bluuebunny/crossref_metadata_2025 huggingface dataset:
Disparity Reduction in U.S. Breast Reconstruction: An Analysis from 2005 to 2017 Using 3 Nationwide Data Sets
Authors: Rubenstein Robyn N. , Nelson Jonas A. , Azoury Saïd C. , Kim Minji , Boe Lillian A. , Chu Jacqueline J. , Stern Carrie S. , Tadros Audree B. , Mehrara Babak J. , Matros Evan
Published: March 2024

Background:

Following passage of the Women’s Health and Cancer Rights Act of 1998 (WHCRA), a steady rise in breast reconstruction rates was reported; however, a recent update is lacking. This study aimed to evaluate longitudinal trends in breast reconstruction (BR) rates in the United States and relevant sociodemographic factors.

Methods:

Mastectomy cases with and without BR from 2005 through 2017 were abstracted from the National Surgical Quality Improvement Program database; the Surveillance, Epidemiology, and End Results Program database; and the National Cancer Database (NCDB). BR rates were examined using Poisson regression. Multivariable logistic regression analysis of NCDB data were used to identify predictors of reconstruction. Race and insurance distributions were evaluated over time.

Results:

Of 1,554,381 mastectomy patients, 507,631 (32.7%) underwent BR. Annual reconstruction rates per 1000 mastectomies increased from 2005 to 2012 (National Surgical Quality Improvement Program incidence rate ratio [IRR], 1.077; Surveillance, Epidemiology, and End Results Program IRR, 1.090; and NCDB IRR, 1.092) and stabilized from 2013 to 2017. NCDB data showed that patients who were younger (≤59 years), privately insured, had fewer comorbidities, and underwent contralateral prophylactic mastectomy were more likely to undergo BR (all P < 0.001). Over time, the increase in BR rates was higher among Black (252.3%) and Asian (366.4%) patients than among White patients (137.3%). BR rates increased more among Medicaid (418.6%) and Medicare (302.8%) patients than among privately insured patients (125.3%).

Conclusions:

This analysis demonstrates stabilization in immediate BR rates over the past decade; reasons behind this stabilization are likely multifactorial. Disparities based on race and insurance type have decreased, with a more equitable distribution of BR rates.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Update and approach to patients with brain abscess
Authors: Omland Lars Haukali , Nielsen Henrik , Bodilsen Jacob
Published: March 2024

Purpose of review

The epidemiology of brain abscess has changed in recent decades. Moreover, acute and long-term management remains challenging with high risks of mortality and neurological sequelae. This review describes recent advances in epidemiology, diagnosis, and treatment of brain abscess.

Recent findings

The incidence of brain abscess is increasing, especially among elderly individuals. Important predisposing conditions include dental and ear-nose-throat infections, immuno-compromise, and previous neurosurgery. Molecular-based diagnostics have improved our understanding of the involved microorganisms and oral cavity bacteria including anaerobes are the predominant pathogens. The diagnosis relies upon a combination of magnetic resonance imaging, neurosurgical aspiration or excision, and careful microbiological examinations. Local source control by aspiration or excision of brain abscess combined with long-term antimicrobials are cornerstones of treatment. Long-term management remains important and should address neurological deficits including epilepsy, timely diagnosis and management of comorbidities, and potential affective disorders.

A multidisciplinary approach to acute and long-term management of brain abscess remains crucial and source control of brain abscess by neurosurgery should be pursued whenever possible. Numerous aspects regarding diagnosis and treatment need clarification. Nonetheless, our understanding of this complicated infection is rapidly evolving.
Same-day Ileostomy Closure Discharge Reduces Costs Without Compromising Outcomes
Authors: Ferrari Davide , Violante Tommaso , Moriarty James P. , Borah Bijan J. , Merchea Amit , Stocchi Luca , Larson David W.
Published: March 2024

Objective:

This study aims to assess the costs of a same-day discharge (SDD) enhanced recovery pathway for diverting loop ileostomy (DLI) closure compared with a standard institutional enhanced recovery protocol.

Background:

Every year, 50,155 patients in the United States undergo temporary stoma reversal. While ambulatory stoma closure has shown promise, widespread adoption remains slow. This study builds on previous research, focusing on the costs of a novel SDD protocol introduced in 2020.

Methods:

A retrospective case-control study was conducted at Mayo Clinic, Rochester, Minnesota, and Mayo Clinic, Jacksonville, Florida, comparing patients undergoing SDD DLI closure from August 2020 to February 2023 to those in a matched cohort receiving standard inpatient enhanced recovery protocol. Patients were matched based on age, sex, american society of anesthesiologists score, surgery period, and hospital. Primary outcomes included direct hospitalization and additional costs in the 30 days postdischarge.

Results:

The SDD group (n = 118) demonstrated a significant reduction in median index episode hospitalization and 30-day postoperative costs compared with the inpatient group (n = 236), with savings of $4827 per patient. Complication rates were similar, and so were readmission and reoperation rates.

