bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of serum iron metabolism with muscle mass and frailty in older adults: A cross-sectional study of community-dwelling older adults
Authors: Ma Anpei , Chen Honggu , Yin Hong , Zhang Ziyi , Zhao Guoyang , Luo Caifeng , Zhuang Ruo , Chen Aihua , Han Tingxia
Published: August 2024

This study aimed to explore the correlation between serum ferritin and additional biomarkers associated with iron metabolism, as well as their connection to muscle atrophy and frailty in the community-dwelling middle-aged and elderly population. The study included 110 middle-aged and elderly participants. Participants were categorized into an iron accumulation group (31 cases) and a normal iron group (79 cases) based on the standard ferritin values for men and women. Based on the criteria of the Asian Working Group on Muscular Dystrophy, participants were classified into a sarcopenia group (31 cases) and a non-sarcopenia group (79 cases). Using the Fried frailty syndrome criteria, participants were categorized into non-frailty (7 cases), pre-frailty (50 cases), and frailty (53 cases) groups. We employed multiple linear regression, binary logistic regression, partial correlation analysis, and ordinal logistic regression to assess the associations between iron metabolism indices and the presence of muscle atrophy and frailty. Compared with the normal iron group, the iron overload group had significantly higher ferritin, weight loss, fatigue, slow gait, and frailty scores (P < .05). Among the 3 models we set, ferritin was not significantly correlated with muscle mass in models 1 and 3 (P > .05), ferritin was positively correlated with muscle mass in model 2 (P
model2 = .048), but Transferrin saturation was positively correlated with muscle mass in all 3 models (P
model1 = .047, P
model2 = .026, P
model3 = .024). Ferritin, body mass index and iron overload were the influencing factors of sarcopenia (P
ferritin = .027, P
BMI < .001, P
iron overload = .028). Ferritin was positively correlated with weight loss, fatigue, slow gait, frailty score, and frailty grade (P < .05). Age, gender and ferritin were the influencing factors of frailty classification (P < .05). Disrupted iron metabolism can lead to decreased muscle mass and function among the middle-aged and elderly, increasing frailty risk. It’s crucial to prioritize community-based frailty screening and prevention, focusing on iron utilization as well as storage, since accelerating the body’s iron metabolism cycle might influence muscle health more significantly than iron reserves.
Simultaneous occurrence of papillary thyroid carcinoma, medullary thyroid carcinoma, and lymphoma: A case report
Authors: Hao Zengfang , Cui Hanjing , Li Yuehong , Wu Wenxin , Wang Yuan , Dan Haijun , Lou Lei , Wang Hengshu , Zhao Pengxin
Published: August 2024

Background:

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, the coexistence of PTC and medullary thyroid carcinoma (MTC) is uncommon. While the simultaneous occurrence of both cancers with small lymphocytic lymphoma (SLL) in lymph nodes with PTC metastasis is very rare. This study presents a unique case of concurrent PTC, MTC, and SLL, highlighting the exceptional rarity of these coexisting tumors.

Methods:

A 75-year-old female with a thyroid tumor underwent total thyroidectomy, bilateral central neck lymph node dissection, and right radical neck lymph node dissection. Histopathological examination revealed a low-grade medullary thyroid carcinoma (MTC) in the left lobe and classical papillary thyroid carcinoma (PTC) in the right lobe, with PTC metastasis in the cervical lymph nodes and concurrent SLL in the affected lymph nodes.

Results:

Coexistence of PTC, MTC and SLL in the same patient is rare, there are currently no standardized treatment guidelines due to the limited literature. However, it is essential to consider not only the treatment for each type of tumor but also the potential risks or conflicts associated with the treatments. In the case reported in this paper, the papillary carcinoma invaded the capsule of the right lobe of the thyroid and metastasized to the cervical lymph nodes, warranting radioactive iodine therapy. However, considering the potential negative impact of radioactive iodine on the pre-existing lymphoma, the radioactive iodine therapy was postponed. Meanwhile, constant monitoring of calcitonin and thyroid globulin should be performed to monitor tumor recurrence as was performed in the present case.

Conclusion:

Since MTC, PTC, and SLL may coexist, patients with PTC deserve careful surveillance for the other disease entities. This case underscores the need for heightened awareness among clinicians, radiologists, and pathologists regarding the possibility of concurrent thyroid tumors and abnormal lymph nodes, guiding comprehensive pre-operative evaluations and postoperative monitoring strategies. This study aims to provide a warning for routine pathological diagnosis and contribute data for related research.
Cholecystopleural fistula: A case report and literature review
Authors: Yang Yong , Chen Qian , Hu Yi , Zhao Liangsong , Cai Pengcheng , Guo Suqi
Published: August 2024

Introduction:

Gallstone with acute cholecystitis is one of the most common diseases in the clinic. If the disease is serious, gallbladder gangrene, perforation, and sepsis may be caused. Gallbladder diseases rarely cause thoracic-related complications, especially pleural fistula, which is very rare in clinical practice.

Patient concerns:

A 52-year-old male patient was admitted to the emergency department for 1 month with recurrent right middle and upper abdominal pain.

Diagnosis:

Computed tomography diagnosis: cholecystitis and peri-inflammation, small abscess around the base of the gallbladder, local peritonitis, and bilateral pleural effusion.

