bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatially resolved molecular and cellular atlas of the mouse brain
Authors: Han Lei , Liu Zhen , Jing Zehua , Liu Yuxuan , Chang Huizhong , Lei Junjie , Peng Yujie , Wang Kexin , Xu Yuanfang , Liu Wei , Wu Zihan , Li Qian , Shi Xiaoxue , Zheng Mingyuan , Wang He , Deng Juan , Zhong Yanqing , Pan Hailin , Lin Junkai , Zhang Ruiyi , Chen Yu , Wu Jinhua , Xu Mingrui , Ren Biyu , Cheng Mengnan , Yu Qian , Song Xinxiang , Lu Yanbing , Tang Yuanchun , Yuan Nini , Sun Suhong , An Yingjie , Ding Wenqun , Sun Xing , Wei Yanrong , Zhang Shuzhen , Dou Yannong , Zhao Yun , Han Luyao , Zhu Qianhua , Xu Junfeng , Wang Shiwen , Chen Hanbo , Wang Dan , Bai Yinqi , Liang Yikai , Liu Yuan , Chen Mengni , Xie Chun , Bo Binshi , Li Mei , Zhang Xinyan , Ting Wang , Chen Zhenhua , Fang Jiao , Li Shuting , Jiang Yujia , Tan Xing , Zuo Guolong , Xie Yue , Li Huanhuan , Tao Quyuan , Li Yan , Liu Jianfeng , Liu Yuyang , Hao Mingkun , Wang Jingjing , Wen Huiying , Liu Jiabing , Yan Yizhen , Zhang Hui , Sheng Yifan , Han Min , Yu Shui , Liao Xiaoyan , Jiang Xuyin , Wang Guangling , Liu Huanlin , Wang Congcong , Feng Ning , Liu Xin , Ma Kailong , Xu Xiangjie , Han Tianyue , Cao Huateng , Zheng Huiwen , Chen Yadong , Lu Haorong , Yu Zixian , Zhang Jinsong , Wang Bo , Wang Zhifeng , Xie Qing , Pan Shanshan , Liu Chuanyu , Xu Chan , Cui Luman , Li Yuxiang , Liu Shiping , Liao Sha , Chen Ao , Wu Qing-Feng , Wang Jian , Liu Zhiyong , Sun Yidi , Mulder Jan , Yang Huanming , Wang Xiaofei , Li Chao , Yao Jianhua , Xu Xun , Liu Longqi , Shen Zhiming , Wei Wu , Sun Yan-Gang
Published: December 2023

A comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding function of the brain. Here, using snRNA-seq and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters with single-cell resolution involving over 6 million cells as well as for 29,655 genes. We have identified new astrocyte clusters, and demonstrated that distinct cell clusters exhibit preference for cortical subregions. In addition, we identified 155 genes exhibiting regional specificity in the brainstem, and 513 long non-coding RNA exhibited regional specificity in the adult brain. Parcellation of brain regions based on spatial transcriptomic information showed large overlap with that by traditional method. Furthermore, we have uncovered 411 transcription factor regulons with spatiotemporal specificity during development. Thus, our study has discovered genes and regulon with spatiotemporal specificity, and provided a high-resolution spatial transcriptomic atlas of the mouse brain.
Characterization of cortical neurodevelopmentin vitrousing gene expression and morphology profiles from single cells
Authors: Sundaresh Adithi , Meistermann Dimitri , Lampela Riina , Yang Zhiyu , Woldegebriel Rosa , Ganna Andrea , Puigdevall Pau , Kilpinen Helena
Published: December 2023

Differentiation of induced pluripotent stem cells (iPSC) towards different neuronal lineages has enabled diverse cellular models of human neurodevelopment and related disorders. However,in vitrodifferentiation is a variable process that frequently leads to heterogeneous cell populations that may confound disease-relevant phenotypes. To characterize the baseline and diversity of cortical neurodevelopmentin vitro, we differentiated iPSC lines from multiple healthy donors to cortical neurons and profiled the transcriptomes of 60,000 single cells across three timepoints spanning 70 days. We compared the cell types observedin vitroto those seenin vivoand in organoid cultures to assess how well iPSC-derived cells recapitulate neurodevelopmentin vivo. We found that over 60% of the cells resembled those seen in the fetal brain with high confidence, while 28% represented metabolically abnormal cell states and broader neuronal classes observed in organoids. Further, we used high-content imaging to quantify morphological phenotypes of the differentiating neurons across the same time points using Cell Painting. By modeling the relationship between image-based features and gene expression, we compared cell type- and donor-specific effects across the two modalities at single cell resolution. We found that while morphological features capture broader neuronal classes than scRNA-seq, they enhance our ability to quantify the biological processes that drive neuronal differentiation over time, such as mitochondrial function and cell cycle. Finally, we show that iPSC-derived cortical neurons are a relevant model for a range of brain-related complex traits. Taken together, we provide a comprehensive molecular atlas of human cortical neuron developmentin vitrothat introduces a relevant framework for disease modeling.
ξ-π: a nonparametric model for neural power spectra decomposition
Authors: Hu Shiang , Zhang Zhihao , Zhang Xiaochu , Wu Xiaopei , Valdes-Sosa Pedro A.
Published: December 2023

