bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosis Of Satoyoshi Syndrome Using A Neuroblastoma Cell (SH-SY5Y) Lysate As Substrate For Western Blot
Authors: Sevilla Avendaño José María , Garrido Carlos , Rodríguez Clemente Irene , Solís-García del Pozo Julián , Stephani Ulrich , Martínez Ricardo , Matsuura Eiji , de Cabo Carlos , Ceña Valentín , Solera Javier
Published: November 2024

Objective

Satoyoshi syndrome is a rare, likely autoimmune disorder that is traditionally diagnosed based on clinical criteria: painful muscle spasms, diarrhea and alopecia. Two previous reports showed a specific immunoreactive band in three patients using Western blot analysis with brain homogenate. The aim of this study was to evaluate the efficacy of SH-SY5Y cell lysate as a potential substitute for brain homogenate in the diagnosis of Satoyoshi syndrome.

Methods

Western blot analyses were conducted using brain homogenate, SH-SY5Y cell lysates, and differentiated SH-SY5Y cell lysates. Serum samples were obtained from three patients diagnosed with Satoyoshi syndrome, alongside control samples from thirty blood donors and six patients with other neurological conditions.

Results

Sera from patients with Satoyoshi syndrome displayed a consistent three band pattern in the 70–100 kDa range. This pattern was reproducible across all tested substrates (brain homogenate, SH-SY5Y lysate, and differentiated SH-SY5Y lysate), but it was not observed for the sera from the control groups. The immunoreactive bands were more patent when using either SH-SY5Y lysate compared to brain homogenate. No differences were found between the SH-SY5Y lysate and differentiated SH-SY5Y lysate.

Conclusion

SH-SY5Y cell lysate could be an alternative to brain homogenate for the immunodiagnostic evaluation of Satoyoshi syndrome. The use of SH-SY5Y cell lysate for Western blot analysis may improve visualization and reproducibility and have a lower cost.

Key messages

Satoyoshi syndrome is a rare disease currently diagnosed based only on clinical criteria

A biological marker test for Satoyoshi syndrome could lead to early diagnosis and treatment thus improving the outcomes.

SH-SY5Y cell lysate may be a better substrate than brain homogenate for Western blot based diagnosis of Satoyoshi syndrome.
Relationship between plasma cortisol concentration and Long COVID symptoms in the post-acute phase of COVID-19: a cross-sectional study and recommendations for future research
Authors: Dalhuisen Thomas , Grebe Halle , Anglin Khamal , Lu Scott , Goldberg Sarah A. , Kallás-Silva Lucas , Hauser Joshua , Conway Emily , Ewing Marin , Chen Jessica Y. , Fehrman Emily A. , Kelly J. Daniel , Martin Jeffrey N. , Hunt Peter W. , Henrich Timothy J. , Durstenfeld Matthew S. , Deeks Steven G. , Murphy Elizabeth , Schambelan Morris , Peluso Michael J.
Published: November 2024

BACKGROUND

Low cortisol concentrations have been reported in some people with Long COVID (LC), but more data from diverse cohorts are needed to validate this observation. A subset of people with LC present with symptoms resembling those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The objective of this study was to compare cortisol concentrations in those with and without Long COVID, with a particular focus on people experiencing ME/CFS-like Long COVID.

METHODS

We measured plasma cortisol in 200 individuals 3-6 months following a SARS-CoV-2 infection. Banked biospecimens collected between 8 AM-12 PM were used. Participants met the case definition for Long COVID if they had ≥1 COVID-attributed symptom at least 3 months after symptom onset. People who did not report any symptoms at least 3 months after symptom onset served as recovered controls. Adapting the 2015 Institute of Medicine criteria for ME/CFS, we further defined those with LC resembling ME/CFS (LC-ME).

RESULTS

We found no difference in overall morning cortisol concentrations between people with LC (n=144) and those who fully recovered (n=56) (median 8.9 µg/dL vs. 8.8 µg/dL, p=0.97). Analyses of samples collected between 8-10 AM, however, revealed that, compared to those who fully recovered, cortisol concentrations were lower between 8-9 AM for those with LC-ME (median 8.2 vs. 14.8, p=0.02), but higher between 9-10 AM for those with severe LC (>=5 symptoms) (median 12.4 vs. 8.5, p=0.009) and those with LC-ME (median 13.7 vs. 8.5, p=0.02).

CONCLUSION

We found no difference in overall morning plasma cortisol concentrations between those with and without Long COVID. Although our data could be suggestive of altered morning cortisol dynamics in a subset of people with Long COVID, longitudinal measures of cortisol in individuals with Long COVID will be critical to further inform the biology of the condition.
Subthalamic Nucleus Deep Brain Stimulation Modulates Strabismus in Parkinson’s Disease
Authors: Gupta Palak , Beylergil Sinem Balta , Kilbane Camilla , McIntyre Cameron C. , Noecker Angela M , Shaikh Aasef G. , Ghasia Fatema F.
Published: November 2024

Objective

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Visual impairments, such as strabismus (misalignment of the eyes during gaze holding), affect up to two-thirds of PD patients, impacting their quality of life. Conventional treatments offer limited relief, prompting exploration of alternatives like deep brain stimulation (DBS) of subthalamic nucleus (STN). This pilot study aims to assess whether STN DBS can alleviate PD-related strabismus and identify specific STN regions associated with favorable outcomes. We hypothesize that STN DBS improves strabismus by modulating subthalamic connectivity with the cerebellum, hence volume of activate tissue (VTA) generated with DBS will be in dorsal STN.

