vera-Ponce , Elsgaard Lars , Bakken Lars R , Arntzen Magnus Ø
Published: July 2024

Freshwater ecosystems can be largely affected by neighboring agriculture fields where potential fertilizer nitrate run-off may leach into surrounding water bodies. To counteract this eutrophic driver, farmers in certain areas are utilizing denitrifying woodchip bioreactors (WBRs) in which a consortium of microorganisms convert the nitrate into nitrogen-gases in anoxia, fueled by the degradation of lignocellulose. Polysaccharide-degrading strategies have been well-described for various aerobic and anaerobic systems, including the use of carbohydrate-active enzymes, utilization of lytic polysaccharide monooxygenases (LPMOs) and other redox enzymes, as well as the use of cellulosomes and polysaccharide utilization loci (PULs). However, for denitrifying microorganisms, the lignocellulose-degrading strategies remain largely unknown. Here, we have applied a combination of enrichment techniques, gas measurements, multi-omics approaches, and amplicon sequencing of fungal ITS and procaryotic 16S rRNA genes to identify microbial drivers for lignocellulose transformation in woodchip bioreactors, and their active enzymes. Our findings highlight a microbial community enriched for lignocellulose-degrading denitrifiers with key players from Giesbergeria, Cellulomonas, Azonexus, and UBA5070 (Fibrobacterota). A wide substrate specificity is observed among the many expressed carbohydrate active enzymes (CAZymes) including PULs from Bacteroidetes. This suggests a broad degradation of lignocellulose subfractions, even including enzymes with auxiliary activities whose functionality is still puzzling under strict anaerobic conditions.
Antagonistic Roles for MITF and TFE3 in Melanoma Plasticity
Authors: Chang Jeremy , Campbell-Hanson Katelyn R. , Vanneste Marion , Bartschat Nicholas I. , Nagel Ryan , Arnadottir Asdis K , Nhung Vu Hong , Montgomery Collin , Yevdash Julius , Jiang Jiarui , Bhinu Ardith , Helverson Annika , Henry Michael D. , Steingrímsson Eiríkur , Weigel Ronald J. , Cornell Robert A. , Kenny Colin
Published: July 2024

Melanoma cells have the ability to switch from a melanocytic and proliferative state to a mesenchymal and invasive state and back again. This plasticity drives intra-tumoral heterogeneity, progression, and therapeutic resistance. Microphthalmia-associated Transcription Factor (MITF) promotes the melanocytic/proliferative phenotype, but factors that drive the mesenchymal/invasive phenotype and the mechanisms that effect the switch between cell states are unclear. Here, we identify the MITF paralog TFE3 and the non-canonical mTORC1 pathway as regulators of the mesenchymal state. We show that TFE3 expression drives the metastatic phenotype in melanoma cell lines and tumors. Deletion of TFE3 in MITF-low melanoma cell lines suppresses their ability to migrate and metastasize. Further, MITF suppresses the mesenchymal phenotype by directly or indirectly activating expression ofFNIP1, FNIP2,andFLCN, which encode components of the non-canonical mTORC1 pathway, thereby promoting cytoplasmic retention and lysosome-mediated degradation of TFE3. These findings highlight a molecular pathway controlling melanoma plasticity and invasiveness.
Peri-centrosomal localization of small interfering RNAs inC. elegans
Authors: Jin Qile , Feng Xuezhu , Hong Minjie , Wang Ke , Chen Xiangyang , Cheng Jiewei , Kuang Yan , Si Xiaoyue , Xu Mingjing , Huang Xinya , Guang Shouhong , Zhu Chengming
Published: July 2024

The centrosome is the microtubule-organizing center and a crucial part of cell division. Centrosomal RNAs (cnRNAs) have been reported to enable precise spatiotemporal control of gene expression during cell division in many species. Whether and how cnRNAs exist inC. elegansare unclear. Here, using the nuclear RNAi Argonaute protein NRDE-3 as a reporter, we observed potential peri-centrosome localized small interfering (si)RNAs inC. elegans. NRDE-3 was previously shown to associate with pre-mRNAs and pre-rRNAs via a process involving the presence of complementary siRNAs. We generated a GFP-NRDE-3 knock-in transgene through CRISPR/Cas9 technology and observed that NRDE-3 formed peri-centrosomal foci neighboring the tubulin protein TBB-2, other centriole proteins and pericentriolar material (PCM) components inC. elegansembryos. The peri-centrosomal accumulation of NRDE-3 depends on RNA-dependent RNA polymerase (RdRP)-synthesized 22G siRNAs and the PAZ domain of NRDE-3, which is essential for siRNA binding. Mutation oferi-1, ergo-1, ordrh-3significantly increased the percentage of pericentrosome-enriched NRDE-3. At the metaphase of the cell cycle, NRDE-3 was enriched in both the peri-centrosomal region and the spindle. Moreover, the integrity of centriole proteins and pericentriolar material (PCM) components is also required for the peri-centrosomal accumulation of NRDE-3. Therefore, we concluded that siRNAs could accumulate in the peri-centrosomal region inC. elegansand suggested that the peri-centrosomal region may also be a platform for RNAi-mediated gene regulation.
Incidence, prevalence, and survival of colorectal cancer in the United Kingdom from 2000-2021: a population-based cohort study
Authors: Pedregal-Pascual Patricia , Guarner-Argente Carlos , Tan Eng Hooi , Golozar Asieh , Duarte-Salles Talita , Weinberger Rosen Andreas , Delmestri Antonella , Man Wai Yi , Burn Edward , PRIETO-ALHAMBRA DANIEL , Newby Danielle
Published: July 2024