The power spectra estimated from the brain recordings are the mixed representation of aperiodic transient activity and periodic oscillations, i.e., aperiodic component (AC) and periodic component (PC). Quantitative neurophysiology requires precise decomposition preceding parameterizing each component. However, the shape, statistical distribution, scale, and mixing mechanism of AC and PCs are unclear, challenging the effectiveness of current popular parametric models such as FOOOF, IRASA, BOSC, etc. Here,ξ-πwas proposed to decompose the neural spectra by embedding the nonparametric spectra estimation with penalized Whittle likelihood and the shape language modeling into the expectation maximization frame-work.ξ-πwas validated on the synthesized spectra with loss statistics and on the sleep EEG and the large sample iEEG with evaluation metrics and neurophysiological evidence. Compared to FOOOF, both the simulation presenting shape irregularities and the batch simulation with multiple isolated peaks indicated thatξ-πimproved the fit of AC and PCs with less loss and higher F1-score in recognizing the centering frequencies and the number of peaks; the sleep EEG revealed thatξ-πproduced more distinguishable AC exponents and improved the sleep state classification accuracy; the iEEG showed thatξ-πapproached the clinical findings in peak discovery. Overall,ξ-πoffered good performance in the spectra decomposition, which allows flexible parameterization using descriptive statistics or kernel functions.ξ-πmay be a promising tool for brain signal decoding in fields such as cognitive neuroscience, brain-computer interface, neurofeedback, and brain diseases.
Satellite glial GPR37L1 regulates maresin and potassium channel signaling for pain control
Authors: Bang Sangsu , Jiang Changyu , Xu Jing , Chandra Sharat , McGinnis Aidan , Luo Xin , He Qianru , Li Yize , Wang Zilong , Ao Xiang , Parisien Marc , Fernandes de Araujo Lorenna Oliveira , Esfahan Sahel Jahangiri , Zhang Qin , Tonello Raquel , Berta Temugin , Diatchenko Luda , Ji Ru-Rong
Published: December 2023

G protein coupled receptor 37-like 1 (GPR37L1) is an orphan GPCR and its function remains largely unknown. Here we report that GPR37L1 transcript is highly expressed compared to all known GPCRs in mouse and human dorsal root ganglia (DRGs) and selectively expressed in satellite glial cells (SGCs). Peripheral neuropathy following diabetes and chemotherapy by streptozotocin and paclitaxel resulted in downregulations of surface GPR37L1 in mouse and human DRGs. Transgenic mice withGpr37l1deficiency exhibited impaired resolution of neuropathic pain symptom (mechanical allodynia), whereas overexpression ofGpr37l1in mouse DRGs can reverse neuropathic pain. Notably, GPR37L1 is co-expressed and coupled with potassium channels in SGCs. We found striking species differences in potassium channel expression in SGCs, with predominant expression of KCNJ10 and KCNJ3 in mouse and human SGCs, respectively. GPR37L1 regulates the surface expression and function of KCNJ10 and KCNJ3. We identified the pro-resolving lipid mediator maresin 1 (MaR1) as a GPR37L1 ligand. MaR1 increases KCNJ10/KCNJ3-mediated potassium influx in SGCs via GPR37L1. MaR1 protected chemotherapy-induced suppression of KCNJ13/KCNJ10 expression and function in SGCs. Finally, genetic analysis revealed that theGPR37L1-E296Kvariant is associated with increased chronic pain risk by destabilizing the protein. Thus, GPR37L1 in SGCs offers a new target for neuropathy protection and pain control.
Spontaneous Intersibling Polymorphism in the Development of Dopaminergic Neuroendocrine Cells in Sea Urchin Larvae: Impacts on the Expansion of Marine Benthic Species
Authors: Obukhova Alexandra L. , Khabarova Marina Yu. , Semenova Marina N. , Starunov Viktor V. , Voronezhskaya Elena E. , Ivashkin Evgeny G.
Published: December 2023

Plasticity of the nervous system enables the formation of the most adaptive neural circuits and the corresponding behavior of animals. The mechanism by which plasticity arises during development and its involvement in animal adaptation is one of the astonishing questions. Sea urchin larvae are known for their evolutionary and ecological diversity as well as their developmental forms and behavioral patterns. This research addresses the intricate neuroendocrine adaptations that govern larval development of sea urchins, focusing on the coordination between dopaminergic (DA) and serotonergic (5-HT) neurons. The study reveals a heterochronic polymorphism in the appearance of post oral DA neurons and confirms the stable differentiation pattern of apical 5-HT neurons in the larvae of Mesocentrotus nudus and Paracentrotus lividus. We demonstrate that an increased number of DA cells and DA application correlate with downward swimming of the larvae. In contrast, 5-HT cells and serotonin application unsure larval upward swimming. As a result, the 5-HT/DA ratio underlay stage-dependent vertical distribution of the larvae within the water column. In larvae of the same age, the precise balance of 5-HT and DA cells underlie the basis for the different potentials of individuals for upward and downward swimming. This coordination in humoral regulation underlies shifts in larval behavior within a single generation. Based on our findings on DA-cells polymorphism, we have proposed a model illustrating how the balance between the serotonin and dopamine systems, shaped by heterochrony in DA cell appearance, impacts larval behavior, reduces competition between siblings and ensures optimal population expansion. The study explores the evolutionary and ecological implications of these neuroendocrine adaptations in marine species.
EfNST: A composite scaling network of EfficientNet for improving spatial domain identification performance
Authors: Zhao Yanan , Long Chunshen , Yin Na , Si Zhihao , Shang Wenjing , Feng Zhenxing , Zuo Yongchun
Published: December 2023