Methods

We studied 12 PD patients with bilateral STN DBS and five healthy controls. Clinical assessments, eye movement measurements using high-resolution eye tracking, and patient-specific DBS models were employed. Analysis included the VTA models, revealing distinct effects based on the location within the STN.

Results

We found significant strabismus in 66% of PD patients. STN DBS improved strabismus in 75% of cases. The improvement was associated with dorsal STN stimulation. STN DBS exacerbated strabismus in 25% of PD patients. The VTA in these participants were located in the ventral aspect of the STN.

Discussion

The findings highlight the significant effects of STN DBS on strabismus in PD, further offering insights into the complex interplay between neurodegeneration and control of eye alignment. This approach, combining clinical assessments, advanced eye tracking, and DBS computational modeling, contributes valuable knowledge towards targeted interventions for visual impairments in PD.
Deep Learning Unlocks the True Potential of Organ Donation after Circulatory Death with Accurate Prediction of Time-to-Death
Authors: Sun Xingzhi , De Brouwer Edward , Liu Chen , Krishnaswamy Smita , Batra Ramesh
Published: November 2024

Increasing the number of organ donations after circulatory death (DCD) has been identified as one of the most important ways of addressing the ongoing organ shortage. While recent technological advances in organ transplantation have increased their success rate, a substantial challenge in increasing the number of DCD donations resides in the uncertainty regarding the timing of cardiac death after terminal extubation, impacting the risk of prolonged ischemic organ injury, and negatively affecting post-transplant outcomes. In this study, we trained and externally validated an ODE-RNN model, which combines recurrent neural network with neural ordinary equations and excels in processing irregularly-sampled time series data. The model is designed to predict time-to-death following terminal extubation in the intensive care unit (ICU) using the last 24 hours of clinical observations. Our model was trained on a cohort of 3,238 patients from Yale New Haven Hospital, and validated on an external cohort of 1,908 patients from six hospitals across Connecticut. The model achieved accuracies of 95.3 ± 1.0% and 95.4 ± 0.7% for predicting whether death would occur in the first 30 and 60 minutes, respectively, with a calibration error of 0.024 ± 0.009. Heart rate, respiratory rate, mean arterial blood pressure (MAP), oxygen saturation (SpO2), and Glasgow Coma Scale (GCS) scores were identified as the most important predictors. Surpassing existing clinical scores, our model sets the stage for reduced organ acquisition costs and improved post-transplant outcomes.
Exploratory Blood Biomarker Patterns in a Mixed Dementia Cohort
Authors: Gezegen Haşim , Alaylıoğlu Merve , Şahin Erdi , Swann Owen , Veleva Elena , Güven Gamze , Yaman Umran , Salih Derviş A. , Bilgiç Başar , Hanağası Haşmet , Gürvit Hakan , Emre Murat , Gezen-Ak Duygu , Dursun Erdinç , Zetterberg Henrik , Hardy John , Heslegrave Amanda , Shoai Maryam , Samancı Bedia
Published: November 2024

Alzheimer’s disease (AD) diagnosis is challenging due to overlapping symptoms with other dementias. Current diagnostic methods are invasive and costly, highlighting the need for accessible biomarkers. This study investigates the diagnostic performance and pathophysiological implications of a novel plasma biomarker panel in a mixed dementia cohort, aiming to enhance diagnosis and elucidate underlying pathogenic mechanisms.

120 plasma biomarkers were analyzed using the NULISA™ platform in a well-characterized mixt dementia. CSF biomarkers were measured via ELISA. Statistical analyses employed ANOVA, and Kruskal-Wallis tests for group comparisons. Spearman correlations assessed relationships between CSF and plasma biomarkers. Diagnostic accuracy was evaluated using regression models and ROC curves. Feature importance and selection were performed using random forest analysis. Protein interactions assessed with GO enrichment analysis.

We evaluated 248 subjects (130 females, 118 males) with 117 AD, 50 MCI, 39 FTD, 25 DLB, and 17 other dementias. Plasma pTau were significantly elevated in AD compared to other groups, and in DLB compared to MCI. Plasma Aβ42 was highest in DLB, while NfL was highest in FTD. Plasma GFAP was highest in AD and elevated in DLB compared to MCI and FTD.

Plasma pTau levels showed a negative correlation with CSF Aβ42 and a positive correlation with CSF pTau in the entire cohort. CSF and plasma NfL levels were also highly correlated. These correlations were stronger in DLB and amyloid-positive MCI groups but weaker or absent in the AD group. Plasma pTau, GFAP, and NfL were negatively correlated with MMSE in AD, while GFAP showed a negative correlation with MMSE in FTD and DLB.

Plasma pTau217 demonstrated the best diagnostic accuracy for AD, DLB, FTD diagnosis and CSF amyloid positivity (AUCs 0.9, 0.84, 0.79, and 0.87, respectively). pTau181, pTau217, pTau231, total-tau and GFAP had lower odds in DLB and FTD compared to AD. AGRN, CXCL1, SCNB, TEK, and UCHL1 had higher odds in DLB compared to AD. SNAP25 had lower odds ratio in FTD compared to AD and DLB. pTau181, pTau217, pTau231, GFAP, MAPT, SNAP25 and PGF is related to AD progression.