Interventions:

After admission, conservative treatment was given. On the 4th day of admission, the symptoms worsened, and an emergency catheter drainage was performed on the right thoracic cavity to extract 900 mL of dark yellow effusion. After the operation, a large amount of bili-like fluid was continuously drained from the thoracic drainage tube. After the iatrogenic biliary fistula caused by thoracic puncture was excluded, cholecystopleural fistula was considered to be cholecystopleural fistula. On the 6th day of admission, endoscopic retrograde cholangiopancreatography (ERCP) + cholecystography + Oddi sphincterotomy + laminating biliary stent was performed in the emergency department, and cholecystopleural fistula was confirmed during the operation.

Outcomes:

The patient recovered well after surgery, computed tomography examination on the 20th day after surgery indicated that pleural effusion was significantly reduced, and the patient was cured and discharged. The patient returned to the hospital 8 months after the ERCP operation to pull out the bile duct–covered stent. The patient did not complain of any discomfort after the postoperative follow-up for 3 years, and no recurrence of stones, empyema, and other conditions was found.

Conclusion:

Cholecystopleural fistula is one of the serious complications of acute cholecystitis, which is easy to misdiagnose clinically. If the gallbladder inflammation is severe, accompanied by pleural effusion, the pleural effusion is bili-like liquid, or the content of bilirubin is abnormally elevated, the existence of the disease should be considered. Once the diagnosis is clear, active surgical intervention is needed to reduce the occurrence of complications. Endoscopic therapy (ERCP) can be used as both a diagnostic method and an important minimally invasive treatment.
Anemia among adult patients with diabetes attending King Abdulaziz University Hospital: A retrospective study
Authors: Ghamri Ranya , Salawati Emad , Edrees Ghalia W. , Alsaleh Aljawhara K. , Srouji Aya F. , Radi Tala O. , Feteih Maha M. , Kary Malak S. , Altalhi Rahaf J. , Almanasif Mersal A. , Ahmed Ferdous A.
Published: August 2024

The prevalence of anemia in adults with diabetes is of growing importance due to its impact on overall health and the management of diabetes-related complications. This study aimed to determine the prevalence of anemia among adult patients with diabetes at King Abdulaziz University Hospital in Jeddah, Saudi Arabia. A retrospective study was done on 1208 patients with diabetes >18 years who attended the study setting from 2010 to 2022. Data about patients’ demographics, body mass index, glycated hemoglobin (HbA1c; %), hemoglobin (Hb), serum ferritin, iron, mean corpuscular Hb, mean corpuscular volume, free thyroxine and triiodothyronine (T3), and serum thyroid–stimulating hormone (TSH) were collected. Of patients, 86.6% had anemia with a prevalence of 30.2%, 47.6%, and 22.2% for mild, moderate, and severe anemias, respectively. The prevalence of anemia was significantly higher among females, those with high serum ferritin, normal serum iron or normal serum T3, lower mean HbA1c level (%), lower serum iron or T3, and higher serum ferritin or TSH. A significant positive correlation was found between Hb level and HbA1c level (%), serum iron, free T3, and body mass index. A significant negative correlation was found between Hb level and mean corpuscular volume, serum ferritin, and serum TSH. Being female, having high serum ferritin, lower mean free T3, and a high TSH were risk factors for anemia. The prevalence of severe anemia was significantly higher among patients with uncontrolled diabetes mellitus. A high prevalence of anemia was found among studied diabetics. Anemia screening should be included in the routine assessment of patients with diabetes. A multidisciplinary approach involving endocrinologists, hematologists, and dietitians is recommended to ensure holistic care and address all aspects of the patient’s health. In addition, further research should be supported to better understand the mechanisms linking diabetes and anemia and to establish evidence-based guidelines for managing anemia in diabetics.
Successful preoperative diagnosis and laparoscopic management of primary small bowel volvulus: A case report and literature review
Authors: Shimizu Seito , Hara Hitoshi , Muto Yasuhide , Kido Tomoki , Miyata Ryohei
Published: August 2024

Rationale:

Small bowel volvulus (SBV) is a rare cause of acute abdominal pain in adults, which requires surgical intervention to prevent small bowel necrosis. Primary SBV is rare, and its preoperative diagnosis is challenging. This report describes a case of primary SBV diagnosed preoperatively and treated laparoscopically.

Patient concerns:

A 56-year-old man presented complaining of sudden-onset abdominal pain of 3-hour duration. Physical examination revealed tenderness in periumbilical and upper abdominal regions with no signs of peritonitis.

Diagnosis:

Contrast-enhanced computed tomography revealed a 360°-clockwise rotation of the small intestine when viewed caudally at the mesenteric base. At this region, the superior mesenteric vein was interrupted. Although no dilation of the small intestine was observed, increased density in the mesentery of the affected area was observed. Minimal ascites was observed in the pelvic cavity. No evidence of congenital or secondary SBV was observed, supporting the diagnosis of primary SBV.

Interventions:

Laparoscopic detorsion of the SBV was performed approximately 6 hours after the onset of symptoms. No signs of bowel necrosis were observed, and the procedure was concluded after releasing the torsion.

Outcomes:

Severe abdominal pain disappeared immediately after surgery. The postoperative course was uneventful, and the patient was discharged on the 8th postoperative day.

