bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Valproic Acid on Promoting the Differentiation of Human Embryonic Stem Cells Into Cholangiocyte-Like Cells
Authors: Deng Shuai , Zhao Xiaoyu , Kou Ziyan , Zhu Yanlun , Zhang Xuerao , Chan Hon Fai
Published: November 2023

Cholangiocytes form a complex 3D network of bile ducts in the liver and contribute to liver function. The damage or destruction of cholangiocytes can lead to biliary diseases, and the shortage of cholangiocytes remains an obstacle for drug development targeting biliary diseases. Valproic acid (VPA) is a potent activator of Notch signaling pathway that is essential for cholangiocyte differentiation. Here, we report a VPA-based approach for cholangiocyte differentiation of human pluripotent stem cells. VPA activated Notch2 expression and upregulated HES-1, HEY-1, and Sox9 gene expression in hESC-derived hepatoblast. After 7 days treatment, VPA promoted successful differentiation of hepatoblast into cholangiocytes expressing cholangiocyte marker genes (AE2, AQP1, CFTR) and proteins (CK19 and CK7). In addition, the differentiated cholangiocytes formed bile duct-like structures after implantation into the spleen of NOD/SCID mice. Our results suggested that VPA can promote hESC differentiation to cholangiocyte-like cells. The induced cholangiocytes may serve as a potential cell source for both in vitro modeling and regenerative therapy of cholangiopathies. The findings can also support further development of small-molecule based differentiation protocols for cholangiocyte production.
Evaluation of recombination detection methods for viral sequencing
Authors: Jaya Frederick R , Brito Barbara P , Darling Aaron E
Published: November 2023

Recombination is a key evolutionary driver in shaping novel viral populations and lineages. When unaccounted for, recombination can impact evolutionary estimations or complicate their interpretation. Therefore, identifying signals for recombination in sequencing data is a key prerequisite to further analyses. A repertoire of recombination detection methods (RDMs) have been developed over the past two decades; however, the prevalence of pandemic-scale viral sequencing data poses a computational challenge for existing methods. Here, we assessed eight RDMs: PhiPack (Profile), 3SEQ, GENECONV, recombination detection program (RDP) (OpenRDP), MaxChi (OpenRDP), Chimaera (OpenRDP), UCHIME (VSEARCH), and gmos; to determine if any are suitable for the analysis of bulk sequencing data. To test the performance and scalability of these methods, we analysed simulated viral sequencing data across a range of sequence diversities, recombination frequencies, and sample sizes. Furthermore, we provide a practical example for the analysis and validation of empirical data. We find that RDMs need to be scalable, use an analytical approach and resolution that is suitable for the intended research application, and are accurate for the properties of a given dataset (e.g. sequence diversity and estimated recombination frequency). Analysis of simulated and empirical data revealed that the assessed methods exhibited considerable trade-offs between these criteria. Overall, we provide general guidelines for the validation of recombination detection results, the benefits and shortcomings of each assessed method, and future considerations for recombination detection methods for the assessment of large-scale viral sequencing data.
Anastomotic Leakage in Relation to Type of Mesorectal Excision and Defunctioning Stoma Use in Anterior Resection for Rectal Cancer
Authors: Rutegård Martin , Svensson Johan , Segelman Josefin , Matthiessen Peter , Lydrup Marie-Louise , Park Jennifer ,   On Behalf of the RectoLeak Study Group
Published: November 2023

BACKGROUND:

Anastomotic leakage after anterior resection for rectal cancer is more common after total compared to partial mesorectal excision but might be mitigated by a defunctioning stoma.

OBJECTIVE:

The aim is to assess how anastomotic leakage is affected by type of mesorectal excision and defunctioning stoma use.

DESIGN:

This is a retrospective multicenter cohort study evaluating anastomotic leakage after anterior resection. Multivariable Cox regression with hazard ratios and 95% confidence intervals was employed to contrast mesorectal excision types and defunctioning stoma use with respect to anastomotic leakage, with adjustment for confounding.

SETTINGS:

This multicenter study included patients from 11 Swedish hospitals between 2014 and 2018.

PATIENTS:

Patients who underwent anterior resection for rectal cancer were included.

MAIN OUTCOMES MEASURES:

Anastomotic leakage rates within and after 30 days of surgery are described up to one year after surgery.

RESULTS:

Anastomotic leakage occurred in 24.2% and 9.0% of 1126 patients operated with total and partial mesorectal excision, respectively. Partial compared to total mesorectal excision was associated with a reduction in leakage, with an adjusted HR of 0.46 (95% CI: 0.29–0.74). Early leak rates within 30 days were 14.9% with and 12.5% without a stoma, while late leak rates after 30 days were 7.5% with and 1.9% without a stoma. After adjustment, defunctioning stoma was associated with a lower early leak rate (HR 0.47; 95% CI: 0.28–0.77). However, the late leak rate was non-significantly higher in defunctioned patients (HR 1.69; 95% CI: 0.59–4.85).

LIMITATIONS:

This study was limited by its retrospective observational study design.

CONCLUSIONS:

Anastomotic leakage is common up to one year after anterior resection for rectal cancer, where partial mesorectal excision is associated with a lower leak rate. Defunctioning stomas seem to decrease the occurrence of leakage, though partially by only delaying the diagnosis
Top 100 Most Cited Articles in Mohs Micrographic Surgery: A Bibliometric Analysis
Authors: Pakhchanian Haig , Aizman Leora , Raiker Rahul , Ng Elise
Published: November 2023

BACKGROUND

Bibliometric analysis is a scientific method that can derive insights into major publications' trends within a field. Currently, no bibliometric study has been conducted for Mohs micrographic surgery (MMS).