Random forest analysis incorporating all plasma biomarkers, age, and gender yielded an AUCs of 0.85 for AD, 0.84 for FTD, and 0.75 for DLB. Refining the model by including biomarkers identified as significant in regression model improved performance, resulting in AUCs of 0.88 for AD, 0.87 for FTD, and 0.81 for DLB. This demonstrates potential for enhancing diagnostic accuracy through targeted biomarker panel refinement.
ELABELA as a Potential Diagnostic Biomarker and Therapeutic Target of Atherosclerosis
Authors: Tang Le , Yi Xiaoli , Yang Huiru , Song Shanshan , Tan Wenting , Xiong Jianhua , Liu Chunju , Zhang Yifeng , Wang Mulan , Zhu Mengzhi , Zheng Lixiang , Yu Jun , Xu Chuanming
Published: November 2024

Atherosclerosis (AS) is a progressive arterial disease characterized by chronic inflammation and plaque formation in blood vessel walls. ELABELA, an endogenous ligand for the G protein-coupled receptor APJ (apelin peptide jejunum, apelin receptor), has multiple pharmacological activities for protecting the cardiovascular system. This study aimed to determine the potential anti-atherosclerotic effect of ELABELA and reveal the underlying mechanisms. Plasma ELABELA levels were significantly reduced and negatively correlated with plasma MMP2 and MMP9 levels in AS patients and high-fat diet-induced atheroscleroticApoE−/−mice. Plasma ELABELA levels exhibited a potential diagnostic value for AS patients. Application of ELABELA-21 (ELA-21) significantly decreased atherosclerotic plaque area and inflammation in the aortas from theApoE-/-mice. ELA-21 administration modulated the balance between M1 and M2 macrophages in the abdominal cavity and aorta roots toward a more anti-inflammatory status, accompanied by reduced MMP2, MMP9, and PRR and enhanced APJ, ACE, and ACE2 protein expression in plaques within aortic roots and decreased plasma sPRR levels.In vitro, ELA-21 effectively suppressed oxidized-low-density lipoprotein-induced foam cell formation and LPS/IFN-γ-induced M1 polarization in THP-1 cells. Interestingly, the anti-inflammatory effect of ELA-21 was further enhanced by APJ inhibitor ML221, accompanied by elevatedACEandATP6AP2and reducedACE2mRNA levels. Collectively, our data highlighted the diagnostic and therapeutic potential of ELABELA on AS. ELA-21 protects against AS by inhibiting atherosclerotic plaque formation and promoting a more stable plaque phenotype, possibly via restoring the M1/M2 macrophage balance, enhancing macrophage ACE and ACE2 expression, and inhibiting the PRR system. ELABELA may be a novel biomarker and candidate therapeutic target for treating AS.
Variable-Interval Temporal Feathering to Optimize Organ-at-Risk Repair for Head and Neck Adaptive Radiotherapy
Authors: Karagoz Aysenur , Hemmati Mehdi , Nosrat Fatemeh , Mavroidis Panayiotis , Dede Cem , McCullum Lucas B. , Garcia Raul , Hosseinian Seyedmohammadhossein , Scott Jacob G. , Bates James E. , Enderling Heiko , Mohamed Abdallah S.R. , Brock Kristy K. , Schaefer Andrew J. , Fuller Clifton D.
Published: November 2024

Purpose

Temporally feathered radiation therapy (TFRT) for head-and-neck cancer (HNC) radiotherapy combines variable-dose daily subplans to increase the rest time of organs-at-risk (OARs) as sought in intensity modulated radiation therapy (IMRT). While the standard TFRT recommends uniform rest time for each OAR, improved toxicity outcomes may be achieved through variable rest time for OARs by incorporating the OARs’ variable radiosensitivity profiles.

Methods and Materials

A decision-making model was constructed to maximize the combined recovery of OARs by determining OARs’ optimal rest times. Two main components were incorporated: the cumulative biologically effective dose based on the linear-quadratic model; and a dynamical model capturing the adjusted recovery of OARs as a function of delivered dose. Further, variable radiosensitivity profiles were allowed across the OARs to capture their variable recovery time. Individual recoveries of each OAR under IMRT and the standard TFRT (sTFRT) was compared against optimized TFRT (oTFRT).

Results

Five OARs (larynx, esophagus, parotid, spinal cord, brainstem) were considered. When the cumulative dose delivered under TFRT and IMRT remains the same, three OARs exhibited higher recovery under oTFRT compared to the second-best approach (larynx (81.8% vs. 74.1%), esophagus (95.9% vs. 93.9%), parotid (85.6% vs. 83.5%), while the recovery of spinal cord (90.5% vs. 90.8%) and brainstem (96.2% vs. 96.6%) remained comparable under TFRT and IMRT approaches. With different cumulative dose under TFRT and IMRT, oTFRT achieved significantly higher recovery for larynx (95.5% vs. 81.8%) and parotid (92.9% vs. 85.6%), while it is slightly outperformed by IMRT for esophagus (93.4% vs. 95.9%), spinal cord (87.1% vs. 90.5%), and brainstem (90.2% vs. 96.6%). When considering the minimum end-of-treatment recovery, oTFRT always achieved higher recovery among the other two approaches.