Lessons:

This case highlights the importance of preoperatively diagnosing SBV, which enables early laparoscopic devolvulation without bowel resection.
The impact of restrictive blood transfusion on the safety of patients with esophageal varices after endoscopic variceal ligation: A single-center retrospective study
Authors: Chen Yufeng , Ming Wen , Chen Jingjing , Wang Xi , He Guobin
Published: August 2024

An investigation was conducted to examine the impact of restrictive blood transfusion on the safety of early rebleeding following endoscopic variceal ligation (EVL) in patients with liver cirrhosis. Data were collected from patients with cirrhosis and esophageal varices who underwent EVL at the Affiliated Hospital of North Sichuan Medical College between September 2021 and March 2023. Clinical information, including serum albumin levels, hemoglobin (Hb) levels, liver function classification, and the occurrence of early rebleeding, was recorded. Patients were divided into 2 groups based on their Hb levels: 60 g/L to 90 g/L (restrictive blood transfusion) or Hb ≥ 90 g/L after EVL. The impact of restrictive transfusion on the post-ligation safety of EVL was observed. A total of 246 cirrhotic patients were included in the analysis. Significant differences were found in Hb levels, liver function classification, early rebleeding rates, length of hospital stay, and hospitalization expenses between the restrictive transfusion and Hb ≥ 90 g/L groups. The early rebleeding rate was significantly varied between the groups with different Hb levels after EVL. Multivariate logistic analysis revealed that restrictive blood transfusion (OR = 4.61, 95% CI: 1.06–19.99; P = .041), Hb (OR = 0.96, 95% CI: 0.95–0.97; P < .001), and Child-Pugh class C (OR = 6.37, 95% CI: 1.28–31.67; P = .024) were identified as independent factors influencing early rebleeding. Our findings suggest that the risk of early rebleeding in cirrhotic patients after EVL may be increased by restrictive blood transfusion, and this should be further investigated in future research.
A case report on congenital hypothyroidism and alpha thalassemia in children with anemia and muscle damage as the main manifestation
Authors: Zhang Ying , Li Xuan , Wang Xiao-jun , Yang Ju-pin , Li Ju-mei , Yuan Wen-qian , Dong Yu-ying , Yu Jin-peng , Wen Yu , Liu Ming-wei
Published: August 2024

Rationale:

This study reports the first case of congenital hypothyroidism (CH) and alpha thalassemia in a child in China, with anemia and muscle damage as the main manifestations. Analyzing and studying this case is of great significance in reducing missed and misdiagnosed CH and will provide a clinical strategy for treating these patients.

Patient concerns:

Child, female, 2 years and 7 months old, the child appeared dispirited, had poor appetite, shallow complexion, reduced activities with anemia, elevated muscle enzymes, height, and growth retardation.

Diagnoses:

The child was diagnosed with CH with alpha thalassemia.

Interventions:

The patient was treated with levothyroxine sodium and anemia correction.

Outcomes:

The children’s current spirit, appetite, red face, normal limb activity, physical development, and intelligence were significantly better than those of normal children of the same age.

Conclusions:

CH with alpha thalassemia, especially anemia and muscle damage as the main manifestations, has not been reported. Administration of levothyroxine sodium is effective in correcting anemia in patients with CH and alpha thalassemia.

Lesson:

Due to CH and alpha thalassemia, there are no specific symptoms and they are prone to missed diagnosis and misdiagnosis. Therefore, patients with anemia and elevated muscle enzyme levels should be routinely tested for thyroid function to diagnose them early and provide proper treatment to avoid negative consequences.
The Level of Psychological Distress Is Associated With Circadian Rhythm, Sleep Quality, and Inflammatory Markers in Adolescent and Young Adults With Gynecological Cancer
Authors: Luo Yating , Duan Yinglong , Zhou Yi , Yi Shuijing , Dai Chanyuan , Luo Xiaofei , Kang Yue , Wan Ziyu , Qin Ning , Zhou Xing , Liu Xiangyu , Xie Jianfei , Cheng Andy S.K.
Published: August 2024

Background

Adolescent and young adult (AYA) patients with cancer commonly experience psychological distress, with female patients experiencing higher levels of psychological distress.

Objective

The aim of this study was to investigate the relationships among circadian rhythm, sleep quality, inflammatory markers, and psychological distress in AYA patients with gynecological cancer in China.

Methods

This cross-sectional study enrolled 75 AYA patients in treatment for gynecological cancer, 64 of whom completed the Chinese version of the Morningness-Eveningness Questionnaire and the Distress Thermometer. Actigraphy was used to measure their objective sleep parameters: total sleep time, sleep onset latency, and sleep efficiency. Blood samples collected 3 times across 1 day were used to measure the average levels of interleukin 6, C-reactive protein, and tumor necrosis factor α.

Results

The mean score on the Distress Thermometer among respondents was 4.23, which was above the cutoff value for clinically significant psychological distress. High levels of psychological distress may be associated with circadian disturbances, poor sleep quality, and elevated inflammatory markers. In addition, total sleep time, sleep onset latency, and tumor necrosis factor α averages were the dominant predictors of these AYA patients’ psychological distress.

Conclusion

Improving sleep quality and reducing the levels of inflammatory markers may relieve psychological distress among AYA patients with gynecological cancer.