OBJECTIVE

To characterize the most frequently cited articles in MMS.

METHODS

Web of Science was used to identify the 100 most cited publications on MMS between 1970 and 2022. Articles were analyzed by title, authorship, institution, journal, year, citation frequency, originating country, funding, citation index, Altmetric score, impact factor, Eigenfactor score, and article influence score.

RESULTS

Since January 2023, the top 100 articles had 9,096 total citations, ranging from 47 to 304. The top cited publication was “Mohs surgery is the treatment of choice for recurrent (previously treated) basal-cell carcinoma” in 1989. The top contributing organization was Harvard University (17%) and top contributing authors were Brodland, DJ (12%) and Zitelli, JA (11%). The year 2005 accounted for most of the articles (12%). Most articles were from the Journal of the American Academy of Dermatology (32%) and Dermatologic Surgery (27%). The United States contributed to 76% of the top articles.

CONCLUSION

This bibliometric analysis offers researchers a detailed overview of important MMS publications and provides useful data into current findings steering MMS research and practice.
Diagnosis of frailty and implications on surgical process in the elderly
Authors: Aceto Paola , Schipa Chiara , Luca Ersilia , Cambise Chiara , Galletta Claudia , Tommasino Concezione , Sollazzi Liliana
Published: November 2023

Longevity has increased the proportion of the elderly in the population, and as a result ageing has become the leading factor for diseases such as cerebrovascular and cardiovascular disorders. It also makes surgical procedures more complex with potential life-threatening complications. In order to further investigate the role of ageing in modern healthcare, the term ‘frailty’ has been proposed to describe a condition of reduced functional reserve that leads to an increased risk of adverse health outcomes. The aim of this study was to review the pathophysiology of frailty and to highlight the most important tools to diagnose it, and their ability to predict the postoperative outcome. There are two major conceptual models that provide guidance for the detection of frailty: the Fried Phenotype Model and the Cumulative Deficit Model. These two main models have provided a base from which the assessment of frailty has developed. Two frailty assessment tools, the modified frailty index and the simplified frailty index play a key role in the preoperative setting because of their predictive power for postoperative risk quantification. Assessments of independence and/or cognitive function represent the main components that an ideal frailty tool should have to identify elderly people who are at risk of postoperative functional and cognitive deterioration. Cognitive impairment undoubtedly has a high association with frailty, but cognitive status is not included in many frailty assessments. In this regard, comprehensive geriatric assessment is a more complete evaluation tool, and it should be used whenever a frailty tool screening gives a positive result. Finally, frailty assessment is useful to explore the cumulative effect of comorbidities on the ageing patients’ functional reserves and to identify the appropriate level of in-hospital and postdischarge care.
Surgical management of a giant kidney tumor weighing 9.2 kg
Authors: Kumar Naveen , Chandra Vipin , Ahmad Parvez , Rizwi Kashif
Published: November 2023

Giant renal tumors are very rare, and they present with abdominal distension without any other symptoms. Complete resection of the tumor is the only curative treatment if metastasis is excluded. We present a case of a giant kidney tumor weighing 9.2 kg removed surgically in toto.
A commentary on ‘Clinical evaluation of the first semi-active total knee arthroplasty assisting robot made in China: a retrospective propensity score-matched cohort study’
Authors: Wan Xufeng , Cao Jian , Zhou Zongke
Published: November 2023

We were highly interested in the article entitled ‘Clinical evaluation of the first semi-active total knee arthroplasty assisting robot made in China: a retrospective propensity score-matched cohort study’ by Yang et al. The authors aim to conduct the postoperative prosthesis position and clinical functions of the semi-active total knee arthroplasty assisting robot (RATKA) using a 1:2 propensity score matching. However, we came across what we believed were flaws in the study methodology and results about the prothesis and tourniquet, and we would like to discuss them with the authors in conjunction with our own research.
Robotassisted abdominal surgery in children less than 5 months of age: Retrospective cohort study
Authors: Jin Yi , Cai Duote , Zhang Shuhao , Luo Wenjuan , Zhang Yuebin , Huang Zongwei , Chen Qingjiang , Gao Zhigang
Published: November 2023

Background:

Robot-assisted surgery is increasingly used in children. While robot-assisted surgery in children has been proved to be safe and feasible, use in infants is controversial. The purpose of this study was to present a study of robot-assisted abdominal surgery in children < 5 months of age.

Materials and Methods:

A retrospective analysis of 111 patients < 5 months of age who underwent abdominal surgery from April 2020 to December 2022 in our hospital. The data included clinical information, operative details, and postoperative outcomes.

Results:

Among these 111 patients, 67 underwent robot-assisted surgery and 44 underwent laparoscopic assisted surgery, the robot-assisted group includes 40 patients with Hirschsprung disease, 20 patients with choledochal cysts, and 7 patients with intestinal duplication, the laparoscopic assisted group includes 26 patients with Hirschsprung disease, 9 patients with choledochal cysts, and 9 patients with intestinal duplication. For Hirschsprung disease, the operation time was significantly longer (P=0.013) and the intraoperative bleeding was significantly less (P=0.000) in the robot-assisted group than the laparoscopic assisted group. For choledochal cysts, the median operation time of 180 mins for the robot-assisted group was not significantly longer than the laparoscopic assisted surgery group at 160 mins (P=0.153). For intestinal duplication, the operation time was significantly longer (P=0.002) in the robot-assisted group than the laparoscopic assisted group. For these three diseases, the hospitalization expense was significantly higher (P < 0.05) in the robot-assisted group than the laparoscopic assisted group, there were no significant differences in complications, and postoperative fasting time between two groups (P > 0.05).