Background: The management of colorectal cancer (CRC) is evolving, with advances in screening and treatment. We leveraged population-based data to generate up-to-date UK estimates of age and sex-specific incidence and prevalence and overall survival for the period 2000-2021. Methods: We analysed nationally representative primary care records from Clinical Practice Research Datalink (CPRD) GOLD, and replicated in CPRD Aurum. We calculated incidence rates, prevalence, and short- and long-term survival stratified by age, sex, and diagnosis year. Results: Unadjusted prevalence increased in the study period, from 15.6 to 46.4/10,000. Overall incidence was 61.5/100,000 person years, increasing in 2000-2011 to drop slightly in 2011-2014, and then plateauing. In contrast, early-onset CRC raised uninterruptedly throughout the study period, from 8.33 to 19.07/100,000 person-years. Overall survival was 78.3%, 51.4% and 38.5% at 1-, 5-, and 10-years respectively, lower in men compared to women. Modest improvements in survival were observed over the study period, particularly for 60-69 year old patients. Conclusion: The overall prevalence of CRC in the UK has tripled in the last 20 years, leading to increased healthcare resource needs and with slight survival improvements. A worrying increasing trend of early-onset CRC is observed, warranting further research into its diagnosis and management.
Topological Kondo effect with spinful Majorana fermions
Authors: Bollmann Steffen , Väyrynen Jukka I. , König Elio J.
Published: July 2024

Motivated by the importance of studying topological superconductors beyond the mean-field approximation, we here investigate mesoscopic islands of time-reversal-invariant topological superconductors. We characterize the spectrum in the presence of strong order-parameter fluctuations in the presence of an arbitrary number of Kramers pairs of Majorana edge states and study the effect of coupling the Coulomb blockaded island to external leads. In the case of an odd fermionic parity on the island, we derive an unconventional Kondo Hamiltonian in which metallic leads couple to both topological Majorana degrees of freedom (which keep track of the parity in different leads) and the overall spin 12 in the island. For the simplest case of a single wire (two pairs of Majorana edge states), we demonstrate that anisotropies are irrelevant in the weak coupling renormalization group flow. This permits us to solve the Kondo problem in the vicinity of a Toulouse-type point using Abelian bosonization. We demonstrate a residual ground-state entropy of ln(2), which is protected by spin-rotation symmetry, but reduced to ln(2) (as in the spinless topological Kondo effect) by symmetry-breaking perturbations. In the symmetric case, we further demonstrate the simultaneous presence of both Fermi-liquid and non-Fermi-liquid-like thermodynamics (depending on the observable) and derive charge and spin transport signatures of the Coulomb blockaded island.

Published by the American Physical Society
2024
Determination of the degree of crystallinity of polyphenylene sulfide composited with crystalline and non-crystalline fillers by applying the direct derivation method
Authors: Toraya Hideo
Published: July 2024

A new procedure for determining the degree of crystallinity (DOC) has been recently proposed, and it has been verified using experimental and computer-generated powder diffractometry data [Toraya (2023). J. Appl. Cryst.
56, 1751–1763]. As an application to real materials like engineering plastics, this procedure is here applied to the DOC determination of plate-like polyphenylene sulfide (PPS) samples, composited with crystalline and non-crystalline fillers. The coexistence of partially crystallized polymer with non-crystalline fillers in target materials makes it difficult to separate the non-crystalline part of the partially crystallized polymer. This problem is here solved by the inverse application of the direct derivation (DD) method for quantitative phase analysis (QPA). The intensity–composition (IC) formula used in the DD method can derive the weight fractions of the individual components from just the total sums of observed intensities and the chemical composition data for these components [Toraya (2016). J. Appl. Cryst.
49, 1508–1516]. For the present purpose, the IC formula has been inversely applied to calculate the relative intensity ratios of individual components under the assumption that the chemical compositions and weight fractions of the respective components are known. The total halo intensity could then be separated into the non-crystalline part of the polymer and the non-crystalline filler. Analyzed results of PPS composites in four different DOCs are reported.
CFD investigation of pouchtype lithium-ion battery
Authors: Mayıl Ayberk Salim , Yetik Ozge
Published: July 2024

Purpose

In the dynamic realm of energy storage, lithium-ion batteries stand out as a frontrunner, powering a myriad of devices from smartphones to electric vehicles. However, efficient heat management is crucial for ensuring the longevity and safety of these batteries. This paper aims to delve into the process of lithium-ion battery heat management systems, exploring how cutting-edge technologies are used to regulate temperature and optimize performance. In addition, computational fluid dynamics (CFD) studies take center stage, offering insights into the intricate thermal dynamics within these powerhouses.

Design/methodology/approach

In this study, thermal behavior of pouch type lithium-ion battery cell has been investigated by using CFD method. Result of different discharge rates have been evaluated by using multi-scale multi-dimensional (MSMD) battery model. By using MSMD Model 0.5C, 1C, 2C, 3C and 5C discharge rates are compared in equivalent circuit model (ECM) and NTGK empirical models by monitoring averaged surface temperature on battery body wall. In addition, on NTGK model, air cooling effect has been studied with the 0.1 m/s, 0.2 m/s and 0.5 m/s air, velocities.

Findings

Results shows that higher discharge rate causes higher temperature on battery zones and air cooling is effective to obtain the lower zone temperatures. Also, ECM model gives higher temperature than NTGK model on battery zone.

Originality/value

When the literature is evaluated, comparison of the models used in battery cooling (ECM and NTGK) has never been done before. Within the scope of this study, model comparison was made. At the same time, the time step has always been ignored in the literature. In this study, both time step and forced convection conditions were considered when comparing the models.