Conclusions

By considering non-identical radiosensitivity profiles of OARs in HNC radiotherapy, TFRT can optimize their rest time to enhance recovery at the end of treatment, potentially reducing patient toxicities.
FlowDesign: Improved Design of Antibody CDRs Through Flow Matching and Better Prior Distributions
Authors: Wu Jun , Kong Xiangzhe , Sun Ningguan , Wei Jing , Shan Sisi , Feng Fuli , Wu Feng , Peng Jian , Zhang Linqi , Liu Yang , Ma Jianzhu
Published: November 2024

Designing antibodies with desired binding specificity and affinity is essential for pharmaceutical research. While diffusion-based models have advanced the co-design of the Complementarity-Determining Regions (CDRs) sequences and structures, challenges remain, including non-informative prior distribution, incompatibility with discrete amino acid types, and impractical computational cost in large-scale sampling. To address these, we proposed FlowDesign, a sequence-structure co-design approach based on Flow Matching, offering: (1) Flexible selection of prior distributions; (2) Direct matching of discrete distributions; (3) Enhanced computational efficiency for large-scale sampling. By leveraging various priors, data-driven structural models proved the most informative. FlowDesign outperformed baselines in Amino Acid Recovery (AAR), RMSD, and Rosetta energy. We also applied FlowDesign to design antibodies targeting the HIV-1 receptor CD4. FlowDesign yielded antibodies with improved binding affinity and neutralizing potency compared to the antibody Ibalizumab across multiple HIV mutants, validated by Biolayer Interferometry (BLI) and pseudovirus neutralization. This highlights FlowDesign's potential in antibody and protein design.
Global kinetic model of lipid-inducedα-synuclein aggregation and its inhibition by small molecules
Authors: Stevenson Alisdair , Staats Roxine , Dear Alexander J. , Voderholzer David , Meisl Georg , Guido Raphael , Galvagnion Céline , Buell Alexander K. , Knowles Tuomas P.J. , Vendruscolo Michele , Michaels Thomas C.T.
Published: November 2024

The aggregation ofα-synuclein into amyloid fibrils is a hallmark of Parkinson’s disease. This process has been shown to directly involve interactions between proteins and lipid surfaces when the latter are present. Despite this importance, the molecular mechanisms of lipid-induced amyloid aggregation have remained largely elusive. Here, we present a global kinetic model to describe lipid-induced amyloid aggregation ofα-synuclein. Using this framework we find thatα-synuclein fibrils form via a two-step primary nucleation mechanism and that lipid molecules are directly involved in both the nucleation and fibril elongation steps, giving rise to lipid-protein coaggregates. To illustrate the applicability of this kinetic approach to drug discovery, we identify the mechanism of action of squalamine, a known inhibitor of α-synuclein aggregation, finding that this small molecule reduces the rate of lipid-dependent primary nucleation. Our work will likely guide the rational design ofα-synuclein aggregation inhibitors.

Significance Statement

Amyloid aggregation is a hallmark of a diverse range of diseases including Parkinson’s Disease, where the proteinα-synuclein is a major con-stituent of proteinaceous deposits found in patients. It is well established that interactions betweenα-synuclein and lipids modulate aggregation. However, the molecular mechanisms driving this lipid-induced aggregation have remained largely elusive, which has frustrated so far the discovery of drugs that prevent lipid-induced aggregation. In this work, we present the first global kinetic model describing lipid-induced aggregation and by integrating this theoretical framework within vitroexperimental data of lipid-inducedα-synuclein aggregation, we reveal the role of lipid membranes in the aggregation process and uncover the mechanism by which small molecule inhibitors interfere with this process.
RNA methylation controls stress granule formation and function during erythropoiesis
Authors: Gunage Rajesh , Lin Shuibin , Wiley David , Choudhuri Avik , Smith Mackenzie , Han Tianxiao , Shah Arish , Coyne Steven , Koczirka Katherine , Chen Kenny Zhi Ming , Yu Chunjie , Drake Kyle , Yang Xin , Yang Song , Zhou Yi , Bauer Daniel , Qian Zhijian , Calo Eliezer , Gregory Richard I. , Zon Leonard I.
Published: November 2024

Stress granules (SGs) are crucial in RNA regulation, affecting cell fate and function. SGs contain RNAs, some of which can be methylated. We studied m6A RNA modifications during the human CD34+HSPCs (hCD34+) differentiating into erythroid cells and found that mRNAs encoding many erythroid-specific proteins had decreased methylation during differentiation. Increased levels ALKBH5 demethylase during erythropoiesis controls the levels of the 3’UTR methylation of these mRNAs. hCD34+carrying ALKBH5 mutations demonstrated a block in erythropoiesis, and mass-spectrometry studies of the mutant cells showed decreased levels of SG proteins, including the core granule protein ATXN2. ALKBH5 directly regulates the methylation of the mRNA ofATXN2.ATXN2overexpression accelerated the erythroid differentiation of HSPCs and rescued the erythroid differentiation ofALKBH5mutant cells. Very few SGs are found in normal human erythroid progenitors. SGs accumulated substantially inALKBH5mutant cells, and surprisingly overexpression ofATNX2reduced SG numbers to normal. Polysome analysis demonstrated m6A-modified RNAs to be enriched in the pre-polysome fractions that were less translated. This work establishes a mechanism by which during stress, ATXN2 facilitates the release of SG-stored m6A-modified RNAs including erythroid-specific and SG-enriched RNAs that are loaded onto functional ribosomes, allowing better translation and accelerated erythroid differentiation during stress.
Neuropeptides specify and reprogram division of labor in the leafcutter antAtta cephalotes
Authors: Gilbert Michael B. , Glastad Karl M. , Fioriti Maxxum , Sorek Matan , Gannon Tierney , Xu Daniel , Pino Lindsay K. , Korotkov Anatoly , Biashad Ali , Baeza Josue , Lauman Richard , Filippova Anastasiia , Kacsoh Balint Z. , Bonasio Roberto , Mathis Mackenzie W. , Garcia Benjamin A. , Seluanov Andrei , Gorbunova Vera , Berger Shelley L.
Published: November 2024