Conclusion:

Robot-assisted abdominal surgery in children < 5 months of age is safe and feasible. This study showed that the surgical indications for the Da Vinci robot system in children can be extended to infants.
The application and therapeutic effect of botulinum toxin type a (BTX-A) in the treatment of patients with pain after cancer treatment: a systematic review and meta-analysis
Authors: Li Shuzhai , Peng Shixuan , Chen Fuchun , Zeng Bin , Zhang Zen , Zhang Zhiming
Published: November 2023

Background:

Botulinum toxin type A (BTX-A) is a potential treatment for cancer pain. This study aimed to analyze the effectiveness and safety of BTX-A in the treatment of pain after cancer treatment.

Patients and methods:

Systematic searches of PubMed, Cochrane Library, and Embase databases were conducted. Randomized controlled trials evaluating the efficacy and safety of BTX-A compared with either placebo or active treatment in patients with pain after cancer treatment were included. The outcomes included pain intensity, quality of life, and adverse events.

Results:

This systematic review included four studies of which 2 were included in the meta-analysis. Compared with a placebo, BTX-A injection in patients with pain after cancer treatment had a clinically meaningful reduction in self-reported pain post-treatment (mean difference=−1.79 [95% confidence interval (CI), −2.14 to −1.43], P＜0.00001, I²=0%).

Conclusion:

This systematic review and meta-analysis demonstrated that BTX-A is safe and effective for pain relief in patients with pain after cancer treatment.
Perspectives of Ethnically and Racially Diverse Nurse Faculty on the Success of Ethnically and Racially Diverse Nursing Students
Authors: Hankins Simona
Published: November 2023

Background:

Ethnically and racially diverse (ERD) nursing students experience unique challenges in the educational environment. Existing research on perspectives of ERD nurse faculty, with emphasis on their perceptions of the factors that support the academic success of ERD nursing students is limited.

Purpose:

The purpose of this study was to explore factors that contribute to the success of ERD nursing students as perceived by ERD nurse faculty.

Methods:

This qualitative study was conducted utilizing a focused ethnography design and methodology, with the theoretical underpinning of Critical Race Theory.

Results:

Twelve themes emerged relating to support, resources, relationships, faculty hiring practices, program structure, instructional content, flexibility, and culture of the educational environment.

Conclusions:

The perspectives of ERD nurse faculty provide an essential body of information that program administrators, faculty, and staff can utilize to positively impact the academic success of ERD nursing students.
Hybrid Oncocytic Tumors (HOTs) in Birt-Hogg-Dubé Syndrome Patients—A Tale of Two Cities
Authors: Wang Xiao-Ming , Mannan Rahul , Zhang Yuping , Chinnaiyan Anya , Rangaswamy Roshni , Chugh Seema , Su Fengyun , Cao Xuhong , Wang Rui , Skala Stephanie L. , Hafez Khaled S. , Vaishampayan Ulka , Mckenney Jesse , Picken Maria M. , Gupta Sounak , Alaghehbandan Reza , Tretiakova Maria , Argani Pedram , Chinnaiyan Arul M. , Dhanasekaran Saravana M. , Mehra Rohit
Published: November 2023

Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of multifocal renal tumors, including hybrid oncocytic tumor (HOT) and chromophobe renal cell carcinoma (chRCC). HOT exhibits heterogenous histologic features overlapping with chRCC and benign renal oncocytoma, posing challenges in diagnosis of HOT and renal tumor entities resembling HOT. In this study, we performed integrative analysis of bulk and single-cell RNA sequencing data from renal tumors and normal kidney tissues, and nominated candidate biomarkers of HOT, L1CAM, and LINC01187, which are also lineage-specific markers labeling the principal cell and intercalated cell lineages of the distal nephron, respectively. Our findings indicate the principal cell lineage marker L1CAM and intercalated cell lineage marker LINC01187 to be expressed mutually exclusively in a unique checkered pattern in BHD-associated HOTs, and these 2 lineage markers collectively capture the 2 distinct tumor epithelial populations seen to co-exist morphologically in HOTs. We further confirmed that the unique checkered expression pattern of L1CAM and LINC01187 distinguished HOT from chRCC, renal oncocytoma, and other major and rare renal cell carcinoma subtypes. We also characterized the histopathologic features and immunophenotypic features of oncocytosis in the background kidney of patients with BHD, as well as the intertumor and intratumor heterogeneity seen within HOT. We suggest that L1CAM and LINC01187 can serve as stand-alone diagnostic markers or as a panel for the diagnosis of HOT. These lineage markers will inform future studies on the evolution and interaction between the 2 transcriptionally distinct tumor epithelial populations in such tumors.
Conjoined Free Fibula Transplantation and First Carpometacarpal Joint Prosthesis for Functional Thumb Reconstruction—A Case Report
Authors: Rein Susanne , Geister Daniela , Kremer Thomas
Published: November 2023

Background

Giant cell tumors grow locally invasive with osseous and soft tissue destruction, requiring wide resection to avoid recurrence. Stable reconstruction of the first carpometacarpal (CMC-1) joint remains a challenge due to its high range of mobility. The latter is of paramount for the functionality of the hand.