Spatial Transcriptomics (ST) leverages Gene Expression Profiling while preserving Spatial Location and Histological Images, enabling it to provide new insights into tissue structure, tumor microenvironment, and biological development. The identification of spatial domains serves as not only the foundation for ST research but also a crucial step in various downstream analyses. However, accurately identifying spatial domains using computational methods remains a tremendous challenge due to the poor computational performance of many existing algorithms. Here, we propose EfNST, a deep learning algorithm based on a composite scaling network of the EfficientNet Network, designed specifically for the analysis of 10X Visium spatial transcriptomics data. We applied EfNST to three different datasets: human Dorsolateral Prefrontal Cortex, human breast cancer and mouse brain anterior. EfNST outperforms five advanced competing algorithms, achieving the best Adjusted Rand Index (ARI) scores of 0.554, 0.607, and 0.466, respectively. Notably, EfNST demonstrated high accuracy in identifying fine tissue structure and discovering corresponding marker genes with an improved running speed. In conclusion, EfNST offers a novel approach for inferring spatial organization of cells from discrete datapoints, facilitating the exploration of new insights in this field.
Homologous recombination contributes to the repair of acetaldehyde-induced DNA damages
Authors: Yamazaki Kosuke , Takayasu Kazuto , Ngo Trinh Thi To , Onuki Ayaka , Kawaji Hideya , Oshima Shunji , Kanda Tomomasa , Masai Hisao , Sasanuma Hiroyuki
Published: December 2023

Acetaldehyde, a chemical that can cause DNA damage and contribute to cancer, is prevalently present in our environment, e.g., in alcohol, tobacco, and food. Although aldehyde potentially promotes crosslinking reaction among biological substances including DNA, RNA, and proteins, it remains unclear what types of DNA damage are caused by acetaldehyde and how they are repaired. In this study, we examined acetaldehyde sensitivity of DNA damage-deficient cells established from human TK6 cell line. Among the mutants, mismatch repair mutants did not show a hypersensitivity to acetaldehyde, while cells deficient in base and nucleotide excision repair pathways increased its sensitivity. We found a delayed repair and hypersensitivity in homologous recombination (HR)-deficient cells but not in non-homologous end joining-deficient cells after acetaldehyde treatment. By analyzing the formation of acetaldehyde-induced RAD51 foci, which represent HR intermediates, HR-deficient cells, but not NHEJ, exhibits delayed repair of acetaldehyde-induced DNA damages, compared withwild-type. These results suggest that acetaldehyde causes complex DNA damages that requires various types of repair pathways. Interestingly, mutants deficient in TDP1 and TDP2, which are involved in the removal of protein adducts from DNA ends, exhibited hypersensitivity to acetaldehyde. the acetaldehyde sensitivity of theTDP1-/-/RAD54-/-double mutant was similar to that of each single mutant. This epistatic relationship between TDP1 and RAD54 suggests that that the removal of protein-DNA adducts generated by acetaldehyde needs to be removed for efficient repair by HR. Our study would help understand the molecular mechanism of genotoxic and mutagenic effects of acetaldehyde.
Structural basis for inhibition of βFXIIa by garadacimab
Authors: Drulyte Ieva , Ghai Rajesh , Ow Saw Yen , Kapp Eugene A. , Quek Adam J. , Panousis Con , Wilson Michael J. , Nash Andrew D. , Pelzing Matthias
Published: December 2023

FXIIa is the principal initiator of the plasma contact system and can activate both procoagulant and proinflammatory pathways. Its activity is important in the pathophysiology of Hereditary Angioedema (HAE). Here, we describe a high-resolution cryo-EM structure of the beta-chain from FXIIa (βFXIIa) complexed with the Fab fragment of garadacimab. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This atypical structural mechanism is likely the primary contributor in the inhibition of activated FXII proteolytic activity in HAE. Garadacimab Fab-βFXIIa structure also reveals critical determinants of high-affinity binding of garadacimab to activated FXII. Structural analysis with other bonafide FXIIa inhibitors, such as benzamidine and C1-INH, reveals a conserved mechanism of βFXIIa inhibition, a novel finding of this study. In summary, garadacimab Fab-βFXIIa structure provides crucial insights into its mechanism of action and delineates primary and auxiliary paratopes/epitopes. This work reaffirms the benefits of cryo-EM as a primary tool to study antigen-antibody complexes in near native state, particularly where other methods have fallen short.
Common variation in a long non-coding RNA gene modulates variation of circulating TGF-β2 levels in metastatic colorectal cancer patients (Alliance)
Authors: Quintanilha Julia C.F. , Sibley Alexander B. , Liu Yingmiao , Niedzwiecki Donna , Halabi Susan , Rogers Layne , O’Neil Bert , Kindler Hedy , Kelly William , Venook Alan , McLeod Howard L. , Ratain Mark J. , Nixon Andrew B. , Innocenti Federico , Owzar Kouros
Published: December 2023

Background

Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC).The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous blood collected at baseline. A robust rank-based method was used to assess the statistical significance of each variant and protein pair against a strict genome-wide level. A given pQTL was tested for validation in two external datasets of prostate (CALGB 90401) and pancreatic cancer (CALGB 80303) patients. Bioinformatics analyses were conducted to further establish biological bases for these findings.

Results

The final analysis was carried out based on data from 540,021 common typed genetic variants and 23 protein markers from 869 genetically estimated European patients with mCRC. Correcting for multiple testing, the analysis discovered a novelcis-pQTL inLINC02869, a long non-coding RNA gene, for circulating TGF-β2 levels (rs11118119; AAF = 0.11;P-value < 1.4e-14). This finding was validated in a cohort of 538 prostate cancer patients from CALGB 90401 (AAF = 0.10,P-value < 3.3e-25). The analysis also validated acis-pQTL we had previously reported for VEGF-A in advanced pancreatic cancer, and additionally identifiedtrans-pQTLs for VEGF-R3, andcis-pQTLs for CD73.