Implications for Practice

Healthcare professionals need to actively focus on circadian rhythm, inflammatory markers, sleep quality, and mental health status in AYA cancer patients to better meet their therapeutic and psychological needs.
Nitrous Oxide Alters Functional Connectivity in Medial Limbic Structures in Treatment-Resistant Major Depression
Authors: Conway Charles R. , Palanca Ben Julian A. , Zeffiro Thomas , Gott Britt M. , Brown Frank , de Leon Victoria , Barnes Linda , Nguyen Thomas , Xiong Willa , Lessov-Schlaggar Christina N. , Espejo Gemma , Mennerick Steven , Zorumski Charles F. , Nagele Peter
Published: August 2024

While nitrous oxide (N2O) has demonstrated antidepressant properties in treatment-resistant major depression (TRD), little is known about neural mechanisms mediating these effects. Employing serial resting-state functional magnetic resonance imaging (rs-fMRI), we compared spatiotemporal effects of inhaled N2O on brain functional connectivity in TRD patients (n=14) and non-depressed healthy controls (n=16, CNTL). Participants received sequential, one-hour inhalations of either 50% N2O/oxygen or air/oxygen (placebo), with sessions separated by at least one month in random cross-over order. BOLD-contrast rs-fMRI scans were acquired at three time points: pre-inhalation, 2 hours post-inhalation, and 24 hours post-inhalation. For the rs-fMRI functional connectivity analyses, fivea prioriseeds in medial limbic structures targeted cortical networks implicated in major depression – the salience, anterior and posterior default mode, reward, and cingulo-opercular networks – and a nexus in the dorsal paracingulate region previously identified in MDD (“dorsal nexus”). Depression, dissociation, and psychosis assessments were made before and after inhalations. In TRD patients, functional connectivity was reduced in all seeded networks and the voxel-wise global analysis after N2O exposure. N2O progressivelydecreasedconnectivity in patients with TRD butincreasedconnectivity in healthy controls. In TRD patients, each seeded network demonstrated post-inhalation functional connectivity reductions in the dorsal paracingulate gyrus (“dorsal nexus”). This study further elucidates neural mechanisms underlying the antidepressant properties of N2O, supporting the notion that N2O specifically alters mood-associated brain regions in the depressed brain state by reducing functional connectivity within these brain networks.

The trial was registered atClinicalTrials.gov(NCT02994433).

One sentence summary

Nitrous oxide reduces long-range functional brain connectivity in treatment-resistant major depression, which may underlie its antidepressant action.
Predicting bacterial phenotypic traits through improved machine learning using high-quality, curated datasets
Authors: Koblitz Julia , Reimer Lorenz C , Pukall Ruediger , Overmann Joerg
Published: August 2024

Predicting prokaryotic phenotypes - observable traits that govern functionality, adaptability, and interactions - holds significant potential for fields such as biotechnology, environmental sciences, and evolutionary biology. This study leverages machine learning to explore the relationship between prokaryotic genotypes and phenotypes. Taking advantage of the highly standardized datasets in the BacDive database, we modeled eight physiological properties based on protein family inventories, discuss the evaluation metrics, and explore the biological implications of our models. The high confidence values of our predictions highlight the importance of data quality and quantity for a reliable inference of bacterial phenotypes. Our approach yielded nearly 55,000 new data points for approximately 20,000 strains which are published openly in the BacDive database, enriching existing phenotypic datasets and paving the way for future research and analysis. The open-source software generated can readily be applied to other datasets, for example the IMG/M system for metagenomics, as well as different applications, like the assessment of the potential of soil bacteria for bioremediation projects.
Leveraging protein-protein interactions in phenotype prediction through graph neural networks
Authors: Smeriglio Riccardo , Rosell-Mirmi Joana , Radeva Petia , Abante Jordi
Published: August 2024

Current genotype-to-phenotype models, such as poly-genic risk scores, only account for linear relationships between genotype and phenotype and ignore epistatic interactions, limiting the complexity of the diseases that can be properly characterized. Protein-protein interaction networks have the potential to improve the performance of the models. Moreover, interactions at the protein level can have profound implications in understanding the genetic etiology of diseases and, in turn, for drug development. In this article, we propose a novel approach for phenotype prediction based on graph neural networks (GNNs) that naturally incorporates existing protein interaction networks into the model. As a result, our approach can naturally discover relevant epistatic interactions. We assess the potential of this approach using simulations and comparing it to linear and other non-linear approaches. We also study the performance of the proposed GNN-based methods in predicting Alzheimer’s disease, one of the most complex neurodegenerative diseases, where our GNN approach outperform state of the art methods. In addition, we show that our proposal is able to discover critical interactions in the Alzheimer’s disease. Our findings highlight the potential of GNNs in predicting phenotypes and discovering the underlying mechanisms of complex diseases.
Single-cell analysis identifies distinct CD4+ T cells associated with the pathobiology of pediatric obesity-related asthma
Authors: Thompson David A. , Wabara Yvonne B. , Duran Sarai , Reichenbach Anna , Chen Laura , Collado Kayla , Yon Changsuek , Greally John M. , Rastogi Deepa
Published: August 2024

Pediatric obesity-related asthma is characterized by non-atopic T helper 1 (Th1) inflammation and steroid resistance. CDC42 upregulation in CD4+T cells underliesTh1 inflammation but the CD4+T cell subtype(s) with CDC42 upregulation and their contribution to steroid resistance are not known. Compared to healthy-weight asthma, obesity-alone and healthy-weight controls, single-cell transcriptomics of obese asthma CD4+T cells revealedCDC42upregulation in 3 clusters comprised of naïve and central memory T cells, which differed from the cluster enriched for Th1 responses that was comprised of effector T cells.NR3C1,coding for glucocorticoid receptor, was downregulated, while genes coding for NLRP3 inflammasome were upregulated, in clusters with CDC42 upregulation and Th1 responses. Conserved genes in these clusters correlated with pulmonary function deficits in obese asthma. These findings suggest that several distinct CD4+T cell subtypes are programmed in obese asthma for CDC42 upregulation, Th1 inflammation, and steroid resistance, and together contribute to obese asthma phenotype.