Conclusions:

Implementation of the SDD for DLI closure is associated with substantial cost savings without compromising patient outcomes. The study advocates for a shift towards SDD protocols, offering economic benefits and potential improvements in health care resource utilization.
Association of National Accreditation Program for Rectal Cancer Accreditation with Outcomes after Rectal Cancer Surgery
Authors: Harbaugh Calista M , Kunnath Nicholas J , Suwanabol Pasithorn A , Dimick Justin B , Hendren Samantha K , Ibrahim Andrew M
Published: March 2024

BACKGROUND:

The National Accreditation Program for Rectal Cancer (NAPRC) defined a set of standards in 2017 centered on multidisciplinary program structure, evidence-based care processes, and internal audit to address widely variable rectal cancer practices and outcomes across US hospitals. There have been no studies to-date testing the association between NAPRC accreditation and rectal cancer outcomes.

STUDY DESIGN:

This was a retrospective, observational study of Medicare beneficiaries aged 65 to 99 years with rectal cancer who underwent proctectomy from 2017 to 2020. The primary exposure was NAPRC accreditation and the primary outcomes included mortality (in-hospital, 30 day, and 1 year) and 30-day complications, readmissions, and reoperations. Associations between NAPRC accreditation and each outcome were tested using multivariable logistic regression with risk-adjustment for patient and hospital characteristics.

RESULTS:

Among 1,985 hospitals, 65 were NAPRC-accredited (3.3%). Accredited hospitals were more likely to be nonprofit and teaching with 250 or more beds. Among 20,202 patients, 2,078 patients (10%) underwent proctectomy at an accredited hospital. Patients at accredited hospitals were more likely to have an elective procedure with a minimally invasive approach and sphincter preservation. Risk-adjusted in-hospital mortality (1.1% vs 1.3%; p = 0.002), 30-day mortality (2.1% vs 2.9%; p < 0.001), 30-day complication (18.3% vs 19.4%; p = 0.01), and 1-year mortality rates (11% vs 12.1%; p < 0.001) were significantly lower at accredited compared with nonaccredited hospitals.

CONCLUSIONS:

NAPRC-accredited hospitals have lower risk-adjusted morbidity and mortality for major rectal cancer surgery. Although NAPRC standards address variability in practice, without directly addressing surgical safety, our findings suggest that NAPRC-accredited hospitals may provide higher quality surgical care.
Molecular characterization of HBV infected Nigerians reveal diverse mutational profiles within the BCP/PC regions
Authors: Faneye Adedayo Omotayo , Motayo Babatunde Olanrewaju , Mustafa Aisha , Odiabo Georgina
Published: March 2024

Background; Hepatis B virus (HBV) is the most implicated cause of severe liver disease and hepatocellular carcinoma worldwide. Studies have shown that the basal core protein (BCP) and pre-core protein (PC) of HBV play a significant role in HBV related carcinogenesis. There is paucity of data on type and effect of BCP and PC mutations in Nigeria. This study aims to genotype HBV and investigate any mutations within the BCP and PC among HBV patients in Ibadan, Nigeria.
Methods; Forty HBV DNA positive were recruited into this study, viral load assay and genotyping by nested multiplex PCR was done. The partial X gene region was amplified and Sanger sequenced. The BPC and PC genomic regions were then analyzed using bioinformatics.
 Results; Twenty-three participants recorded HBV DNA viral load of >20,000 International Units (IU), while 17 had <20,000 IU, while 28 samples were genotyped.  Five genotypes A, B, C, D and E and 4 mixed genotypes AC, AD ACD and ABCD were detected. Genotype AC was the most frequently encountered while genotypes E and B were the least encountered. Mutation was highest in ages 34 to 45 years. Double mutation A1762T and G1764A within the BCP region was the most encountered mutation.
Conclusions; We report a diverse HBV genetic landscape, with mixed infections between genotypes with BCP double mutation A1762T/G1764A, signaling the likelihood of poor HBV related liver disease prognosis. Our findings contribute to our understanding of the molecular characteristics of HBV and its potential implications for disease progression and management among HBV infected Nigerians.
Cardiac glycosides inhibit early and late vaccinia virus protein expression
Authors: Samolej Jerzy , White Ian J. , Strang Blair L. , Mercer Jason
Published: March 2024

Cardiac glycosides (CGs) are natural steroid glycosides, which act as inhibitors of the cellular sodium-potassium ATPase pump. Although traditionally considered toxic to human cells, CGs are widely used as drugs for the treatment of cardiovascular-related medical conditions. More recently, CGs have been explored as potential anti-viral drugs and inhibit replication of a range of RNA and DNA viruses. Previously, a compound screen identified CGs that inhibited vaccinia virus (VACV) infection. However, no further investigation of the inhibitory potential of these compounds was performed, nor was there investigation of the stage(s) of the poxvirus lifecycle they impacted. Here, we investigated the anti-poxvirus activity of a broad panel of CGs. We found that all CGs tested were potent inhibitors of VACV replication. Our virological experiments showed that CGs did not impact virus infectivity, binding, or entry. Rather, experiments using recombinant viruses expressing reporter proteins controlled by VACV promoters and arabinoside release assays demonstrated that CGs inhibited early and late VACV protein expression at different concentrations. Lack of virus assembly in the presence of CGs was confirmed using electron microscopy. Thus, we expand our understanding of compounds with anti-poxvirus activity and highlight a yet unrecognized mechanism by which poxvirus replication can be inhibited.
Deciphering changes in the incidence of hemorrhagic stroke and cerebral venous sinus thrombosis during the coronavirus disease 2019 pandemic: a nationwide time-series correlation study
Authors: Cho Soohyeon , Kim Dong Kyu , Song Min Cheol , Lee Euiho , Park Seoncheol , Chung Darda , Ha Jongmok
Published: March 2024

Introduction

Hemorrhagic stroke and cerebral venous sinus thrombosis (CVST) are associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination. We aimed to investigate changes in the incidence of hemorrhagic stroke and CVST in South Korea before and during the coronavirus disease 2019 pandemic and the factors associated with these changes.