Conclusions

This study has provided evidence of a novelcisgermline genetic variant that regulates circulating TGF-β2 levels in plasma of patients with advanced mCRC and prostate cancer. Moreover, the validation of previously identified pQTLs for VEGF-A, CD73, and VEGF-R3, potentiates the validity of these associations.
Associations of infections and vaccines with Alzheimer’s disease point to a major role of compromised immunity rather than specific pathogen in AD
Authors: Ukraintseva Svetlana , Yashkin Arseniy P. , Akushevich Igor , Arbeev Konstantin , Duan Hongzhe , Gorbunova Galina , Stallard Eric , Yashin Anatoliy
Published: December 2023

INTRODUCTION

Diverse pathogens (viral, bacterial, fungal) have been linked to Alzheimer’s disease (AD) indicating a possibility that the culprit may be compromised immunity rather than particular microbe. If true, then vaccines with broad beneficial effects on immunity might be protective against AD.

METHODS

We estimated associations of common adult infections, including herpes simplex, zoster (shingles), pneumonia, and recurrent mycoses, as well as vaccinations against shingles and pneumonia, with the risk of AD in a pseudorandomized sample of the Health and Retirement Study.

RESULTS

Shingles, pneumonia, and mycoses diagnosed between ages 65-75, were all associated with higher risk of AD later in life, by 16%-42%. Pneumococcal and shingles vaccines received between ages 65-75 both lowered the risk of AD, by 15%-21%.

DISCUSSION

Our results support the idea that the connection between AD and infections involves compromised immunity rather than specific pathogen. We discuss mechanisms by which the declining immune surveillance may promote AD, and the role of biological aging in it. Repurposing of vaccines with broad beneficial effects on immunity could be a reasonable approach to AD prevention. Pneumococcal and zoster vaccines are promising candidates for such repurposing.
Acoustic enrichment of heterogenous circulating tumor cells and clusters from patients with metastatic prostate cancer
Authors: Magnusson Cecilia , Augustsson Per , Undvall Anand Eva , Lenshof Andreas , Josefsson Andreas , Welén Karin , Bjartell Anders , Ceder Yvonne , Lilja Hans , Laurell Thomas
Published: December 2023

Background

There are important unmet clinical needs to develop cell enrichment technologies to enable unbiased label-free isolation of both single cell and clusters of circulating tumor cells (CTCs) manifesting heterogeneous lineage specificity. Here, we report a pilot study based on microfluidic acoustophoresis enrichment of CTCs using the CellSearch CTC assay as a reference modality.

Methods

Acoustophoresis uses an ultrasonic standing wave field to separate cells based on biomechanical properties (size, density, and compressibility) resulting in inherently label-free and epitope-independent cell enrichment. Following red blood cell lysis and paraformaldehyde fixation, 6 mL of whole blood from 12 patients with metastatic prostate cancer and 20 healthy controls were processed with acoustophoresis and subsequent image cytometry.

Results

Acoustophoresis enabled enrichment and characterization of phenotypic CTCs (EpCAM+, Cytokeratin+, DAPI+, CD45-/CD66b-) in all patients with metastatic prostate cancer and detected CTC-clusters composed of only CTCs or heterogenous aggregates of CTCs clustered with various types of white blood cells in 9 out of 12 patients. By contrast, CellSearch did not detect any CTC-clusters, but detected comparable numbers of phenotypic CTCs as acoustophoresis, with trends of finding higher number of CTCs using acoustophoresis.

Conclusion

Our preliminary data indicate that acoustophoresis provides excellent possibilities to detect and characterize CTC-clusters as a putative marker of metastatic disease and outcomes. Moreover, acoustophoresis enables sensitive label-free enrichment of cells with epithelial phenotype in blood and offers opportunities to detect and characterize CTCs undergoing epithelial-to-mesenchymal transitioning and lineage plasticity.
Clinical coding of long COVID in primary care 2020-2023 in a cohort of 19 million adults: an OpenSAFELY analysis
Authors: Henderson Alasdair D , Butler-Cole Ben FC , Tazare John , Tomlinson Laurie A , Marks Michael , Jit Mark , Briggs Andrew , Lin Liang-Yu , Carlile Oliver , Bates Chris , Parry John , Bacon Sebastian CJ , Dillingham Iain , Dennison William A , Costello Ruth E , Wei Yinghui , Walker Alex J , Hulme William , Goldacre Ben , Mehrkar Amir , MacKenna Brian ,   The OpenSAFELY Collaborative, Herrett Emily , Eggo Rosalind M
Published: December 2023

Background

Long COVID is the patient-coined term for the persistent symptoms of COVID-19 illness for weeks, months or years following the acute infection. There is a large burden of long COVID globally from self-reported data, but the epidemiology, causes and treatments remain poorly understood. Primary care is used to help identify and treat patients with long COVID and therefore Electronic Health Records (EHRs) of past COVID-19 patients could be used to help fill these knowledge gaps. We aimed to describe those with long COVID in primary care records in England.

Methods

With the approval of NHS England we used routine clinical data from over 19 million adults in England linked to SARS-COV-2 test result, hospitalisation and vaccination data to describe trends in the recording of 16 clinical codes related to long COVID between November 2020 and January 2023. We calculated rates per 100,000 person-years and plotted how these changed over time. We compared crude and minimally adjusted rates of recorded long COVID in patient records between different key demographic and vaccination characteristics using negative binomial models.