CD4+T cells from obese children with asthma are distinctly programmed for non-allergic immune responses, steroid resistance and inflammasome activation, that underlie the obese asthma phenotype.
A Design Principle for slow-wave sleep firing pattern with Na+dynamics
Authors: Sato Tomohide R. , Ode Koji L. , Kinoshita Fukuaki L. , Ueda Hiroki R.
Published: August 2024

Non-rapid eye movement (NREM) sleep is characterized by electroencephalography (EEG) signals with high amplitude and low frequency. This signal is thought to originate from the synchronized activity of cortical neurons, showing the alternating bursting state (up state) and resting state (down state). This activity is termed as slow-wave sleep (SWS) firing pattern. We previously proposed the importance of Ca2+-dependent hyperpolarization pathway in generating this firing pattern by introducing the averaged-neuron (AN) model, which describes neuronal activity based on the Hodgkin-Huxley type model. In the AN model, Ca2+-dependent K+channels are involved in the transition from the up to the down state. Here we focus on the intracellular Na+dynamics which are not explicitly described in the AN model. A revised AN model, termed as Na+-centered AN (NAN) model, proposes that the activation of voltage-gated Na+channels leads to intracellular Na+accumulation, which in turn triggers the activation of Na+-dependent K+(KNa) channels or Na+/K+ATPases, resulting in the down state. Changes in the activation kinetics of voltage-gated Na+channels are important in shaping SWS firing pattern as well as explaining the inter-spike interval changes between SWS and AWAKE firing pattern. Mathematically, transition from the up state to the down state occurs in accordance with the change in the number of the fixed point in the dynamical system with the changes in the intracellular Na+concentration. The importance of Na+-dependent pathway is elucidated even with the coexistence of Ca2+-dependent pathway. Subsequent analysis with network model suggests that the result of averaged neuron model with Na+pathway can be extended to the population of neurons. Therefore, our model proposes that voltage-gated Na+channels and Na+-dependent K+channels or Na+/K+ATPases are also the candidate pathways for the generation of SWS firing pattern.
Brain wave dynamics in Hopfield Kuramoto model
Authors: Yao Ruwei , Li Yichao , Yao Xintong , Wang Kang , Qu Jingling , Hong Bo , Zou Xiaolong
Published: August 2024

Whole brain neural oscillation activities exhibit multiple wave patterns and seem to be supported by the common circuit network structure. We proposed a Hebbian-like Kuramoto model based entirely on heterogeneous connectivity strength rather than phase delay, which encodes the multiple phase patterns as attractors. We systematically investigated how the model dynamic landscape influenced by attractors and their corresponding eigenvalues, as well as how to control the stability of equilibrium points and the occurrence of high dimension bifurcations. This framework enables us to reproduce the dominant wave activity components in human brain functional MRI signal, and provides a canonical model for the multi body physical system spatio-temporal pattern attractor dynamics.
Biologically-informed Killer cell immunoglobulin-like receptor (KIR) gene annotation tool
Authors: Ford Michael K.B. , Hari Ananth , Zhou Qinghui , Numanagić Ibrahim , Sahinalp S. Cenk
Published: August 2024

Natural killer (NK) cells are essential components of the innate immune system, with their activity significantly regulated by Killer cell Immunoglobulin-like Receptors (KIRs). The diversity and structural complexity of KIR genes present significant challenges for accurate genotyping, essential for understanding NK cell functions and their implications in health and disease. Traditional genotyping methods struggle with the variable nature of KIR genes, leading to inaccuracies that can impede immunogenetic research. These challenges extend to high-quality phased assemblies, which have been recently popularized by the Human Pangenome Consortium. This paper introduces BAKIR (Biologically-informed Annotator for KIR locus), a tailored computational tool designed to overcome the challenges of KIR genotyping and annotation on high-quality, phased genome assemblies. BAKIR aims to enhance the accuracy of KIR gene annotations by structuring its annotation pipeline around identifying key functional mutations, thereby improving the identification and subsequent relevance of gene and allele calls. It uses a multi-stage mapping, alignment, and variant calling process to ensure high-precision gene and allele identification, while also maintaining high recall for sequences that are significantly mutated or truncated relative to the known allele database. BAKIR has been evaluated on a subset of the HPRC assemblies, where BAKIR was able to improve many of the associated annotations and call novel variants. BAKIR is freely available on GitHub, offering ease of access and use through multiple installation methods, including pip, conda, and singularity container, and is equipped with a user-friendly command-line interface, thereby promoting its adoption in the scientific community.
Cecelia: a multifunctional image analysis toolbox for decoding spatial cellular interactions and behaviour
Authors: Schienstock Dominik , Hor Jyh Liang , Devi Sapna , Mueller Scott N.
Published: August 2024