Materials and Methods

We conducted a nationwide time-series study using population-based databases between 2007 and 2022. The real-world and forecasted incidences of acute non-traumatic subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and CVST during the pandemic period (2020–2022) were estimated and compared with the pre-pandemic period (2007–2019). The prevalence of conventional risk factors was measured using time-series data. Finally, a time-series correlation analysis was performed to examine the temporal association between conventional risk factors, SARS-CoV-2 infection, and SARS-CoV-2 vaccination.

Results

The incidence of hemorrhagic stroke (SAH and ICH) was lower during the pandemic than during the pre-pandemic period. This observed decrease was associated with a reduction in the prevalence of conventional risk factors but not with SARS-CoV-2 infection or vaccination. The incidence of CVST was higher during the pandemic than during the pre-pandemic period, which may be temporally related to SARS-CoV-2 vaccination (Pearson correlation coefficient [r] = 0.349,P= 0.031).

Conclusion

We report reassuring evidence of hemorrhagic stroke associated with SARS-CoV-2 infection and vaccination. However, awareness of CVST may be required for future vaccine rollouts and SARS-CoV-2 outbreaks.
Differences in polygenic associations with educational attainment between West and East Germany before and after reunification
Authors: Fraemke D. , Willems Y.E. , Okbay A. , Wagner G. , Tucker-Drob E.M. , Harden K.P. , Hertwig R. , Koellinger P. , Raffington L.
Published: March 2024

Here we examine geographical and historical differences in polygenic associations with educational attainment in East and West Germany around reunification. We test this in n = 1902 25-85-year-olds from the German SOEP-G[ene] cohort. We leverage a DNA-based measure of genetic influence, a polygenic index calculated based on a previous genome-wide association study of educational attainment in individuals living in democratic countries. We find that polygenic associations with educational attainment were significantly stronger among East, but not West, Germans after but not before reunification. Negative control analyses of a polygenic index of height with educational attainment and height indicate that this gene-by-environemt interaction is specific to the educational domain. These findings suggest that the shift from an East German state-socialist to a free-market West German system increased the importance of genetic variants previously identified as important for education.

One Sentence Summary

We find that polygenic associations with educational attainment were significantly stronger among East, but not West, Germans after but not before reunification.
How do Large Language Models understand Genes and Cells
Authors: Fang Chen , Wang Yidong , Song Yunze , Long Qingqing , Lu Wang , Chen Linghui , Wang Pengfei , Feng Guihai , Zhou Yuanchun , Li Xin
Published: March 2024

Researching genes and their interactions is crucial for deciphering the fundamental laws of biological activity, advancing disease treatment, drug discovery and so on. Large language Models (LLMs), with their profound text comprehension and generation capabilities, have made significant strides across various natural science fields. However, their application in cell biology remains notably scarce. To alleviate this issue, in this paper, we selects seven mainstream LLMs and evaluates their performance across a range of problem scenarios. Our findings indicate that LLMs possess a certain level of understanding of genes and cells, and hold potential for solving real-world problems. Moreover, we have improved the current method of textual representation of cells, enhancing the LLMs’ ability to tackle cell annotation tasks. We encourage cell biology researchers to leverage LLMs for problem-solving while also being mindful of some challenges associated with their use. We release our code and data athttps://github.com/epang-ucas/Evaluate_LLMs_to_Genes.

CCS Concepts

Applied computing → Recognition of genes and regulatory elements; Bioinformatics; Computational genomics; Computational transcriptomics.

ACM Reference Format

Chen Fang, Yidong Wang, Yunze Song, Qingqing Long, Wang Lu, Linghui Chen, Pengfei Wang, Guihai Feng, Yuanchun Zhou, and Xin Li. 2024. How do Large Language Models understand Genes and Cells. 1, 1 (March 2024), 14 pages.https://doi.org/10.1145/nnnnnnn.nnnnnnn
Causality in the natural selection of the population ecological life histories of birds
Authors: Witting Lars
Published: March 2024

Contingent life history theory explains evolution backwards by analysing the fitness consequences of tradeoffs and constraints in the evolved species of today, bypassing the essential challenge of predicting evolution forwardly by the cause and effect of natural selection. I do the latter to decompose the population ecological life histories of 11,187 species of birds. This shows how the selection of mass accounts for inter-specific variation, with 76% of the within order variance, and 72% of the between order differences, in the body mass, demography, and population ecological traits being reconciled by the response of population dynamic feedback selection to variation in net energy, mortality, and intra-specific interactive competition.
Algorithms for a Commons Cell Atlas
Authors: Booeshaghi A. Sina , Galvez-Merchán Ángel , Pachter Lior
Published: March 2024