Findings

We identified a total of 55,465 people recorded to have long COVID over the study period, with incidence of new long COVID records increasing steadily over 2021, and declining over 2022. The overall rate per 100,000 person-years was 177.5 cases in women (95% CI: 175.5-179) and 100.5 men (99.5-102). In terms of vaccination against COVID-19, the lowest rates were observed in those with 3+ vaccine doses (103.5 [95% CI: 101.5-105]). Finally, the majority of those with a long COVID record did not have a recorded positive SARS-COV-2 test 12 weeks before the long COVID record.

Interpretation

EHR recorded long COVID remains very low compared and incident records of long COVID declined over 2022. We found the lowest rates of recorded long COVID in people with 3 or more vaccine doses. We summarised several sources of possible bias for researchers using EHRs to study long COVID.
Hospital segregation, critical care strain, and inpatient mortality during the COVID-19 pandemic in New York City
Authors: Zhilkova Anna , Alsabahi Laila , Olson Donald , Maru Duncan , Tsao Tsu-Yu , Morse Michelle
Published: December 2023

Background

Hospital segregation by race, ethnicity, and health insurance coverage is prevalent, with some hospitals providing a disproportionate share of undercompensated care. We assessed whether New York City (NYC) hospitals serving a higher proportion of Medicaid and uninsured patients pre-pandemic experienced greater critical care strain during the first wave of the COVID-19 pandemic, and whether this greater strain was associated with higher rates of in-hospital mortality.

Methods

In a retrospective analysis of all-payer NYC hospital discharge data, we examined changes in admissions, stratified by use of intensive care unit (ICU), from the baseline period in early 2020 to the first COVID-19 wave across hospital quartiles (265,329 admissions), and crude and age-adjusted inpatient mortality rates, also stratified by ICU use, in the first COVID wave across hospital quartiles (23,032 inpatient deaths), based on the proportion of Medicaid or uninsured admissions from 2017-2019 (quartile 1 lowest to 4 highest). Logistic regressions were used to assess the cross-sectional association between ICU strain, defined as ICU volume in excess of the baseline average, and patient-level mortality.

Results

ICU admissions in the first COVID-19 wave were 84%, 97%, 108%, and 123% of the baseline levels by hospital quartile 1-4, respectively. The risk-adjusted mortality rates for ICU admissions were36.4 (CI=34.7,38.2), 43.6 (CI=41.5,45.8), 45.9 (CI=43.8,48.1), and 45.7 (CI=43.6,48.0) per 100 admissions, and those for non-ICU admissions were 8.6 (CI=8.3,9.0), 10.9 (CI=10.6,11.3), 12.6 (CI=12.1,13.0), and 12.1 (CI=11.6,12.7) per 100 admissions by hospital quartile 1-4, respectively. Compared with the reference group of 100% or less of the baseline weekly average, ICU admissions on a day for which the ICU volume was 101-150%, 151-200%, and > 200% of the baseline weekly average had odds ratios of 1.17 (95% CI=1.10, 1.26), 2.63 (95% CI=2.31, 3.00), and 3.26 (95% CI=2.82, 3.78) for inpatient mortality, and non-ICU admissions on a day for which the ICU volume was 101-150%, 151-200%, and > 200% of the baseline weekly average had odds ratios of 1.28 (95% CI=1.22, 1.34), 2.60 (95% CI=2.40, 2.82), and 3.44 (95% CI=3.11, 3.63) for inpatient mortality.

Conclusions

Our findings are consistent with hospital segregation as a potential driver of COVID-related mortality inequities and highlight the need to desegregate health care to address structural racism, advance health equity, and improve pandemic resiliency.
The potential economic impact of the updated COVID-19 mRNA fall 2023 vaccines in Japan
Authors: Fust K , Joshi K , Beck E , Maschio M , Kohli M , Lee A , Hagiwara Y , van de Velde N , Igarashi A
Published: December 2023

This analysis estimates the economic and clinical impact of a Moderna updated COVID-19 mRNA Fall 2023 vaccine for adults ≥18 years in Japan. A previously developed Susceptible-Exposed-Infected-Recovered (SEIR) model with a 1-year analytic time horizon (September 2023-August 2024) and consequences decision tree were used to estimate symptomatic infections, COVID-19–related hospitalizations, deaths, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio (ICER) for a Moderna updated Fall 2023 vaccine versus no additional vaccination, and versus a Pfizer-BioNTech updated mRNA Fall 2023 vaccine. The Moderna vaccine is predicted to prevent 7.2 million symptomatic infections, 272,100 hospitalizations and 25,600 COVID-19 related deaths versus no vaccine. In the base case (healthcare perspective), the ICER was ¥1,300,000/QALY gained ($9,400 USD/QALY gained). Sensitivity analyses suggest results are most affected by COVID-19 incidence, initial vaccine effectiveness (VE), and VE waning against infection. Assuming the relative VE between both bivalent vaccines apply to updated Fall 2023 vaccines, the base case suggests the Moderna version will prevent an additional 1,100,000 symptomatic infections, 27,100 hospitalizations, and 2,600 deaths compared to the Pfizer-BioNTech vaccine. The updated Moderna vaccine is expected to be highly cost-effective at a ¥5 million willingness-to-pay threshold across a wide range of scenarios.
Perioperative Pressure Injury: Bibliometric Analysis
Authors: Handayani Luh Titi , Pandin Moses Glorino Rumambo , Nursalam
Published: December 2023

Background

The occurrence of pressure injuries in the perioperative period presents a significant clinical hurdle for surgical patients. Surgery is recognized as a risk factor contributing to the onset of pressure injuries, which can manifest shortly after the operation, within a few hours, or up to 72 hours post-surgery. Bibliometric analysis has been carried out to assess publication patterns, rank research studies, and uncover emerging themes in perioperative pressure injury research.