With the ever-increasing complexity of microscopy modalities, it is imperative to have computational workflows that allow researchers to process and perform in-depth quantitative analysis of the resulting images. However, workflows that enable flexible, interactive and intuitive analysis from raw images to analysed data are lacking. We present Cecelia, a toolbox that integrates various open-source packages into a coherent data management suite to make quantitative image analysis accessible for non-specialists.
Miniaturizing, Modifying, and Augmenting Nature’s Proteins with Raygun
Authors: Devkota Kapil , Shonai Daichi , Mao Joey , Soderling Scott , Singh Rohit
Published: August 2024

Proteins are nature’s versatile nanomachines, but engineering them for enhanced function or novel applications remains challenging. Current methods for protein modification struggle to design sequence alterations, especially insertions and deletions, that preserve structure. Here, we introduce Raygun, a template-guided protein design framework that unlocks efficient miniaturization, modification, and augmentation of existing proteins. Using a novel probabilistic encoding of protein sequences constructed from language model embeddings, Raygun is able to generate diverse candidates with deletions, insertions, and substitutions while maintaining core structural elements. We show that Raygun can shrink proteins by 10-25% (sometimes over 50%) while preserving predicted structural integrity and fidelity, introduce extensive sequence diversity while preserving functional sites, and even expand proteins beyond their natural size. In experimental validation, we successfully miniaturize the fluorescent proteins eGFP and mCherry to synthesize functional variants, two of which are smaller than 96% of fluorescent proteins reported in FPbase. Raygun’s conceptual innovations in template-based protein design open new avenues for protein engineering, potentially catalyzing the development of more efficient molecular tools and therapeutics.
Quantifying transmissibility and dispersion of SARS-CoV-2 variants and subvariants of concern in England
Authors: Swallow Ben , Grier Joshua , Panovska-Griffiths Jasmina
Published: August 2024

The SARS-CoV-2 pandemic was characterised by continual emergence of variants. For improved future pandemic preparedness it is important to understand whether each successive variant has been more infectious and more widely spread. In this paper, we used genetic sequencing data from the COVID-19 Genomics UK Consortium in England and robust statistical models to quantify transmissibility advantage and spatial heterogeneity of successive SARS-CoV-2 variants and their sub-variants circulating between September 2020 and December 2022.

Our results show that each variant was progressively more transmissible and more heterogeneously spread. Alpha was 10-40% more transmissible than B.1.177, Delta was 40-100% more transmissible than Alpha, and Omicron was 80-120% more transmissible than the Delta variant. Progressive variants were also more spatially heterogeneous: Alpha was mostly clustered in London and Southeast England, Delta was less clustered and prevalent in both Northwest and Southeast England, while Omicron was dispersed across the country. Successive sub-variants of different clade were more transmissible and spatially spread than the previous ones (e.g. the Omicron BA.1.1 variant was 20-60% more transmissible than the previous Delta AY.4 variant). However, sub-variants of the same clade didn’t differ in transmissibility or spatial spread. Our study improves understanding of transmission intensity and spatial heterogeneity across SARS-CoV-2 variants.

Ascertaining the threat posed by emerging variants and across infectious diseases is crucial to be better prepared for the next pandemic. Our method provides a tool for analysis of variant surveillance data, translatable across pathogens and settings, that can capture an emerging variant early and as part of the pandemic preparedness strategy.
Assessing innovative care models for musculoskeletal disorders’ management in the emergency department using Time-Driven Activity-Based Costing
Authors: Gagnon Rose , Perreault Kadija , Guertin Jason R. , Hébert Luc J. , Berthelot Simon
Published: August 2024

Abstract

Objectives

Compare the average cost of an emergency department (ED) visit between three ED care models, namely management by an emergency physician (EP) alone (usual care), management by a primary contact physiotherapist (PT) and an EP (intervention), and management by a PT alone (sensitivity analysis).

Methods

Cost study (Canadian Public Payer perspective) based on data collected during a pragmatic randomized clinical trial (2018-2019) conducted in an urban Canadian academic ED (CHUL, Quebec City, Canada; n=78, 18-80 years old). Costs incurred for the management of persons presenting to the ED for a minor musculoskeletal disorder (MSKD) were calculated using Time-Driven Activity-Based Costing, in which time invested with a patient determines care costs. The main outcome measure was the average cost of an ED visit. Generalized linear models with Gamma distributions and log links were used to assess whether there were significant differences in average costs between the care models.

Results

Mean ED visit cost was $267.08 (2019 $CAD, 95%CI: $212.75, $346.40) for PT and EP management, compared with $245.14 for EP management ($169.46, $336.72), resulting in a non- significant absolute difference of 21.94 CAD/patient ($-87.33, $132.63) between models (p=.60). Sensitivity analyses showed that the average cost of ED management by a PT was $194.38 ($161.50, $234.34), representing a non-significant average saving of 50.76 CAD/patient ($- 156.91, $37.54) compared to EP management.