Cell atlas projects curate representative datasets, cell types, and marker genes for tissues across an organism. Despite their ubiquity, atlas projects rely on duplicated and manual effort to curate marker genes and annotate cell types. The size of atlases coupled with a lack of data-compatible tools make reprocessing and analysis of their data near-impossible. To overcome these challenges, we present a collection of data, algorithms, and tools to automate cataloging and analyzing cell types across tissues in an organism, and demonstrate its utility in building a human atlas.
Intercellular Signaling Pathways as Therapeutic Targets for Vascular Dementia Repair
Authors: Tian Min , Kawaguchi Riki , Shen Yang , Machnicki Michal , Villegas Nikole G. , Cooper Delaney R. , Montgomery Natalia , Haring Jacqueline , Lan Ruirui , Yuan Angelina H. , Williams Christopher K. , Magaki Shino , Vinters Harry V. , Zhang Ye , De Biase Lindsay M. , Silva Alcino J. , Carmichael S. Thomas
Published: March 2024

Vascular dementia (VaD) is a white matter ischemic disease and the second-leading cause of dementia, with no direct therapy. Within the lesion site, cell-cell interactions dictate the trajectory towards disease progression or repair. To elucidate the underlying intercellular signaling pathways, a VaD mouse model was developed for transcriptomic and functional studies. The mouse VaD transcriptome was integrated with a human VaD snRNA-Seq dataset. A custom-made database encompassing 4053 human and 2032 mouse ligand-receptor (L-R) interactions identified significantly altered pathways shared between human and mouse VaD. Two intercellular L-R systems, Serpine2-Lrp1 and CD39-A3AR, were selected for mechanistic study as both the ligand and receptor were dysregulated in VaD. Decreased Seprine2 expression enhances OPC differentiation in VaD repair. A clinically relevant drug that reverses the loss of CD39-A3AR function promotes tissue and behavioral recovery in the VaD model. This study presents novel intercellular signaling targets and may open new avenues for VaD therapies.
Topographical polarity reveals continuous EEG microstate transitions and electric field direction in healthy aging
Authors: Kashihara Shiho , Asai Tomohisa , Imamizu Hiroshi
Published: March 2024

EEG microstate sequences, representing whole-brain spatial potential distribution patterns of the EEG, offer valuable insights for capturing spatiotemporally continuous and fluctuating neural dynamics with high temporal resolution through appropriate discretization. Recent studies suggest that EEG microstate transitions are gradual and continuous phenomena, contrary to the classical view of binary transitions. This study aimed to update conventional microstate analysis to reflect continuous EEG dynamics and examine differences in age-related electrophysiological state transitions. We considered the relative positions of EEG microstates on the neural manifold and their topographical polarity. Transition probability results showed fewer transitions on the microstate D-C-E axis in older adults. In contrast, transitions among microstates A, D, and B increased in the older group and were mainly observed within polarity. Furthermore, the 100 microstate transitions, which are variations of the shortest transitions between 10 microstates, could be reduced to 8 principal components based on the co-occurrence of each transition, including hubs C and E, planar transitions through msA/B and D, and unidirectional transition components. Several transition components were potentially significant predictors of age group. These features were nearly replicated in independent data, indicating their robustness in characterizing age-related electrophysiological spatiotemporal dynamics.
Evolutionary Co-Option of an Ancestral Cloacal Regulatory Landscape During the Emergence of Digits and Genitals
Authors: Hintermann Aurélie , Bolt Christopher Chase , Brent Hawkins M. , Valentin Guillaume , Lopez-Delisle Lucille , Gitto Sandra , Gómez Paula Barrera , Mascrez Bénédicte , Mansour Thomas A. , Nakamura Tetsuya , Harris Matthew P. , Shubin Neil H. , Duboule Denis
Published: March 2024

The transition from fins to limbs has been a rich source of discussion for more than a century. One open and important issue is understanding how the mechanisms that pattern digits arose during vertebrate evolution. In this context, the analysis ofHoxgene expression and functions to infer evolutionary scenarios has been a productive approach to explain the changes in organ formation, particularly in limbs. In tetrapods, the transcription ofHoxdgenes in developing digits depends on a well-characterized set of enhancers forming a large regulatory landscape1,2. This control system has a syntenic counterpart in zebrafish, even though they lackbona fidedigits, suggestive of deep homology3between distal fin and limb developmental mechanisms. We tested the global function of this landscape to assess ancestry and source of limb and fin variation. In contrast to results in mice, we show here that the deletion of the homologous control region in zebrafish has a limited effect on the transcriptionof hoxdgenes during fin development. However, it fully abrogateshoxdexpression within the developing cloaca, an ancestral structure related to the mammalian urogenital sinus. We show that similar to the limb,Hoxdgene function in the urogenital sinus of the mouse also depends on enhancers located in this same genomic domain. Thus, we conclude that the current regulation underlyingHoxdgene expression in distal limbs was co-opted in tetrapods from a preexisting cloacal program. The orthologous chromatin domain in fishes may illustrate a rudimentary or partial step in this evolutionary co-option.
Aging-associated weakening of the action potential in fast-spiking interneurons in the human neocortex
Authors: Szegedi Viktor , Tiszlavicz Ádám , Furdan Szabina , Douida Abdennour , Bakos Emoke , Barzo Pal , Tamas Gabor , Szucs Attila , Lamsa Karri
Published: March 2024