Method

Data covering the period from 2015 to 2023 were extracted through the indexing metadata of Scopus and CINAHL using the keywords “pressure injury” OR “pressure ulcer” AND “perioperative.” Bibliometric parameters were extracted, and VOSviewer was employed to obtain bibliometric network and overlay visualization results.

Result

The mapping and clustering results from the VOSviewer network and overlay visualization identified various factors, including risk factors, postoperative complications, Electronic Health Record (EHR), prediction models, perioperative leadership, perioperative hypotension, responsibility, skin lesions, positioning, infection, risk assessment, attitude, peripheral nerve injury, and interface injury.

Conclusion

The outcomes of mapping, clustering, ranking, and citation analysis of pressure injury in perioperative patients indicate that patient safety is the primary focus. From this main issue, indicators can be developed and transformed into variables that need analysis related to risk assessment, knowledge and attitude, policies, and referrals. The underlying theory in perioperative patient care is the middle-range theory by Myra Estrine Levine, with her esoteric nursing model, Conservation Model of Nursing.
Sexual Dimorphism in Systemic Inflammatory Responses to Femur Fracture in Mice Infected with SARS-CoV-2-Like Virus
Authors: Patrick Matthew , Foster Austin , Aneja Arun , Annamalai Ramkumar T.
Published: December 2023

Patients with femur fractures who are concurrently infected with COVID-19 face a threefold increase in mortality, likely due to a compounded inflammatory response. Furthermore, sex-specific differences in immune responses to COVID-19 have been documented, implicating gender as a potential modulator of disease severity in these comorbid conditions. Understanding the inflammatory interplay underlying this association is critical for the development of effective, targeted therapies to mitigate mortality.

In this study, we investigated the systemic, sex-specific inflammatory response in mice that sustain a fracture while infected with a murine coronavirus (MHV), which belongs to the same genus as SARS-CoV-2. Our findings reveal that the combined inflammatory incidents of MHV infection and fracture disrupt the systemic immune response in both female and male mice, leading to immune dysregulation characterized by altered cell recruitment and disruption of the normal inflammatory cascade. Notably, the study identifies sex-specific differences in immune response, with female subjects exhibiting significantly elevated levels of inflammatory cytokines, including IL-18 and TNFα, while males exhibit a diminished response. These sexually dimorphic differences are also reflected in the systemic immune cell populations, suggesting that the quantity of immune factors released may contribute to the observed discrepancies. Notably, these differences were minimal or moderate in animals that either got an MHV infection or fracture alone.

Our findings indicate that the overproduction of proinflammatory cytokines, such as IFNγ, IL-18, and TNFα—reminiscent of cytokine storm syndrome—drives immune dysregulation, exacerbating outcomes in patients with these comorbidities. The observed sex-specific responses may be influenced by factors such as sex hormones, including estrogen, highlighting the importance of considering gender in therapeutic approaches. These insights provide a foundation for the development of tailored interventions to improve outcomes for COVID-19 patients with musculoskeletal trauma, including fractures.
Membrane specificity of the human cholesterol transfer protein STARD4
Authors: Talandashti Reza , Ek Larissa van , Gehin Charlotte , Xue Dandan , Moqadam Mahmoud , Gavin Anne-Claude , Reuter Nathalie
Published: December 2023

STARD4 regulates cholesterol homeostasis by transferring cholesterol between plasma membrane and endoplasmic reticulum. The STARD4 structure features a helix-grip fold surrounding a large hydrophobic cavity holding the sterol. Its access is controlled by a gate formed by two flexible loops - Ω1 and Ω4- and the C-terminal α-helix. Besides this, little is known about the mechanisms by which STARD4 binds to membranes and extract/releases cholesterol. All available structures of STARD4 are without a bound sterol and display the same closed conformation of the gate. The cholesterol transfer activity of the mouse STARD4 is enhanced in the presence of anionic lipids, and in particular of phosphatidylinositol biphosphates (PIP2) for which two binding sites were proposed on the mouse STARD4 surface. Yet only one of these sites is conserved in human STARD4. We here report the results of a liposome microarray-based assay and microseconds-long molecular dynamics simulations of apo-and holo forms of human STARD4 with complex lipid bilayers mimicking the composition of the donor and acceptor membranes. We show that the binding of apo form of human STARD4 is sensitive to the presence of PIP2 through two specific binding sites, one of which was not identified on mouse STARD4. We report two novel conformations of the gate in holo-STARD4: a yet-unobserved close conformation and an open conformation of Ω4 shedding light on the opening/closure mechanism needed for cholesterol uptake/release. Overall, the modulation of human STARD4 membrane-binding by lipid composition, and by the presence of the cargo supports the capacity of human STARD4 to achieve directed transfer between specific organelle membranes.
Comparison of the mechanism of antimicrobial action of the gold(I) compound auranofin in Gram-positive and Gram-negative bacteria
Authors: Quadros Barsé Laísa , Ulfig Agnes , Varatnitskaya Marharyta , Vázquez-Hernández Melissa , Yoo Jihyun , Imann Astrid M. , Lupilov Natalie , Fischer Marina , Becker Katja , Bandow Julia E. , Leichert Lars I.
Published: December 2023