Purpose

Therefore, the aim of this study was to report our approach for a combined reconstruction of the first metacarpal and the CMC-1 joint.

Methods

A 58-year-old woman underwent wide resection of a benign giant cell tumor at the base and shaft of the first metacarpal of the left thumb. Because of the loss of the CMC-1 joint and the instability of the thumb, an osseous reconstruction using a vascularized fibular graft combined with a TOUCH Dual Mobility CMC-1 prosthesis was performed to reconstruct the CMC-1 joint.

Results

Osseous healing was observed after 3 months. No tumor recurrence and good joint function were documented at the follow-up investigation after 1 year. The patient reported only minor restrictions during activities of daily living. Thumb opposition was possible with a Kapandji score of 8/10. A slight pain while walking remained as a donor-side morbidity at the right lower leg.

Conclusion

Metacarpal reconstruction with vascularized fibula bone grafts allowed a combined joint reconstruction with a commercially available prosthesis, which is an approach to restore the complex range of motion of the thumb.
Staphylococcus aureusskin colonization is mediated by SasG lectin variation
Authors: Mills Krista B. , Maciag Joseph J. , Wang Can , Crawford John A. , Enroth Timothy J. , Keim Klara C. , Dufrêne Yves F. , Robinson D. Ashley , Fey Paul D. , Herr Andrew B. , Horswill Alexander R.
Published: November 2023

Staphylococcus aureuscauses the majority of skin and soft tissue infections, but this pathogen only transiently colonizes healthy skin. However, this transient skin exposure enablesS. aureusto transition to infection. Initial adhesion ofS. aureusto skin corneocytes is mediated by surface protein G (SasG). Here, phylogenetic analyses reveal the presence of two major divergent SasG alleles inS. aureus, SasG-I and SasG-II. Structural analyses of SasG-II identified a unique non-aromatic arginine in the binding pocket of the lectin subdomain that mediates adhesion to corneocytes. Atomic force microscopy and corneocyte adhesion assays indicated SasG-II can bind to a broader variety of ligands than SasG-I. Glycosidase treatment resulted in different binding profiles between SasG-I and SasG-II on skin cells. Additionally, SasG-mediated adhesion was recapitulated using differentiated N/TERT keratinocytes. Our findings indicate that SasG-II has evolved to adhere to multiple ligands, conferring a distinct advantage toS. aureusduring skin colonization.
ColabFold predicts alternative protein structures from single sequences, coevolution unnecessary for AF-cluster
Authors: Porter Lauren L. , Chakravarty Devlina , Schafer Joseph W. , Chen Ethan A.
Published: November 2023

Though typically associated with a single folded state, globular proteins are dynamic and often assume alternative or transient structures important for their functions1,2. Wayment-Steele, et al. steered ColabFold3to predict alternative structures of several proteins using a method they call AF-cluster4. They propose that AF-cluster “enables ColabFold to sample alternate states of known metamorphic proteins with high confidence” by first clustering multiple sequence alignments (MSAs) in a way that “deconvolves” coevolutionary information specific to different conformations and then using these clusters as input for ColabFold. Contrary to this Coevolution Assumption, clustered MSAs are not needed to make these predictions. Rather, these alternative structures can be predicted from single sequences and/or sequence similarity, indicating that coevolutionary information is unnecessary for predictive success and may not be used at all. These results suggest that AF-cluster’s predictive scope is likely limited to sequences with distinct-yet-homologous structures within ColabFold’s training set.
Revisiting Reddy: A DLBCL Do-over
Authors: Dreval Kostiantyn , Cruz Manuela , Rushton Christopher , Liuta Nina , Mirhosseini Houman Layegh , Brown Callum , Morin Ryan D. ,   the GAMBL consortium
Published: November 2023

The 2017 study by Reddyet aldescribed the comprehensive characterization of somatic drivers of diffuse large B-cell lymphoma using whole exome sequencing.1After additional large studies relying on exome or whole genome sequencing were published, several oddities unique to the Reddy results have emerged. Seeking to explain the discrepancies, we reanalyzed their data using established open-source pipelines. This revealed thousands of mutations that could not be independently reproduced by these pipelines and a larger set of high-quality mutations that were not reported by Reddy. This caused an artificial under-representation of the mutation prevalence in many genes including clinically relevant hot spots affectingEZH2andCD79B. More generally, the study had an under-representation of mutations in DLBCL genes that disproportionately affected genes known to have the highest mutation rates. The missing variants and the spurious variants can be attributed to distinct problems with the analytical approaches employed in that study. Our analysis also identified strong associations between mutations and patient outcome includingTP53, KMT2DandPIM1, which were not found in the Reddy study. Overall, we demonstrate that this combination of errors influenced many of the central novel findings from their study rendering their results largely non-replicable. The full results of our analyses are included as supplemental items as a resource for other researchers with an interest in the genetics of B-cell lymphomas.
Stratification of human gut microbiomes by succinotype is associated with inflammatory bowel disease status
Authors: Anthamatten Laura , von Bieberstein Philipp Rogalla , Menzi Carmen , Zünd Janina N. , Lacroix Christophe , de Wouters Tomas , Leventhal Gabriel E.
Published: November 2023