Aging is associated with the slowdown of neuronal processing and cognitive performance in the brain; however, the exact cellular mechanisms behind this deterioration in humans are poorly elucidated. Recordings in human acute brain slices prepared from tissue resected during brain surgery enable the investigation of neuronal changes with age. Although neocortical fast-spiking cells are widely implicated in neuronal network activities underlying cognitive processes, they are vulnerable to neurodegeneration. Herein, we analyzed the electrical properties of 147 fast-spiking interneurons in neocortex samples resected in brain surgery from 106 patients aged 11–84 years. By studying the electrophysiological features of action potentials and passive membrane properties, we report that action potential overshoot significantly decreases and spike half-width increases with age. Moreover, the action potential maximum-rise speed (but not the repolarization speed or the afterhyperpolarization amplitude) significantly changed with age, suggesting a particular weakening of the sodium channel current generated in the soma. Cell passive membrane properties measured as the input resistance, membrane time constant, and cell capacitance remained unaffected by senescence. Thus, we conclude that the action potential in fast-spiking interneurons shows a significant weakening in the human neocortex with age. This may contribute to the deterioration of cortical functions by aging.
Approach to standardized material characterization of the human lumbopelvic system – Testing and evaluation
Authors: Gebhardt Marc , Kurz Sascha , Grundmann Fanny , Klink Thomas , Slowik Volker , Heyde Christoph-Eckhard , Steinke Hanno
Published: March 2024

The osseo-ligamentous lumbopelvic complex is a crucial component of the human musculoskeletal system and has been increasingly the focus of medical research and treatment planning. Numerical simulations can play a key role in better understanding the load-carrying behavior of this system, but material data in this arena remain rare. In addition, the literature lacks standardized and reproducible methods for determining biomechanical material parameters.

To address these shortcomings, we obtained bone and soft tissue samples from three female and two male cadavers (average age: 77.3 years) for testing and evaluation. The elastic modulus of cortical bone averaged at 1750 MPa with a mean ultimate strength of 28.2 MPa. Whereas for trabecular bone the evaluation yields to 32.7 MPa and 1.26 MPa. Furthermore, the soft tissue specimens exhibited a mean elastic modulus of 148 MPa and an ultimate strength of 14.3 MPa for fascial tissue, in contrast to ligamentous tissue with 103 MPa and 10.7 MPa.

Knowledge of these material parameters of the human pelvis, which differ from those of long bones, could, in combination with the revealed dependence on harvesting location and density, lead to more precise mechanical simulations. Such simulations might in turn promote the development of better suited implants.

Together with a previous publication dealing with sample preparation, this work is intended to contribute to the standardization of mechanical testing of human tissue. Easy-to-conduct bending tests as well as direct tension and compression tests are recommended, and the proposed mechanical boundary conditions are explained and documented. These technical recommendations allow for better comparability and reproducibility in future biomechanical studies. This protocol, developed for the human pelvis, could easily be transferred to other anatomical regions.
Neural signatures of human psychological resilience driven by acute stress
Authors: Watanabe Noriya , Yoshida Shinichi , Keerativittayayut Ruedeerat , Takeda Masaki
Published: March 2024

Neurophysiological mechanisms underlying psychological resilience, the ability to overcome adversity1,2, have been extensively studied in animals. However, in comparison with animals, human resilience is unique in that it is underpinned by higher cognitive functions, such as self-confidence and a positive attitude to challenges3,4. Given these discrepancies, the neurophysiological mechanisms underlying human resilience remain unclear. To address this issue, we recorded multimodal responses after acute stress exposure over 1.5 hours using functional brain imaging and peripheral physiological measurements. Here, we showed that the degree of individual resilience is indexed by multiple changes in neural dynamics 1 hour after acute stress. Both functional magnetic resonance imaging and electroencephalography show that activity in the cortical salience network and power in high-beta and gamma oscillations increase in less resilient individuals. Contrastingly, activity in the cortical default mode network and spontaneous activity in the posterior hippocampus increase in more resilient individuals. Machine learning analysis confirmed that, 1 hour after stress exposure, the functional connectivity in the salience network was the most influential, followed by that in the default mode network, gamma power, high-beta power, and hippocampal activity. The neurophysiological dynamics for resilience do not occur as previously thought, but rather in a time-lagged manner against stress exposure. Our findings Shed light on a new approach to recovery from stress-induced deficits such as delayed neuromodulation after a stressful event.
A hybrid simulation-based workshop improves knowledge and confidence in the management of hemorrhagic conversion of stroke among interventional neurology trainees
Authors: Pergakis Melissa B. , Misra Asit , Al-Mufti Fawaz , Motola Ivette , Morris Nicholas A.
Published: March 2024

Objectives

To assess the feasibility of a hybrid simulation-based workshop at a national meeting for interventional neurology trainees focused on the management of acute ischemic stroke and tissue-plasminogen activator (tPA)-related hemorrhage.

Methods

In this prospective, observational, hybrid simulation-based study at a fellows’ workshop at a national conference, participants were asked to manage a patient with acute ischemic stroke in the neurointerventional suite followed by thrombolytic-related hemorrhage leading to cerebral herniation during mechanical thrombectomy. We evaluated the participants’ ability to complete critical actions that were developed based on best practices and relevant American Heart Association guidelines and the Neurocritical Care Society’s Emergency Neurological Life Support protocols. The primary outcome was the improvement in knowledge from a pre-course to post-course test. Secondary outcomes included participant reactions.