The antirheumatic gold(I) compound auranofin has been suggested to exhibit bactericidal activity by disrupting the thiol homeostasis through direct inhibition of bacterial thioredoxin reductase (TrxB). While highly effective at killing Gram-positive bacteria, it lacks significant activity against Gram-negative species for reasons that largely remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the low susceptibility of the Gram-negative model organismEscherichia colito auranofin when compared to the Gram-positive model organismBacillus subtilis. A change in the proteome ofE. coliexposed to auranofin suggested that the effect of this gold compound is a combination of inactivation of thiol-containing enzymes, upregulation of proteins involved in basal metabolism, and the consequent induction of systemic oxidative stress. Susceptibility tests inE. colimutants lacking the proteins upregulated upon auranofin treatment suggested that none of them are directly involved inE. coli’s high tolerance to auranofin. To elucidate factors that could make Gram-negative bacteria less susceptible to auranofin, we testedE. colicells lacking the efflux pump component TolC. These cells were more sensitive to auranofin treatment than the wild type, but not to an extent that would fully explain the observed difference in susceptibility of Gram-positive and Gram-negative organisms. We thus tested ifE. coli’s thioredoxin reductase (TrxB) is inherently less sensitive to auranofin than TrxB fromB. subtilis, which was not the case.E. colicells lacking components of the thioredoxin-system were also only marginally more susceptible to auranofin. However,E. colistrains lacking the low molecular weight thiol glutathione, but not glutathione reductase, showed a high susceptibility to auranofin. Bacterial cells expressing the genetically encoded redox probe roGFP2 allowed us to observe the oxidation of cellular protein thiolsin situ. In line with their susceptibility, the kinetics of probe oxidation and the degree of oxidation promoted by auranofin is significantly higher in Gram-positive bacteria when compared to Gram-negative bacteria. Based on our findings, we hypothesize that auranofin leads to a global disturbance in the cellular thiol redox homeostasis in bacteria, but Gram-negative bacteria are inherently more resistant due to the presence of drug export systems and high cellular concentrations of glutathione.
Editing of highly homologous gamma-globin genes by nickase deficient Base Editor mitigates large intergenic deletions
Authors: George Anila , Ravi Nithin Sam , Vaishnavi B , Marepally Srujan , Thangavel Saravanbhavan , Velayudhan Shaji R , Srivastava Alok , Mohankumar Kumarasamypet Murugesan
Published: December 2023

Base editing in gamma-globin promoter is a promising approach for reactivation of fetal-hemoglobin. Recent studies have shown that base editing could result in genotoxic events at the gamma globin locus including 4.9 kb large deletion of intervening region due to nicking in the paralogousHBG1 andHBG2 genes. Although the deletion frequency is less than what is observed with Cas9, it could diminish the therapeutic potential. We sought to evaluate if large deletion could be overcome while maintaining the editing efficiency by replacing the nCas9 of ABE8e with a catalytically inactive deadCas9 (dCas9). Using 3 therapeutically relevant gRNAs targeting the gamma globin promoter, we performed a comprehensive evaluation of the editing outcome and frequency of large deletion using dCas9, nCas9, dCas9-ABE8e and nCas9-ABE8e. Our findings indicate that while nicking in itself induced large deletions, the frequency reduced upon efficient base editing. Notably, there was no appreciable deletion with the use of dCas9-ABE8e making it a safer approach, in terms of genome integrity, for therapeutic genome editing in the gamma-globin locus. Further, we also demonstrate that dCas9 ABE8e can edit efficiently in primary human CD34+ hematopoietic stem and progenitor cells (HSPCs) to achieve therapeutic benefits.
When Age Tips the Balance: a Dual Mechanism Affecting Hemispheric Specialization for Language
Authors: Roger Elise , Labache Loїc , Hamlin Noah , Kruse Jordanna , Baciu Monica , Doucet Gaelle E.
Published: December 2023

Aging engenders neuroadaptations, generally reducing specificity and selectivity in functional brain responses. Our investigation delves into the functional specialization of brain hemispheres within language-related networks across adulthood. In a cohort of 728 healthy adults spanning ages 18 to 88, we modeled the trajectories of inter-hemispheric asymmetry concerning the principal functional gradient across 37 homotopic regions of interest (hROIs) of an extensive language network, known as the Language-and-Memory Network. Our findings reveal that over two-thirds of Language-and-Memory Network hROIs undergo asymmetry changes with age, falling into two main clusters. The first cluster evolves from left-sided specialization to right-sided tendencies, while the second cluster transitions from right-sided asymmetry to left-hemisphere dominance. These reversed asymmetry shifts manifest around midlife, occurring after age 50, and are associated with poorer language production performance. Our results provide valuable insights into the influence of functional brain asymmetries on language proficiency and present a dynamic perspective on brain plasticity during the typical aging process.
Commensal skin bacteria exacerbate inflammation and delay skin healing
Authors: Khadka Veda D. , Markey Laura , Boucher Magalie , Lieberman Tami D.
Published: December 2023