Social insects offer powerful models to investigate the mechanistic foundation of elaborate individual behaviors comprising a cooperative community. Workers of the leafcutter ant genusAttaprovide an extreme example of behavioral segregation among many phenotypically distinct worker types. We utilize the complex worker system ofAtta cephalotesto test the molecular underpinnings of behavioral programming and, in particular, the extent of plasticity to reprogramming. We identify specific neuropeptides as mediators of worker division of labor inA. cephalotes, finding two neuropeptides associated with characteristic behaviors of leafcutting and of brood care. Manipulation via genetic knockdown or by injection of these neuropeptides led to stark loss or gain of each behavior and to transcriptomic shifts in the predicted direction, that is, towards gene pathways expressed in the natural caste. We also compare specificA. cephalotesworker transcriptomes with those of orthologous workers of the eusocial mammal, the naked mole ratH. gaber, revealing global similarities between caste-biased expression and link to specific roles of our studied neuropeptides in ants. This work underscores the essential function of neuropeptides in establishing complex social behavior and a remarkable plasticity among individual behavioral types.
IL-10 Targets IRFs to Suppress IFN and Inflammatory Response Genes by Epigenetic Mechanisms
Authors: Mishra Bikash , Bachu Mahesh , Wingert Claire , Yuan Ruoxi , Chaudhary Vidyanath , Brauner Caroline , Bell Richard , Ivashkiv Lionel B.
Published: November 2024

Interleukin-10 (IL-10) is pivotal in suppressing inflammation and innate immune activation, in large part by suppressing induction of genes by potent inflammatory factors such as TLR ligands. Despite decades of research, molecular mechanisms underlying this inhibition have not been resolved. This study utilized an integrated epigenomic analysis of gene transcription, chromatin accessibility, histone modifications and transcription factor binding to investigate IL-10-mediated suppression of LPS and TNF responses in primary human monocytes. Instead of inhibiting core TLR4-activated pathways such as NF-κB, MAPK-AP-1 and TBK1-IRF3 signaling, IL-10 targeted IRF transcription factor activity and DNA binding, particularly IRF5 and an IRF1-mediated amplification loop that is operative in monocytes. This resulted in suppression of inflammatory NF-κB target genes, in whose activation IRFs play an amplifying role, and near-complete suppression of interferon-stimulated genes. Mechanisms of TLR4 and TNFR target gene inhibition included downregulation of chromatin accessibility, de novo enhancer formation, and IRF1-associated H3K27ac activating histone marks. These results provide a mechanism by which IL-10 suppresses inflammatory NF-κB target genes, highlight the role of IRF1 in inflammatory gene expression, and describe an underappreciated suppression of IFN responses by epigenetic mechanisms.
Gut Microbial Utilization of the Alternative Sweetener, D-Allulose, via AlsE
Authors: Ndjite Glory Minabou , Jiang Angela , Ravel Charlotte , Grant Maggie , Jiang Xiaofang , Hall Brantley
Published: November 2024

D-allulose, a rare sugar with emerging potential as a low-calorie sweetener, has garnered attention as an alternative to other commercially available alternative sweeteners, such as sugar alcohols, which often cause severe gastrointestinal discomfort. D-allulose-6-phosphate 3-epimerase (AlsE) is a prokaryotic enzyme that converts D-allulose-6-phosphate into D-fructose-6-phopshate, enabling its use as a carbon source. However, the taxonomic breadth of AlsE across gut bacteria remains poorly understood, hindering insights into the utilization of D-allulose by microbial communities. In this study, we provide experimental evidence showing thatClostridium innocuumis capable of D-allulose metabolism via a homologous AlsE. A bioinformatics search of 85,202 bacterial genomes identified 116 bacterial species with AlsE homologs, suggesting a limited distribution of AlsE in bacteria. Additionally,Escherichia colicontains a copy ofalsE, but it does not grow on D-allulose as a sole carbon source unlessalsEis heterologously expressed. A metagenomic analysis revealed that 15.8% of 3,079 adult healthy human metagenomic samples that we analyzed containedalsE, suggesting a limited prevalence of the enzyme in the gut microbiome. These results suggest that the gut microbiome has limited capacity to metabolize D-allulose viaalsE, supporting its use as an alternative sweetener with minimal impact on microbial composition and gastrointestinal symptoms. This finding also enables personalized nutrition, allowing diabetic individuals to assess their gut microbiota foralsE, and manage glycemic response while reducing gastrointestinal distress.
Pathological tau alters head direction signaling and induces spatial disorientation
Authors: Jiang Shan , Hijazi Sara , Sarkany Barbara , Gautsch Verena G. , LaChance Patrick A. , Hasselmo Michael E. , Bannerman David , Viney Tim J.
Published: November 2024