Results

Sixty trainees completed the simulation session in 8 groups. The mean sum of critical actions completed by trainees was 9.75/14 (70%). There was a moderate effect of the intervention on trainees’ knowledge from pre-test (mean 3.8, standard deviation (SD) = 0.3) to post-test (mean 4.3, SD=0.3). The simulation scenario was described as moderately realistic, very engaging, and extremely satisfactory. Following the workshop, all fellows endorsed an increase in proficiency and confidence in neurological emergency management.

Conclusions

Simulation-based workshops at national conferences are feasible and a potentially useful tool for safely educating a large audience of trainees who may not have access to high-fidelity simulation platforms at their institutions.
Targeting protein-ligand neosurfaces using a generalizable deep learning approach
Authors: Marchand Anthony , Buckley Stephen , Schneuing Arne , Pacesa Martin , Gainza Pablo , Elizarova Evgenia , Neeser Rebecca M. , Lee Pao-Wan , Reymond Luc , Elia Maddalena , Scheller Leo , Georgeon Sandrine , Schmidt Joseph , Schwaller Philippe , Maerkl Sebastian J. , Bronstein Michael , Correia Bruno E.
Published: March 2024

Molecular recognition events between proteins drive biological processes in living systems. However, higher levels of mechanistic regulation have emerged, where protein-protein interactions are conditioned to small molecules. Here, we present a computational strategy for the design of proteins that target neosurfaces, i.e. surfaces arising from protein-ligand complexes. To do so, we leveraged a deep learning approach based on learned molecular surface representations and experimentally validated binders against three drug-bound protein complexes. Remarkably, surface fingerprints trained only on proteins can be applied to neosurfaces emerging from small molecules, serving as a powerful demonstration of generalizability that is uncommon in deep learning approaches. The designed chemically-induced protein interactions hold the potential to expand the sensing repertoire and the assembly of new synthetic pathways in engineered cells.
A benchmarked, high-efficiency prime editing platform for multiplexed dropout screening
Authors: Cirincione Ann , Simpson Danny , Ravisankar Purnima , Solley Sabrina C. , Yan Jun , Singh Mona , Adamson Britt
Published: March 2024

Prime editing installs precise edits into the genome with minimal unwanted byproducts, but low and variable editing efficiencies have complicated application of the approach to high-throughput functional genomics. Leveraging several recent advances, we assembled a prime editing platform capable of high-efficiency substitution editing across a set of engineered prime editing guide RNAs (epegRNAs) and corresponding target sequences (80% median intended editing). Then, using a custom library of 240,000 epegRNAs targeting >17,000 codons with 175 different substitution types, we benchmarked our platform for functional interrogation of small substitution variants (1-3 nucleotides) targeted to essential genes. Resulting data identified negative growth phenotypes for nonsense mutations targeted to ∼8,000 codons, and comparing those phenotypes to results from controls demonstrated high specificity. We also observed phenotypes for synonymous mutations that disrupted splice site motifs at 3′ exon boundaries. Altogether, we establish and benchmark a high-throughput prime editing approach for functional characterization of genetic variants with simple readouts from multiplexed experiments.
Tracking how attentional focusing in working memory benefits long-term memory
Authors: Wang Sisi , van Ede Freek
Published: March 2024

Human working memory serves as a key gateway to the formation of lasting memories in long-term memory. While it is well established how attentional focusing during working memory can prioritize internal representation for an imminent task, how such internal focusing affects subsequent long-term memory remains less understood. Here, we developed a two-stage visual working memory/long-term memory task in which we cued attention during working memory and tracked the dynamics of attentional deployment through a recently established gaze marker of internal focusing. Across two experiments, we found that attentional focusing in visual working memory reliably affects subsequent visual long-term memory, driven by a benefit to internally attended objects without a cost to unattended objects. Gaze biases associated with internal focusing revealed how this benefit was mediated by the speed – but not necessarily the degree – of attentional deployment, with faster attentional deployment predicting better subsequent memory. Together, these results highlight how attentional focusing in working memory benefits subsequent long-term memory, and uncover the dynamic processes that instill such lasting benefits – offering new insights into the catalyst function of attention in bridging working memory and long-term memory.
Spatial structure could explain the maintenance of alternative reproductive tactics in tree cricket males
Authors: Sadiq Mohammed Aamir , Bhat Ananda Shikhara , Guttal Vishwesha , Balakrishnan Rohini
Published: March 2024

Trait polymorphisms are widespread in nature, and explaining their stable co-existence is a central problem in ecology and evolution. Alternative reproductive tactics, in which individuals of one or more sex exhibit discrete, discontinuous traits in response to reproductive competition, represent a special case of trait polymorphism in which the traits are often complex, behavioural, and dynamic. Thus, studying how alternative reproductive tactics are maintained may provide general insights into how complex trait polymorphisms are maintained in populations. We construct a spatially explicit individual-based model inspired from extensively collected empirical data to address the mechanisms behind the co-existence of three behavioural alternative reproductive tactics in males of a tree cricket (Oecanthus henryi). Our results show that the co-existence of these tactics over ecological time scales is facilitated by the spatial structure of the landscape they inhabit, which serves to equalize the otherwise unequal mating benefits of the three tactics. We also show that this co-existence is unlikely if spatial aspects of the system are not considered. Our findings highlight the importance of spatial dynamics in understanding ecological and evolutionary processes and underscore the power of integrative approaches that combine models inspired from empirical data.
Bettering of Learning Activity through Elevated P-Cresol Levels in the Brain: Insights from Active Avoidance Testing in Wistar Rats
Authors: Tevzadze Gigi , Kikvidze Zaal
Published: March 2024