Conclusion

This study is a first step towards a better understanding of the costs incurred by the Canadian Public Payer for the management of persons presenting with MSKDs in the ED. Primary contact physiotherapists have the potential to complement care of MSKD ED patients without increasing healthcare costs.
The OMG dataset: An Open MetaGenomic corpus for mixed-modality genomic language modeling
Authors: Cornman Andre , West-Roberts Jacob , Camargo Antonio Pedro , Roux Simon , Beracochea Martin , Mirdita Milot , Ovchinnikov Sergey , Hwang Yunha
Published: August 2024

Biological language model performance depends heavily on pretraining data quality, diversity, and size. While metagenomic datasets feature enormous biological diversity, their utilization as pretraining data has been limited due to challenges in data accessibility, quality filtering and deduplication. Here, we present the Open MetaGenomic (OMG) corpus, a genomic pretraining dataset totalling 3.1T base pairs and 3.3B protein coding sequences, obtained by combining two largest metagenomic dataset repositories (JGI’s IMG and EMBL’s MGnify). We first document the composition of the dataset and describe the quality filtering steps taken to remove poor quality data. We make the OMG corpus available as a mixed-modality genomic sequence dataset that represents multi-gene encoding genomic sequences with translated amino acids for protein coding sequences, and nucleic acids for intergenic sequences. We train the first mixed-modality genomic language model (gLM2) that leverages genomic context information to learn robust functional representations, as well as coevolutionary signals in protein-protein interfaces and genomic regulatory syntax. Furthermore, we show that deduplication in embedding space can be used to balance the corpus, demonstrating improved performance on downstream tasks. The OMG dataset is publicly hosted on the Hugging Face Hub athttps://huggingface.co/datasets/tattabio/OMGand gLM2 is available athttps://huggingface.co/tattabio/gLM2_650M.
Mutations in ErbB2 accumulating in the male germline measured by error-corrected sequencing
Authors: Yasari Atena , Heinzl Monika , Mair Theresa , Karimian Tina , Moukbel Shehab Ali , Hartl Ingrid , Betancourt Andrea J , Lanzerstorfer Peter , Tiemann-Boege Irene
Published: August 2024

Mutations in the male germline are a driving force behind rare genetic diseases. Driver mutations enjoying a selective advantage expand to mutant clusters within the aged testis and are thus overrepresented in sperm with age. Other kinds of driver mutations, occurring prepubescently, have been the focus of recent attention given their high occurrence rate independent of age. Here, we investigated the ErbB2 gene via error-corrected sequencing and detected a high percentage of missense mutations, including recurrent mutations, which were observed mainly in the tyrosine kinase domain with likely functional consequences, as we verified for a subset via biophysical methods. While these mutations increased with age, we found no evidence that they originated from mutational clusters in the aged testis, and young donors also showed an accumulation of driver mutations, suggesting that mutational enrichment is not exclusive to the sexually mature germline but can occur earlier during germline development, and are likely evenly distributed in the testis and stable in size.
A Novel Computational Machine Learning Pipeline to Quantify Similarities in Three-Dimensional Protein Structures
Authors: Hirway Shreyas U , Xu Xiao , Fan Fan
Published: August 2024

Animal models are widely used during drug development. The selection of suitable animal model relies on various factors such as target biology, animal resource availability and legacy species. It is imperative that the selected animal species exhibit the highest resemblance to human, in terms of target biology as well as the similarity in the target protein. The current practice to address cross-species protein similarity relies on pair wise sequence comparison using protein sequences, instead of the biologically relevant 3-dimensional (3D) structure of proteins. We developed a novel quantitative machine learning pipeline using 3D structure-based feature data from the Protein Data Bank, nominal data from UNIPROT and bioactivity data from ChEMBL, all of which were matched for human and animal data. Using the XGBoost regression model, similarity scores between targets were calculated and based on these scores, the best animal species for a target was identified. For real-world application, targets from an alternative source, i.e., AlphaFold, were tested using the model, and the animal species that had the most similar protein to the human counterparts were predicted. These targets were then grouped based on their associated phenotype such that the pipeline could predict an optimal animal species.
Pressure protein denaturation compared to thermal and chemical unfolding - Analyses with cooperative models
Authors: Seelig Joachim , Seelig Anna
Published: August 2024

The thermodynamics of pressure induced protein unfolding (denaturation) could so far not be directly compared with protein unfolding induced by temperature or chemical agents. Here we provide a new cooperative model for pressure induced protein denaturation, that allows the quantitative comparison of the three denaturing processes based on their free energy, enthalpy, entropy, and cooperativity. As model proteins we use apolipoprotein A-1 and lysozyme. The comparison shows that heat-induced unfolding is the most cooperative process. It is characterized by large positive enthalpies and entropies and (due to enthalpy-entropy compensation) a small negative free energies. Pressure denaturation is less cooperative. The entropies and enthalpies are less positive, and the resulting free energies are more negative. Chemically induced unfolding is least cooperative and shows the most negative free energies, in particular, if guanidinium hydrochloride (exhibiting a high binding affinity to certain proteins) is used as a denaturant. The three unfolding processes not only differ with respect to their cooperativity and the thermodynamic parameters, but also with respect to the volume changes. Whereas thermal and chemical denaturation increase the protein volume, denaturation by pressure reduces the protein volume, suggesting significant structural differences of the denatured proteins. Using cooperative models for protein analyses thus yields significant new insights into the protein unfolding/folding processes.
First laboratory-confirmed human case of infection with influenza A(H5N2) virus reported in Mexico
Authors: Vázquez-Pérez Joel Armando , Wong-Arámbula Claudia , Solís-Hernández Mario , Becerril-Vargas Eduardo , Barrera-Badillo Gisela , Ahumada-Topete Víctor Hugo , Avila-Rios Santiago , Pérez-Padilla Rogelio , Mejía-Nepomuceno Fidencio , Mendoza-Ramírez Enrique , Rocha-Martinez Marisol Karina , Alcazar-Ramiro Carlos Javier , Cruz Alfredo , Zúñiga Joaquin , Bozena-Piekarska Karolina , Arellano-Suarez Dayanira Sarith , Cruz-Ortiz María Natividad , Núñez-García Tatiana Ernestina , Molina-Gómez Eréndira , Flores-Cisneros Laura Adriana , Aparicio-Antonio Rodrigo , Rodríguez-Maldonado Abril , Landa-Flores Magaly , García-López Armando , Membrillo-Hernández Jorge , García-Rodríguez Gabriel , García-Lozano Herlinda , López-Martínez Irma , González-Sánchez Ruth P. , Reyes-Terán Gustavo , Hernández-Cárdenas Carmen M.
Published: August 2024