The human gut microbiome produces and consumes a variety of compounds that interact with the host and impact health. Succinate is of particular interest as it intersects with both host and microbiome metabolism. However, which gut bacteria are most responsible for the consumption of intestinal succinate is poorly understood. Here, we build upon an enrichment-based whole fecal sample culturing approach and identify two main bacterial taxa that are responsible for succinate consumption in the human intestinal microbiome,PhascolarctobacteriumandDialister. These two taxa have the hallmark of a functional guild and are strongly mutual exclusive across over 20,000 fecal samples in nearly 100 cohorts and can thus be used to assign a robust ‘succinotype’ to an individual. We show that they differ with respect to their rate of succinate consumptionin vitroand that this is associated with higher concentrations of fecal succinate. Finally, individuals suffering from inflammatory bowel disease (IBD) are more likely to have theDialistersuccinotype compared to healthy subjects. The functionally meaningful classification of human intestinal microbiota based on ‘succinotype’ thus builds a bridge between microbiome function and IBD pathophysiology related to succinate.
Intermolecular interactions between cysteine and aromatic amino acids with phenyl moiety in the DNA-binding domain of heat shock factor 1 regulate thermal stress-induced trimerization
Authors: Lee Chang-Ju , Choi Bo-Hee , So-Sun-Kim  , Kim David Nahm-Joon , Choi Jeong-Mo , Park Young-Shang , Park Jang-Su
Published: November 2023

In this study, we investigated the trimerization mechanism and structure of heat shock factor 1 (HSF1) in humans, goldfish, and walleye pollock at various temperatures. The trimerization of HSF1s were confirmed using western blotting using their respective antibodies. First, we examined the HSF1 DNA-binding domains of human (Homo sapiens), goldfish (Carassius auratus), and walleye pollock (Gadus chalcogrammus) by mutating key residues (36 and 103) that are thought to directly affect trimer generation. Humans, goldfish, and walleye pollock contain cysteine at residue 36, but cysteine (C), tyrosine (Y), and phenylalanine (F) at residue 103. Also, the trimer formation temperature of each species was found to be 42, 37, and 20 °C, respectively. In the mutation experiment, trimerization formed at 42 °C when residue 103 was C, at 37 °C it was Y, and at 20 °C it was F, regardless of the species. In addition, it was confirmed that when residue 103 of the three species was mutated to alanine (A), trimer was not formed. This suggest that, in addition to the previously identified C-C disulfide bonds in humans, C forms a trimer with a new type of bond with aromatic ring residues such as Y and F. Thus, HSF1 trimer formation temperature reveals the trimer creation mechanism through the fact that goldfish can have C-Y bonds at 37 °C, and walleye pollock can have C-F bonds at 20 °C. This study suggests that the trimer formation temperature and mechanism of HSF1 are regulated by the amino acid at residue 103.
Systems levels analysis of lipid metabolism in oxygen-induced retinopathy
Authors: Singh Charandeep
Published: November 2023

Hyperoxia induces glutamine-fueled anaplerosis in the Muller cells, endothelial cells, and retinal explants. Anaplerosis takes away glutamine from the biosynthetic pathway to the energy-producing TCA cycle. This process depletes biosynthetic precursors from newly proliferating endothelial cells. The induction of anaplerosis in the hyperoxic retina is a compensatory response, either to decreased glycolysis or decreased flux from glycolysis to the TCA cycle. We hypothesized that by providing substrates that feed into TCA, we could reverse or prevent glutamine-fueled anaplerosis, thereby abating the glutamine wastage for energy generation. Using an oxygen-induced retinopathy (OIR) mouse model, we first compared the difference in fatty acid metabolism between OIR-resistant BALB/cByJ and OIR susceptible C57BL/6J strains to understand if these strains exhibit metabolic difference that protects BALB/cByJ from the hyperoxic conditions and prevents their vasculature in oxygen-induced retinopathy model. Based on our findings from the metabolic comparison between two mouse strains, we hypothesized that the medium-chain fatty acid, octanoate, can feed into the TCA and serve as an alternative energy source in response to hyperoxia. Our systems levels analysis of OIR model shows that the medium chain fatty acid can serve as an alternative source to feed TCA. We here, for the first time, demonstrate that the retina can use medium-chain fatty acid octanoate to replenish TCA in normoxic and at a higher rate in hyperoxic conditions.
Neuroticism levels in severe depression may reveal association with higher levels of intelligence
Authors: Nitchie Frederick , Moore Tyler , Scott J. Cobb , Makhoul Walid , Sheline Yvette
Published: November 2023

The anxious-misery spectrum of disorders encompasses some of the most debilitating mental disorders that effect the population at-large. In addition, neuroticism is a trait that has been shown to correlate with higher levels of reported symptomatology for individuals diagnosed with anxious-misery disorders. However, it is less understood which of these might be more predictive of the cognitive impairments typically associated with mental illness. Therefore, we selected a group of participants with high trait neuroticism and comorbid anxious-misery symptoms. Using confirmatory factor analysis, we loaded the results of seventeen neuropsychological measures from each participant onto five distinct factors that exists on the anxious-misery spectrum: Depression, Anxiety, Impulsivity, Insomnia, and Somatizing. These factors were then compared to the results that participants had on to neurocognitive batteries: the University of Pennsylvania Computerized Neurocognitive Test Battery as well and the National Institute of Health Toolbox. Contrary to our expectations, we found that those in the top quartile of depressive symptom severity performed better than controls on working memory measures. These results are thought to be the result of correlations that have been shown previously between high levels of neuroticism and higher levels of intelligence.
IsoVEM: Isotropic Reconstruction for Volume Electron Microscopy Based on Transformer
Authors: He Jia , Zhang Yan , Sun Wenhao , Yang Ge , Sun Fei
Published: November 2023