It is established that p-cresol, a compound produced by bacterial colonies within the gastrointestinal tract of mammals, plays a contributory role in the manifestation of various mental disorders. Recently, our research demonstrated that diminishing p-cresol levels in the brain adversely impact the behavioral manifestation of cognitive abilities in rats. In this study, we aimed to investigate the impact of augmenting p-cresol levels in the brain on learning. The Active Avoidance Test was employed to assess learning capabilities. The results, with a high level of confidence, indicated that rats with an increased concentration of p-cresol in the brain exhibited superior task performance and accelerated learning compared to the control group.
Age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death
Authors: Baldensperger Tim , Jung Tobias , Heinze Tom , Schwerdtle Tanja , Höhn Annika , Grune Tilman
Published: March 2024

Accumulation of the age pigment lipofuscin represents a ubiquitous hallmark of the aging process. However, our knowledge about cellular effects of lipofuscin accumulation is potentially flawed, because previous research mainly utilized highly artificial methods of lipofuscin generation. In order to address this tremendous problem, we developed a convenient protocol for isolation of authentic lipofuscin from human and equine cardiac tissue in high purity and quantity. Isolated lipofuscin aggregates contained elevated concentrations of proline and metals such as calcium or iron. The material was readily incorporated by fibroblasts and caused cell death at low concentrations (LC50= 5.0 µg/mL) via a pyroptosis-like pathway. Lipofuscin boosted mitochondrial ROS production and caused lysosomal dysfunction by lysosomal membrane permeabilization leading to reduced lysosome quantity and impaired cathepsin D activity. In conclusion, this is the first study utilizing authentic lipofuscin to experimentally validate the concept of the lysosomal-mitochondrial axis theory of aging and cell death.
HNF4α is a target of the Wnt/β-catenin pathway and regulates colorectal carcinogenesis
Authors: Sang Lei , Bai Weiyu , Lu Chenglu , Dong Rui , Hao Qinggang , Zhang Yingru , Sun Rongyuan , Shen Junling , Sun Yan , Sun Jianwei
Published: March 2024

Hepatocyte nuclear factor 4alpha (HNF4α) is a transcription factor involved in liver function. Dysregulation of HNF4α leads to hepatocarcinogenesis. However, the role and mechanism of HNF4α in colorectal cancer is still unknown. Here we demonstrate that HNF4α is upregulated in colorectal cancers. and HNF4α upregulation promotes colorectal tumorigenesis. Notably, expression levels of HNF4α are positively correlated with the Wnt/β-catenin signaling pathway in colorectal cancer patients. Further, we showed that HNF4α is transcriptionally activated by Wnt/β-catenin/TCF3 and is at least partially responsible for the oncognesis activity of the Wnt signaling in colorectal cancer. Our findings indicate that HNF4α is a direct target of that Wnt/β-catenin pathway and could play an important role in colorectal carcinogenesis.

Author Summary

Here we demonstrate that HNF4α is upregulated in colorectal cancers and HNF4α upregulation promotes colorectal tumorigenesis. Notably, expression level of HNF4α are positively correlated with the Wnt/β-catenin pathway in colorectal cancer patients. Further, we showed that HNF4α is transcriptionally activated by Wnt/β-catenin/TCF3 and is at least partially responsible for the oncognesis activity of the Wnt signaling pathway in colorectal cancer.
Fatty acids are not a significant contributor to the TCA cycle in cancer cell lines: evidence of incomplete fatty acid oxidation.
Authors: Santiappillai Nancy T. , Hakeem-Sanni Mariam F. , Ghasemi Masih , Withy Anabel , Quek Lake-Ee , Hoy Andrew J
Published: March 2024

Fatty acid (FA) oxidation (FAO) is upregulated in many cancers, which has been contextualised to thereby be significantly fuel the TCA cycle and generate vast amounts of ATP to support cancer cell viability. However, direct evidence of this is lacking. Here, we set out to determine the capacity of FAO in a pan-cancer setting and if this relates to the amount of carbon FAO contributes to the TCA cycle relative to other substrates. We profiled the baseline FAO rate and capacity of 27 cancer cell lines from 10 tissue origins, and then selected 6 cancer cell lines that represented the diversity of this panel. Despite the diverse range of FAO rates, we consistently found that exogenous long-chain FAs (LCFAs) were a minor (<10%) TCA cycle substrate in all cells compared to glucose and glutamine. Glucose withdrawal significantly increased FAO rates, while glucose and/or glutamine deprivation marginally increased incorporation of 13C-palmitate into TCA cycle metabolites. Palmitate alone modestly assisted cataplerosis but did not sustain TCA cycle fluxes, leading to reduced cell viability. The low contribution of fatty acids to the TCA cycle in cancer cells may be explained by incomplete oxidation of LCFAs of varying chain lengths of saturations to produce shortened acyl-carnitines. Overall, our results provide significant insights into mitochondrial FA metabolism in cultured cancer cells and challenges the belief that the oxidation of FAs is a complete process, contributing significant fuel for the TCA cycle and ATP generation.
Orthohantavirus Diversity in Central-East Argentina: Insights from Complete Genomic Sequencing on Phylogenetics, Geographic patterns and Transmission scenarios
Authors: Alonso Daniel Oscar , Kehl Sebastian , Coelho Rocio , Periolo Natalia , Poklepovich Tomas , Perez-Sautu Unai , Sanchez-Lockhart Mariano , Palacios Gustavo F. , Bellomo Carla , Martinez Valeria
Published: March 2024