Spatial disorientation, an early symptom of dementia, is emerging as an early and reliable cognitive biomarker predicting future memory problems associated with Alzheimer’s disease, but the underlying neural mechanisms have yet to be fully defined. The anterodorsal thalamic nucleus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau, a major hallmark of Alzheimer’s disease and ageing. The ADn contains a high density of head direction (HD) cells, which contribute to spatial navigation and orientation. Hence, their disruption may contribute to spatial disorientation. To test this, we virally expressed human mutant tau (htau) in the ADn of adult mice. HD-tau mice were defined by phosphorylated and oligomeric forms of htau in ADn somata and in axon terminals in postsynaptic target regions. Compared to controls, HD-tau mice exhibited increased looping behavior during spatial learning, and made a greater number of head turns during memory recall, indicative of spatial disorientation. Usingin vivoextracellular recordings, we identified htau-expressing ADn cells and found a lower proportion of HD cells in the ADn from HD-tau mice, along with reduced directionality and altered burst firing. These findings provide evidence that expression of pathological human tau can alter HD signaling, leading to impairments in spatial orientation.
Effects of Soluble Electron Shuttles on Microbial Iron Reduction and Methanogenesis
Authors: Thapa Bhim Sen , Flynn Theodore M. , Jensvold Zena D. , Kemner Kenneth M. , Sladek Margaret F. , O’Loughlin Edward J. , Marshall Christopher W.
Published: November 2024

In many aquatic and terrestrial ecosystems, iron (Fe) reduction by microorganisms is a key part of biogeochemical cycling and energy flux. The presence of redox active electron shuttles in the environment potentially enables a phylogenetically diverse group of microbes to use insoluble iron as a terminal electron acceptor. We investigated the impact that different electron shuttles had on respiration, microbial physiology, and microbial ecology. We tested eight different electron shuttles, seven quinones and riboflavin, with redox potentials between 0.217 V and -0.340 V. Fe(III) reduction coupled to acetate oxidation was observed with all shuttles. Once Fe(III) reduction began to plateau, a rapid increase in acetate consumption was observed and coincided with the onset of methane production, except in the incubations with the shuttle 9,10-anthraquinone-2-carboxylic acid (AQC). The rates of iron reduction, acetate consumption, methanogenesis, and the microbial communities varied significantly across the different shuttles independent of redox potential. In general, shuttles appeared to reduce the overall diversity of the community compared to no shuttle controls, but certain shuttles were exceptions to this trend. Geobacteraceae were the predominant taxonomic family in all enrichments except in the presence of AQC or 1,2,-dihydroxyanthraquinone (AQZ), but each shuttle enriched a unique community significantly different from the no shuttle control conditions. This suggests that the presence of different redox-active electron shuttles can have a large influence on the microbial ecology and total carbon flux in the environment.

Importance

Iron is the fourth most abundant element in the Earth’s crust and the reduction of iron by microbes is an important component of global biogeochemical cycles. A phylogenetically diverse group of microbes are capable of conserving energy with oxidized iron as a terminal electron acceptor, but the environmental conditions favoring certain taxonomic clades in iron-reducing environments is unclear. One complicating factor often overlooked in small-scale enrichments is the influence of soluble, redox-active electron shuttles on the rate and microbial ecology of iron reduction. We tested the effects of eight different electron shuttles on the microbial physiology and ecology in iron-reducing enrichments derived from a local wetland. Each electron shuttle varied the microbial activity and enriched for a microbial community distinct from the no shuttle control condition. Therefore, in complex subsurface environments with many redox-active compounds present, we propose electron shuttles as a reason for the coexistence of multiple clades of iron-reducing bacteria.
Preliminary report on the molecular epidemiology of mpox, South Africa 2024
Authors: Featherston Jonathan , Grobbelaar Antoinette , Glass Allison , Goedhals Dominique , Hoek Kim , Maritz Jean , Govender Kamini , Govender Nevashan , Ismail Arshad , le Roux Chantel , Marshall Terry , Morobadi Daniel , Moodley Mishalan , Moolla Naazneen , Mtshali Senzo , Msimang Veerle , Vardas Eftyxia , Weyer Jacqueline
Published: November 2024

Mpox is an emerging viral infection and has since May 2022 been reported in a multi-country outbreak involving predominantly previously non-endemic countries. In addition, the number of cases of mpox is also rising in some endemic countries in Western and Central Africa. The disease is a notifiable medical condition in South Africa, with no cases reported before 2022. However, in 2022, coinciding with the peak of a multi-country mpox outbreak, five mpox cases were diagnosed in the country. Genomic sequencing and analysis revealed the presence of a monkeypox virus variant, which was circulating during the multi-country outbreak, namely Clade IIb sub-lineage B.1.7 (hMPXV). After the fifth case was reported in 2022, there were no cases detected for the following 20 months. In May 2024, mpox cases were again detected in South Africa leading to concerns that the virus may have been silently transmitting in the country since 2022. Whole genome sequencing and analysis for 22 mpox cases reported during May to September 2024, were compared with sequences obtained from mpox cases reported in South Africa in 2022, and cases that have been reported globally. It was found that the sequences of the 2024 cases analysed in this study, clustered with Clade IIb hMPXV and sub-lineage B.1.20 and B.1.6 sequences. The results indicate that the detection of mpox cases in South Africa was an extension of the ongoing multi-country outbreak. Detection of different sub-lineages of hMPXV indicates reintroductions of the virus in the country since 2022, with local transmission of Clade IIb B1.20 hMPXV.
Electronic health records reveal variations in the use of blood units by hour and medical specialty
Authors: Turkulainen Esa , Peltola Elissa , Perola Markus , Koskinen Miika , Arvas Mikko , Ilmakunnas Minna
Published: November 2024

BACKGROUND AND OBJECTIVES

Efficient blood supply chain requires accurate demand estimates. Blood demand is created by clinicians making transfusion decisions based on patient status. To better understand the use of blood units, we tracked their use hourly and across a large hospital organization.