The skin microbiome can both trigger beneficial immune stimulation and pose a potential infection threat. Previous studies have shown that colonization of mouse skin with the model human skin commensalStaphylococcus epidermidisis protective against subsequent excisional wound or pathogen challenge. However, less is known about concurrent skin damage and exposure to commensal microbes, despite growing interest in interventional probiotic therapy. Here, we address this open question by applying commensal skin bacteria at a high dose to abraded skin. While depletion of the skin microbiome via antibiotics delayed repair from damage, application of commensals-- including the mouse commensalStaphylococcus xylosus, three distinct isolates ofS. epidermidis,and all other tested human skin commensals-- also significantly delayed barrier repair. Increased inflammation was observed within four hours ofS. epidermidisexposure and persisted through day four, at which point the skin displayed a chronic-wound-like inflammatory state with increased neutrophil infiltration, increased fibroblast activity, and decreased monocyte differentiation. Transcriptomic analysis suggested that the prolonged upregulation of early canonical proliferative pathways inhibited the progression of barrier repair. These results highlight the nuanced role of members of the skin microbiome in modulating barrier integrity and indicate the need for caution in their development as probiotics.
Trends in daily cigarette consumption among smokers: a population study in England, 2008-2023
Authors: Jackson Sarah E. , Tattan-Birch Harry , Buss Vera , Shahab Lion , Brown Jamie
Published: December 2023

Objectives

To estimate time trends in cigarette consumption among smokers in England between 2008 and 2023, and explore differences by key potential moderators.

Methods

We used data from 57,778 adult cigarette smokers participating in a nationally-representative monthly cross-sectional survey between January-2008 and September-2023. We estimated monthly time trends in mean daily consumption of (i) any, (ii) manufactured, and (iii) hand-rolled cigarettes among all smokers and by main type of cigarettes smoked, smoking frequency, age, gender, occupational social grade, region, nicotine replacement therapy use, and vaping status.

Results

Overall cigarette consumption fell from 13.6 [95%CI=13.3-13.9] to 10.6 [10.5-10.8] per day between January-2008 and October-2019 (a 22% decrease), then remained stable up to September-2023. Over this period, the proportion mainly/exclusively smoking hand-rolled cigarettes increased (from 30.6% [29.1-32.1%] in 2008 to 52.1% [49.7-54.5%] in 2023). As a result, manufactured cigarette consumption fell by 47%, from 9.5 [9.2-9.8] per day in January-2008 to 5.0 [4.7-5.3] in September-2023, while hand-rolled cigarette consumption increased by 35%, from 4.2 [3.9-4.4] to 5.6 [5.3-5.9]. The decline in overall cigarette consumption was observed across all subgroups, but was greater among non-daily smokers, younger smokers, and those who vaped.

Conclusions

Over the last 15 years, the average number of cigarettes consumed each day by smokers in England has fallen by almost a quarter, but has plateaued since October-2019. There has been a sharp decline in the number of manufactured cigarettes consumed and an increase in the number of hand-rolled cigarettes consumed, as smokers have increasingly shifted towards using hand-rolled tobacco.
Estimation of the mass density of biological matter from refractive index measurements
Authors: Möckel Conrad , Beck Timon , Kaliman Sara , Abuhattum Shada , Kim Kyoohyun , Kolb Julia , Wehner Daniel , Zaburdaev Vasily , Guck Jochen
Published: December 2023

The quantification of physical properties of biological matter gives rise to novel ways of understanding functional mechanisms by utilizing models that explicitly depend on physical observables. One of the basic biophysical properties is the mass density (MD), which determines the degree of crowdedness. It impacts the dynamics in sub-cellular compartments and further plays a major role in defining the opto-acoustical properties of cells and tissues. As such, the MD can be connected to the refractive index (RI) via the well known Lorentz-Lorenz relation, which takes into account the polarizability of matter. However, computing the MD based on RI measurements poses a challenge as it requires detailed knowledge of the biochemical composition of the sample. Here we propose a methodology on how to account fora priorianda posterioriassumptions about the biochemical composition of the sample as well as respective RI measurements. To that aim, we employ the Biot mixing rule of RIs alongside the assumption of volume additivity to find an approximate relation of MD and RI. We use Monte-Carlo simulations as well as Gaussian propagation of uncertainty to obtain approximate analytical solutions for the respective uncertainties of MD and RI. We validate this approach by applying it to a set of well characterized complex mixtures given bybovinemilk and intralipid emulsion. Further, we employ it to estimate the mass density of trunk tissue of living zebrafish (Danio rerio) larvae. Our results enable quantifying changes of mass density estimates based on variations in thea prioriassumptions. This illustrates the importance of implementing this methodology not only for MD estimations but for many other related biophysical problems, such as mechanical measurements using Brillouin microscopy and transient optical coherence elastography.
The absence of yeast Pex23 and Pex29 results in a mitochondrial fusion defect
Authors: Chen Haiqiong , de Boer Rinse , Krikken Arjen M. , Wu Fei , van der Klei Ida
Published: December 2023

Pex23 family proteins are membrane proteins of the endoplasmic reticulum that play a role in peroxisome and lipid body formation. The yeastHansenula polymorphacontains four members: Pex23, Pex24, Pex29 and Pex32. We previously showed that the loss of Pex24 or Pex32 results in severe peroxisomal defects, caused by reduced peroxisome-endoplasmic reticulum membrane contact sites. We now analyzed whether the absence of Pex23 proteins affects other organelles. Vacuoles were normal in all deletion strains. The number of lipid droplets was reduced inpex23andpex29, but not inpex24andpex32, indicating that peroxisome and lipid droplet formation require different Pex23 proteins. Inpex23andpex29cells, mitochondria were fragmented and clustered. This phenotype was not suppressed by an artificial mitochondria-endoplasmic reticulum tether, indicating that the abnormalities were not caused by reduced membrane contact sites. Deletion ofDNM1inpex23cells partially suppressed the phenotype. Also, the level of the mitochondrial fusion protein Fzo1 was reduced inpex23andpex29cells. These observations indicate that certain Pex23 family proteins are required for normal mitochondrial fusion.