Hantavirus Pulmonary Syndrome (HPS), characterized by its high fatality rate, poses a significant public health concern in the Americas. Phylogenetic relationships of orthohantaviruses in the country were inferred from partial genomic sequences. The objectives of this work were to report new complete viral genomes of the known viral variants associated with HPS cases in Central-East region of Argentina, to assess viral diversity, phylogenetic relationships, and to elucidate the geographic patterns of distribution of each variant. To accomplish this, a detailed analysis was conducted of the geographic distribution of reported cases within the most impacted province of the region. The phylogenetic analysis defined clearly separated clades in the country according to their geographic origin. Andes virus (ANDV) segregated from the rest of the sequences, and those representative from the Central East region, Buenos Aires (BAV) and Lechiguanas virus (LECV), were grouped in the same cluster but segregated in two different branches.

Importance

In Argentina, most of the HPS cases were associated with ANDV and closely related viruses distributed in four endemic regions. This work focused on obtaining and studying the complete genome of the orthohantaviruses present in the Central East (CE) region (BAV and LECV). Both viruses were responsible for major and minor outbreaks of person- to-person transmission in the country, and the findings may pave the way to study the impact of genetic determinants of viral transmission and to consider the reclassification of the speciesOrthohantavirus andesense.
Cbf11 and Mga2 function as a single regulatory entity to activate transcription of lipid metabolism genes and promote mitotic fidelity in fission yeast
Authors: Marešová Anna , Grulyová Michaela , Hradilová Miluše , Zemlianski Viacheslav , Princová Jarmila , Převorovský Martin
Published: March 2024

Within a eukaryotic cell, both lipid homeostasis and faithful cell cycle progression are meticulously orchestrated. The fission yeastSchizosaccharomyces pombeprovides a powerful platform to study the intricate regulatory mechanisms governing these fundamental processes. InS. pombe, the Cbf11 and Mga2 proteins are transcriptional activators of non-sterol lipid metabolism genes, with Cbf11 also known as a cell cycle regulator. Despite sharing a common set of target genes, little was known about their functional relationship. This study reveals that Cbf11 and Mga2 function together as a single regulatory entity critical for both lipid metabolism and mitotic fidelity. Deletion of either gene results in a similar array of defects, including slow growth, dysregulated lipid homeostasis, impaired cell cycle progression (cut phenotype), abnormal cell morphology, perturbed transcriptomic and proteomic profiles, and compromised response to the stressors camptothecin and thiabendazole. Remarkably, the double deletion mutant does not exhibit a more severe phenotype compared to the single mutants, suggesting that Cbf11 and Mga2 work together in the same pathway. In addition, ChIP-nexus analysis reveals that both Cbf11 and Mga2 bind to nearly identical positions within the promoter regions of target genes. Interestingly, Mga2 binding appears to be dependent on the presence of Cbf11 and Cbf11 likely acts as a tether to DNA, while Mga2 is needed to activate the target genes. In addition, the study explores the distribution of Cbf11 and Mga2 homologs across fungi. The presence of both Cbf11 and Mga2 homologs in Basidiomycota contrasts with Ascomycota, which mostly lack Cbf11 but retain Mga2. This suggests an evolutionary rewiring of the regulatory circuitry governing lipid metabolism and mitotic fidelity. In conclusion, this study offers compelling support for Cbf11 and Mga2 functioning jointly as a single regulator of lipid metabolism and mitotic fidelity in fission yeast.

SUMMARY STATEMENT

Cbf11 and Mga2, transcriptional activators of non-sterol lipid metabolism genes, function as a single regulatory unit and are both required for proper cell cycle progression in the fission yeastSchizosaccharomyces pombe.
Structural basis for recognition of the FLAG-tag by anti-FLAG M2
Authors: Beugelink J. Wouter , Sweep Els , Janssen Bert J.C. , Snijder Joost , Pronker Matti F.
Published: March 2024

The FLAG-tag/anti-FLAG system is a widely used biochemical tool for protein detection and purification. Anti-FLAG M2 is the most popular antibody against the FLAG-tag, due to its ease of use, versatility, and availability in pure form or as bead conjugate. M2 binds N-terminal, C-terminal and internal FLAG-tags and binding is calcium-independent, but the molecular basis for the FLAG-tag specificity and recognition remains unresolved.

Here we present an atomic resolution (1.17 Å) structure of the FLAG peptide in complex with the Fab of anti-FLAG M2, revealing key binding determinants. Five of the eight FLAG peptide residues form direct interactions with paratope residues. The FLAG peptide adopts a 310helix conformation in complex with the Fab. These structural insights allowed us to rationally introduce point mutations on both the peptide and antibody side. We tested these by surface plasmon resonance, leading us to propose a shorter yet equally binding version of the FLAG-tag for the M2 antibody.