In late April, 2024, we detected a non-subtypeable influenza virus in a hospitalized patient, resident of the Metropolitan area of Mexico City. Our results using 5 complete viral segments M, NS, NA, NP and HA, showed identity of 99% with avian influenza A(H5N2) from Texcoco, Mexico of 2024. This case is the first with direct evidence of human infection caused by the H5N2 influenza virus, relationship with severity remain unknow.
CHAMP delivers accurate taxonomic profiles of the prokaryotes, eukaryotes, and bacteriophages in the human microbiome
Authors: Pita Sara , Myers Pernille Neve , Johansen Joachim , Russel Jakob , Nielsen Mads Cort , Eklund Aron C , Nielsen Henrik Bjørn
Published: August 2024

Accurate taxonomic profiling of the human microbiome composition is crucial for linking microbial species to health outcomes. Therefore, we created the Clinical Microbiomics Human Microbiome Profiler (CHAMP), a comprehensive tool designed for the profiling of prokaryotes, eukaryotes, and viruses across all body sites. Boasting a reference database derived from 30,382 human microbiome samples, CHAMP covers 6,567 prokaryotic and 244 eukaryotic species as well as 64,003 viruses. We used a diverse set of in silico metagenomes and DNA mock communities to benchmark CHAMP against the established profiling tools MetaPhlAn 4, Bracken 2, mOTUs 3, and Phanta. CHAMP demonstrated unparalleled species recall, F1 score, and significantly reduced false positives compared to all other tools benchmarked. Indeed, the false positive relative abundance (FPRA) for CHAMP was, on average, 50-fold lower than the second-best performing profiler. CHAMP also proved to be more robust than the other tools to low sequencing depths, highlighting its application for low biomass samples. Taken together, this establishes CHAMP as a best-in-class human microbiome profiler of prokaryotes, eukaryotes, and viruses in diverse and complex communities across low and high biomass samples. CHAMP profiling is offered as a service by Clinical Microbiomics A/S and available for a fee at https://cosmosidhub.com.
Novel tau filament folds in individuals withMAPTmutations P301L and P301T
Authors: Schweighauser Manuel , Shi Yang , Murzin Alexey G. , Garringer Holly J. , Vidal Ruben , Murrell Jill R. , Erro M. Elena , Seelaar Harro , Ferrer Isidro , van Swieten John C. , Ghetti Bernardino , Scheres Sjors H.W. , Goedert Michel
Published: August 2024

Mutations inMAPT, the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions in brain cells. Individuals with pathologicalMAPTvariants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most commonMAPTmutations associated with FTDP-17, give rise to the assembly of mutant four-repeat tau into filamentous inclusions, in the absence of extracellular deposits. Here we report the cryo-EM structures of tau filaments from five individuals belonging to three unrelated families with mutation P301L and from one individual belonging to a family with mutation P301T. A novel three-lobed tau fold resembling the two-layered tau fold of Pick’s disease was present in all cases with the P301L tau mutation. Two different tau folds were found in the case with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. These findings suggest that FTDP-17 with mutations in P301 should be considered distinct inherited tauopathies and that model systems with these mutations should be used with caution in the study of sporadic tauopathies.
Kin-discriminating partner choice promotes the evolution of helping
Authors: Scott Thomas W. , Wild Geoff , Gardner Andy
Published: August 2024

Kin selection theory predicts that individuals should evolve to help relatives, either by helping indiscriminately in a population where they do not move very far from their relatives, or by discriminating kin and conditionally helping them. It has been argued that, because kin discrimination enables individuals to reduce how helpful they are with some social partners as well increase how helpful they are with others, this could lead to an increase or a decrease in the overall level of helping, depending on the curvature of the function relating the optimal level of help and genetic relatedness. However, this prediction was based on a model in which individuals were not able to choose their social partners but only adjust how helpful they should be towards those social partners they have been allocated. Here, we perform a mathematical analysis showing that if kin discriminators are allowed to choose whom they help, kin discrimination is more likely to increase the overall level of helping than previously anticipated. We obtained these results in two complementary theoretical settings: one more general and the other more specific and concrete.