MATERIALS AND METHODS

We analyzed blood use in adult patients over 2021-2022 at HUS Helsinki University Hospital, serving a population of 1.7 million and consuming a third of blood units used in Finland. We utilized electronic health records (EHR) to map transfusions to patient demographics, diagnoses, medical specialties, treatment events, surgical procedures, and laboratory values. Data were matched to transfusion of red blood cells, platelets and plasma using timestamps and treatment episodes.

RESULTS

In total, 107,331 units were transfused to 19,637 unique patients in 50,978 transfusion episodes. Most transfusions occurred in emergency settings, with 61.5% of use driven by emergency department admissions. The most common diagnoses were malignant neoplasms, anemias, and cardiovascular diseases. In total, 47.9% of transfusions were associated with a surgical procedure. Of these, 72.9% were for urgent surgery. Blood use peaked in the early evening and was lowest during morning office hours.

CONCLUSION

The study offers a comprehensive picture of blood use in one of the largest European hospital organizations. In addition to elective use, a significant portion of blood demand is driven by urgent and emergency needs, which introduces some uncertainty in predicting blood use. Future studies should aim to understand both elective and emergency blood use to help improve demand estimates.

Highlights

This study presents the first investigation into intraday blood use within a large hospital district, with precise transfusion timestamps enabling alignment with patient events.

Over the past 25 years, blood demand has shifted from surgery to hematology in the HUS Helsinki University Hospital.

The majority of blood is used in emergencies and urgent care, mostly outside office hours.
Association of hypotension with mortality among US adults: prospective cohort study
Authors: Han Yan , Tang Jing , Wu Na , Li Zhao , Cai Dachuan , Ren Hong , Hu Peng , Chen Zhiwei
Published: November 2024

Background

The associations of hypotension with mortality in general population remains incompletely understood. We aimed to investigate whether hypotension is associated with higher all-cause and cardiovascular disease (CVD) mortality in this population.

Methods

In this prospective analysis, we utilized data from the National Health and Nutrition Examination Survey (NHANES, 1999-2018), with mortality information linked until 2019. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs for the associations of different blood pressure (BP) with all-cause and CVD mortality.

Findings

Among the 37,832 participants, a total of 5261 deaths and 1664 deaths attributed to CVD causes were recorded over a median of 8.4 years of follow-up. The prevalence of hypotension was 7.6%. Both systolic BP and diastolic BP exhibited a J-shaped association with the all-cause and CVD mortality in restricted cubic spline modeling analysis (nonlinear-P <0.01). Compared to the normal BP group, the adjusted HRs for all-cause and CVD mortality in the hypotension group were 1.44 (1.20-1.74) and 1.57 (1.10-2.24), respectively. Subgroup analyses revealed that older individuals (age ≥60 years) and those with obesity exhibited more pronounced HRs for all-cause mortality, with HRs of 1.60 (1.28-2.00) and 1.95 (1.45-2.61), respectively (P for interaction <0.05).

Interpretation

In this nationally representative cohort of US adults, hypotension demonstrated a significant association with both all-cause and cardiovascular disease mortality, particularly among elderly and obesity individuals. The findings underscore the significance of paying attention to and optimizing the management of hypotension in the general population.
Using a Bayesian network to classify time to return to sport based on football injury epidemiological data
Authors: Yung Kate K.Y. , Wu Paul P.Y. , aus der Fünten Karen , Hecksteden Anne , Meyer Tim
Published: November 2024

Objective

The return-to-sport (RTS) process is multifaceted and complex, as multiple variables may interact and influence the time to RTS. These variables include intrinsic factors of the player, such as anthropometrics and playing position, or extrinsic factors, such as competitive pressure. Providing an individualised estimation is often challenging, and yet clinical decision support tools are often rare in the industry. This study aims to demonstrate the functions of a Bayesian network by the use of a set of basic epidemiological data.

Methods

To exemplify the use of Bayesian network in sports medicine, such as providing an individualised estimation time to RTS for individual players, we applied Bayesian network to a set of basic epidemiological data. Bayesian network was used as a decision support tool to model the epidemiological data and to integrate clinical data, non-clinical factors and expert knowledge. Specifically, we used the Bayesian network to capture the interaction between variables in order to 1) classify days to RTS and 2) injury severity (minimal, mild, moderate and severe).

Results

Retrospective injury data of 3374 player seasons and 6143 time-loss injuries from seven seasons of the professional German football league (Bundesliga, 2014/2015 through 2020/2021) were collected from public databases and media resources. A total of twelve variables from three main categories (player’s characteristics and anthropometrics, match information and injury information) were included. The key response variables are 1)days to RTS(1-3, 4-7, 8-14, 15-28, 29-60, >60, and 2)severity(minimal, mild, moderate and severe). As there are more than two categories, producer’s and user’s accuracy was used to reflect the sensitivity and specificity of the model. The producer’s accuracy of the model for days to RTS ranges from 0.24 to 0.97, while for severity categories range from 0.73 to 1.00. The user’s accuracy of the model for days to RTS ranges from 0.52 to 0.83, while for severity categories, it ranges from 0.67 to 1.00.