Volume electron microscopy (vEM) has become a rapidly developing technique for studying the 3D architecture of biological specimens, such as cells, tissues, and organs at nanometer resolution; this technique involves collecting a series of electron micrographs of axial sequential sections and reconstructing the 3D volume, providing useful information on the cellular ultrastructural spectrum. This technique currently suffers from anisotropic resolution between the lateral (x, y) and axial (z) directions and the loss/damage of sections. Here, we develop a new algorithm, IsoVEM, based on a video transformer model to boost the axial resolution and achieve isotropic reconstruction of vEM. By learning high-resolution axial structures and utilizing the 3D continuity of biological structures, IsoVEM can recover axial information and repair random lost/damaged sections based on a self-supervision strategy, achieving a higher resolution than existing methods, which has been validated for both simulated FIB-SEM datasets and experimental ssTEM datasets. In addition to visual validation, the segmentation efficiency and statistical precision of various ultrastructures, e.g., neurons, mitochondria, vesicles, and membrane bilayers, also prove the better performance of IsoVEM. Therefore, using IsoVEM, we achieve isotropic reconstruction via anisotropic axial sampling, which increases the vEM throughput for studying large-scale biological architectures.
Predicting phage-bacteria interactions at the strain level from genomes
Authors: Gaborieau Baptiste , Vaysset Hugo , Tesson Florian , Charachon Inès , Dib Nicolas , Bernier Juliette , Dequidt Tanguy , Georjon Héloïse , Clermont Olivier , Hersen Pascal , Debarbieux Laurent , Ricard Jean-Damien , Denamur Erick , Bernheim Aude
Published: November 2023

Predicting how phages can selectively infect specific bacterial strains holds promise for developing novel approaches to combat bacterial infections and better understanding microbial ecology. Experimental studies on phage-bacteria interactions have been mostly focusing on a few model organisms to understand the molecular mechanisms which makes a particular bacterial strain susceptible to a given phage. However, both bacteria and phages are extremely diverse in natural contexts. How well the concepts learned from well-established experimental models generalize to a broad diversity of what is encountered in the wild is currently unknown. Recent advances in genomics allow to identify traits involved in phage-host specificity, implying that these traits could be utilized for the prediction of such interactions. Here, we show that we could predict outcomes of most phage-bacteria interactions at the strain level inEscherichianatural isolates based solely on genomic data. First, we established a dataset of experimental outcomes of phage-bacteria interactions of 403 natural, phylogenetically diverse,Escherichiastrains to 96 bacteriophages matched with fully sequenced and genomically characterized strains and phages. To predict these interactions, we set out to define genomic traits with predictive power. We show that most interactions in our dataset can be explained by adsorption factors as opposed to antiphage systems which play a marginal role. We then trained predictive algorithms to pinpoint which interactions could be accurately predicted and where future research should focus on. Finally, we show the application of such predictions by establishing a pipeline to recommend tailored phage cocktails to target pathogenic strains from their genomes only and show higher efficiency of tailored cocktails on a collection of 100 pathogenicE. coliisolates. Altogether, this work provides quantitative insights into understanding phage–host specificity at the strain level and paves the way for the use of predictive algorithms in phage therapy.
Tertiary folds of the SL5 RNA from the 5′ proximal region of SARS-CoV-2 and related coronaviruses
Authors: Kretsch Rachael C. , Xu Lily , Zheludev Ivan N. , Zhou Xueting , Huang Rui , Nye Grace , Li Shanshan , Zhang Kaiming , Chiu Wah , Das Rhiju
Published: November 2023

Coronavirus genomes sequester their start codons within stem-loop 5 (SL5), a structured, 5′ genomic RNA element. In most alpha- and betacoronaviruses, the secondary structure of SL5 is predicted to contain a four-way junction of helical stems, some of which are capped with UUYYGU hexaloops. Here, using cryogenic electron microscopy (cryo-EM) and computational modeling with biochemically-determined secondary structures, we present three-dimensional structures of SL5 from six coronaviruses. The SL5 domain of betacoronavirus SARS-CoV-2, resolved at 4.7 Å resolution, exhibits a T-shaped structure, with its UUYYGU hexaloops at opposing ends of a coaxial stack, the T’s “arms.” Further analysis of SL5 domains from SARS-CoV-1 and MERS (7.1 and 6.4-6.9 Å resolution, respectively) indicate that the junction geometry and inter-hexaloop distances are conserved features across the studied human-infecting betacoronaviruses. The MERS SL5 domain displays an additional tertiary interaction, which is also observed in the non-human-infecting betacoronavirus BtCoV-HKU5 (5.9-8.0 Å resolution). SL5s from human-infecting alphacoronaviruses, HCoV-229E and HCoV-NL63 (6.5 and 8.4-9.0 Å resolution, respectively), exhibit the same coaxial stacks, including the UUYYGU-capped arms, but with a phylogenetically distinct crossing angle, an X-shape. As such, all SL5 domains studied herein fold into stable tertiary structures with cross-genus similarities, with implications for potential protein-binding modes and therapeutic targets.

Significance

The three-dimensional structures of viral RNAs are of interest to the study of viral pathogenesis and therapeutic design, but the three-dimensional structures of viral RNAs remain poorly characterized. Here, we provide the first 3D structures of the SL5 domain (124-160 nt, 40.0-51.4 kDa) from the majority of human-infecting coronaviruses. All studied SL5s exhibit a similar 4-way junction, with their crossing angles grouped along phylogenetic boundaries. Further, across all species studied, conserved UUYYGU hexaloop pairs are located at opposing ends of a coaxial stack, suggesting that their three-dimensional arrangement is important for their as-of-yet defined function. These conserved tertiary features support the relevance of SL5 for pan-coronavirus fitness and highlight new routes in understanding its molecular and virological roles and in developing SL5-based antivirals.

Classification:Biological Sciences, Biophysics and Computational Biology
The effect of clinically relevant beta-lactam, aminoglycoside, and quinolone antibiotics on bacterial extracellular vesicle release fromE. coli
Authors: Torabian Panteha , Singh Navraj , Crawford James , Gonzalez Gabriela , Burgado Nicholas , Videva Martina , Miller Aidan , Perdue Janai , Dinu Milena , Pietropaoli Anthony , Gaborski Thomas , Michel Lea Vacca
Published: November 2023

Sepsis, a leading cause of death in hospitals, can be defined as a dysregulated host inflammatory response to infection, which can lead to tissue damage, organ failure, and cardiovascular complications. Although there is no cure for sepsis, the condition is typically managed with broad spectrum antibiotics to eliminate any potential bacterial source of infection. However, a potential side-effect of antibiotic treatment is the enhanced release of bacterial extracellular vesicles (BEVs). BEVs are membrane-bound nanoparticles produced by a variety of mechanisms, one of which includes the pinching-off of the outer membrane (in Gram-negative bacteria) to enclose proteins and other biological molecules for transport and intercellular communication. Some of the Gram-negative EV cargo, including Peptidoglycan associated lipoprotein (Pal) and Outer membrane protein A (OmpA), have been shown to induce both acute and chronic inflammation in host tissue. We hypothesize that antibiotic concentration and its mechanism of action can have an effect on the amount of released BEVs, which could potentially exacerbate the host inflammatory response. In this study, we evaluated nine clinically relevant antibiotics for their effect on EV release fromEscherichia coli. EVs were characterized using immunoblotting, nanoparticle tracking analysis, and transmission electron microscopy. Several beta-lactam antibiotics caused significantly more EV release, while quinolone and aminoglycosides caused relatively less vesiculation. Further study is warranted to corroborate the correlation between an antibiotic’s mechanism of action and its effect on EV release, but these results underline the importance of antibiotic choice when treating sepsis patients.
Impact of electrodes design and insertion methods to surrounding cortical tissues from high-density arrays
Authors: McNamara Ingrid N. , Wellman Steven M. , Li Lehong , Eles James R. , Savya Sajishnu , Sohal Harbaljit S. , Angle Matthew R. , Kozai Takashi D. Y.
Published: November 2023

Objective

Over the past decade, neural electrodes have played a crucial role in bridging biological tissues with anthropomorphic devices. This study focuses on evaluating the optimal pitch, tip profile, and insertion speed for effectively implanting Paradromics’ high-density Fine Microwire Arrays (FμA) prototypes into the primary visual cortex (V1) of mice and rats, addressing the challenges associated with the “bed-of-nails” effect and tissue dimpling.

Approach

Tissue response was assessed by investigating the impact of electrodes on the blood-brain barrier (BBB) and cellular damage, with a specific emphasis on tailored insertion strategies to minimize tissue disruption during electrode implantation.

Main Results

Electro-sharpened arrays demonstrated a marked reduction in cellular damage within 50 μm of the electrode tip compared to blunt and angled arrays. Histological analysis revealed that slow insertion speeds led to greater BBB compromise than fast and pneumatic methods. Successful single-unit recordings validated the efficacy of the optimized electro-sharpened arrays in capturing neural activity.

Significance

These findings underscore the critical role of tailored insertion strategies in minimizing tissue damage during electrode implantation, highlighting the suitability of electro-sharpened arrays for long-term neural recording applications. This research contributes to a deeper understanding of the complexities associated with high-channel-count microelectrode array implantation, emphasizing the importance of meticulous assessment and optimization of key parameters for effective integration and minimal tissue disruption. By elucidating the interplay between insertion parameters and tissue response, our study lays a strong foundation for the development of advanced implantable devices with a reduction in reactive gliosis and improved performance in neural recording applications.
Identification of Essential Temperature-Stressed Genes FromApis melliferaHypopharyngeal Glands Transcriptomes Under Variable Temperatures
Authors: Maigoro Abdulkadir Yusif , Lee Jeong Hyeon , Lee Sujin , Kwon Hyung Wook
Published: November 2023