Conclusions

The Bayesian network can help to capture different types of data to model the probability of an outcome, such as days to return to sports. In our study, the result from the BN may support coaches and players in predicting days to RTS given an injury, 2) support team planning via assessment of scenarios based on player’s characteristics and injury risk and 3) provide evidence-based support of understanding relationships between factors and RTS. This study shows the key functions and applications of the Bayesian network in RTS, and we suggest further experimenting and developing the Bayesian network into a decision-supporting aid.
Autistic Neural Shiftability: The Distinct Pharmacological Landscape of the Autistic Brain
Authors: Whelan Tobias P. , Franca Lucas G.S. , Dimitrov Mihail , Pretzsch Charlotte M. , Velthuis Hester , Pereira Andreia C. , Ellis Claire L. , Irvin Glynis , Findon James L. , Wichers Robert H. , Ponteduro Francesca M. , Kangas Johanna , Mulcrone Naoise , Wong Nichol M.L. , Batalle Dafnis , Puts Nicolaas A.J. , Daly Eileen , Murphy Declan G.M. , McAlonan Grainne M.
Published: November 2024

Functionally inter-connected large-scale brain networks regulated by multiple neurotransmitter systems underpin complex human behaviour. A wide range of alterations in this neurofunctional landscape have been associated with autism. However, this evidence is mostly derived from cross-sectional analyses and thus assumes that any differences are static. Indeed, large sample sizes are required to identify reproducible baseline differences in functional connectivity between autistic and non-autistic individuals. Instead, we propose what is different in autism is not necessarily the baseline functional connectivity of resting-state networks, but rather their responsivity or regulation by neurotransmitter systems. We tested this hypothesis using a uniform analytical framework to capture the modulation of functional connectivity by single doses of pharmacological probes targeting three major neurotransmitter systems implicated in autism, namely gamma-amino-butyric-acid (GABA), serotonin (5HT) and mu opioid systems. Every drug challenge altered resting-state network connectivity differentially in the autistic compared to the non-autistic group. However, regardless of the neurotransmitter system probed, drug challenge elicited increases in between-network connectivity in autistic participants but minimal or decreased between-network connectivity in their non-autistic peers. There was no group difference in the responsivity of within-network connectivity. Thus, there is altered responsivity of neurotransmitter systems in the autistic brain. This has important implications for pharmacotherapy in autism because these neurotransmitter systems are the targets of several medications commonly prescribed to manage mental health conditions that frequently co-occur in autism. Investigating if these drug-induced shifts in functional connectivity can help provide better targeted clinical interventions, will be important next translational steps.
The effects of left vagus nerve block on postoperative nausea and vomiting in patients undergoing thoracic or abdominal laparoscopic surgery: A randomized controlled trial
Authors: Chen Chen , Yang Zhongyu , Zheng Qi , Ren Yanghao , Yang Tianyu , Zhen Xinyue , Ding Liang , Fan Bingqian , Wang Tianhai , Dai Hongyan
Published: November 2024

Purpose

To explore the influence of preoperative vagus nerve block (VNB) on postoperative nausea and vomiting (PONV) in patients undergoing thoracic or abdominal laparoscopic surgery.

Methods

Patients were randomly divided into the VNB group (V group, n=60) and the control group (C group, n=60). The V group received left VNB before anesthesia induction, while the C group did not receive any intervention. The incidence and severity of PONV within one day after surgery were compared between the two groups to evaluate the effect of left VNB on PONV in patients.

Results

The incidence of PONV in the V group (25%) was significantly lower than that in the C group (60%) (χ2= 15.038,P< 0.001). The incidences of mild and severe PONV in the V group were 16.67% and 8.33%, respectively, while those in the C group were 36.67% and 23.33%, respectively. The differences between the two groups were significant (mild: χ2= 6.136,P= 0.013; severe: χ2= 5.065,P= 0.024).

Conclusion

Left VNB can reduce the incidence and severity of PONV caused by thoracic or abdominal laparoscopic surgery.
Post-SARS-CoV-2 Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Symptoms in Two Cohort Studies of COVID-19 Recovery
Authors: Jamal Armaan , Dalhuisen Thomas , Gallego Márquez Nuria , Dziarski Alisha D. , Uy Julian , Walch Samantha N. , Thomas Sean A. , Fehrman Emily A. , Romero Arianna E. , Zelaya Ashley S. , Akasreku Enam A. , Adeagbo Tamilore V. , Pasetes Elizabeth C. , Akbas Selin Y. , Azola Alba M. , Deeks Steven G. , Kelly J. Daniel , Martin Jeffrey N. , Henrich Timothy J. , Landay Alan L. , Peluso Michael J. , Antar Annukka A. R.
Published: November 2024

Objective

To determine how many people with long COVID also meet diagnostic criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Methods

We identified which participants with long COVID also met the Institute of Medicine (IOM) or the 2003 Canadian Consensus Criteria (CCC) for ME/CFS at approximately 6-8 months post-SARS-CoV-2 infection in two cohorts: (1) the JHU COVID Recovery cohort, which enrolled participants within 4 weeks of infection and (2) the Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort, which enriched for participants with long COVID. Neither study administered ME/CFS-specific surveys, so available data elements were mapped onto each ME/CFS diagnostic criteria.

Results

Of 97 JHU participants with long COVID, 5 met IOM criteria and 2 met CCC criteria. Of 281 LIINC participants with long COVID, 51 met the IOM criteria and 29 met the CCC criteria. In LIINC, participants with long COVID meeting ME/CFS criteria were more likely to be female and report a greater number of post-COVID symptoms (p<0.001).

Conclusions

The co-occurrence of ME/CFS symptoms and long COVID suggests that SARS-CoV-2 is a cause of ME/CFS. ME/CFS-specific measures should be incorporated into studies of post-acute COVID-19 to advance studies of post-SARS-CoV-2 onset ME/CFS.