Temperature is one of the essential abiotic factors required for honey bee survival and pollination. It affects honey bee physiology, behavior, and expression of related genes. Also, considered one of the major factors contributing to colony collapse disease (CCD). In this research, RNA-seq analysis was performed using hypopharyngeal glands (HGs) tissue at low (18 °C), high (25 °C), and regular (22 °C) temperatures. Differentially expressed genes (DEGs) were identified after comparing the three groups with one another based on temperature differences using DESeq analysis. 5196 common DEGs (cDEGs) were identified among the groups. They are highly enriched in RNA processing and RNA metabolism process while the KEGG pathway enrichment analysis showed that the cDEGs are enriched in longevity regulating pathway, MAPK signaling pathway-fly, and Glycerophospholipid metabolism. Further, 360 temperature-stressed genes identified are highly enriched in translation, oxidative activity, and ribonucleoprotein complex. The enriched KEGG pathway includes ribosome, oxidative phosphorylation, fatty acid metabolism, and citrate cycle (TCA cycle). All the top ten (10) hub genes among the 360 temperature-stressed genes are found up-regulated. In addition, heat-shock protein 90 (HSP90) known as the stressed response gene, and Gr10, the amino acid response gene were up-regulated and down-regulated respectively in the temperature-stressed group. Low expression of Gr10 under temperature-stress can affect nursing behavior and bee development. Ultimately, these findings will help in identifying honeybee-temperature survival mechanisms under varying temperature effects.
Ion occupancy of the selectivity filter controls opening of a cytoplasmic gate in the K2P channel TALK-2
Authors: Neelsen Lea C. , Riel Elena B. , Rinné Susanne , Schmid Freya-Rebecca , Jürs Björn C. , Bedoya Mauricio , Langer Jan P. , Eymsh Bisher , Kiper Aytug K. , Cordeiro Sönke , Decher Niels , Baukrowitz Thomas , Schewe Marcus
Published: November 2023

Two-pore domain K+(K2P) channel activity was previously thought to be controlled primarily via a selectivity filter (SF) gate. However, recent crystal structures of TASK-1 and TASK-2 revealed a lower gate at the cytoplasmic pore entrance. Here, we report functional evidence of such a lower gate in the K2Pchannel K2P17.1 (TALK-2, TASK-4). We identified compounds (drugs and lipids) and mutations that opened the lower gate allowing the fast modification of pore cysteine residues. Surprisingly, stimuli that exclusively target the SF gate (i.e., pHe., Rb+permeation, membrane depolarization) also opened the cytoplasmic gate suggesting that the SF can induce global structural changes in TALK-2. Reciprocally, opening of the lower gate reduced the electrical work required to force ions into the SF to induce its opening as apparent in large shifts of the conductance-voltage (G-V) curves. These shifts, thereby, represent the mechanical work done by the SF to induce a global structural re-arrangement that opened the lower gate. In conclusion, it appears that the SF is so rigidly locked into the TALK-2 protein structure that changes in ion occupancy can pry open a distant lower gate. Vice versa, we show that opening of the lower gate concurrently forces the SF gate to open. This concept might extent to other K+channels that contain two gates (e.g., voltage-gated K+channels) for which such a positive gate coupling has been suggested, but so far not directly demonstrated.

Synopsis

TALK-2 channels, like most K2Pchannels, possess a functional gate in the selectivity filter (SF; the upper gate) that is opened by rising extracellular pH and voltage-dependent ion binding (voltage gating).

A second (lower) permeation gate in TALK-2 at the cytoplasmic end of TM4 is identified using cysteine modification, scanning mutagenesis and structural modelling. This gate can be opened by anionic lipids (LC-CoA) as well as pharmacological ligands (e.g., 2-APB).

The modification reactivity of a cysteine introduced between the two gates reveal that stimuli targeting the SF gate also open the lower gate. Furthermore, stimuli that open the lower gate reduce the voltage (i.e., electrical work or mechanical load) required to open the SF gate. These findings demonstrate a tight positive coupling between the two gates.

The concept of strong positive gate coupling might extend to other K+channels with two gates (e.g., voltage-gated K+channels) for which positive gate coupling has been suggested but so far not directly demonstrated.
Impact of blood meals taken on ivermectin-treated livestock on survival and fecundity of the malaria vectorAnopheles coluzziiunder laboratory conditions
Authors: Pooda Sié Hermann , de Salle Hien François , Pagabeleguem Soumaïla , Heinrich Andre Patrick , Porciani Angélique , Sagna André Barembaye , Zela Lamidi , Percoma Lassane , Lefèvre Thierry , Dabiré Roch Kounbobr , Koffi Amnan Alphonsine , Düring Rolf-Alexander , Pennetier Cédric , Moiroux Nicolas , Mouline Karine
Published: November 2023

Treatment of livestock with endectocides such as ivermectin is viewed as a complementary vector control approach to address residual transmission of malaria. However, efficacy of this treatment may vary between animal species. Hence, our purpose was to investigate the effects of ivermectin treatments of common livestock species on life history traits of the opportunistic malaria vectorAnopheles coluzzii.

Sheep, goats and pigs were treated using injectable veterinary ivermectin formulation at the species-specific doses (recommended dose for all species and high dose in pig). Mosquito batches were exposed to treated and control (not injected) animals at different days after treatment. Daily mosquito mortality was recorded and fecundity assessed through the count of gravid females and the number of eggs they developed.

The recommended dose of ivermectin induced a significant decrease in mosquito survival for up to 7 days after injection (DAI), with a decrease of 89.7%, 66.7%, and 48.4% in treated pigs, goats and sheep, respectively, compared to control animals. In treated pigs, the triple therapeutic dose decreased mosquito survival of 68.97% relatively to controls up to 14 DAI. The average number in gravid femalesAnophelesthat survived after feeding on treated animals were reduced when blood-meals were taken on sheep (2.57% and 42.03% at 2 and 7 DAI), or on goats (decrease of the 28.28% and 73.64% respectively at 2 and 7 DAI).

This study shows that ivermectin treatments to animals negatively impactsAn. coluzziilife history traits and could reduce vector densities in areas where livestock live near humans. However, due to short-term efficacy of single dose treatments, repeated treatments and potentially increased dosages would be required to span the transmission season. The use of long-acting ivermectin formulations is discussed as a mean for extending efficacy while remaining cost effective.