bluuebunny/crossref_metadata_2025 huggingface dataset:
ACEI or not to ACEI: Review on using ACEI and ARBs on COVID-19 patients: Systemic review
Authors: Walia Ribhav
Published: March 2023

Purpose and motivation of this study

Angiotensin-converting enzyme inhibitors (ACEI) and Aldosterone receptor blockers (ARBs) are one most commonly used drugs for the treatment of cardiovascular disease among other comorbidities. As multiple studies have shown that covid virus binds to the ACE2 receptor for entry into the cell. ACEI and ARBs are shown to modulate the ACE2 receptor hence, it is important to see if there are any correlations between the use of medicine and the infectivity of COVID-19. The purpose of this study is to find if the use of ACEI /ARBs can in fact increase or decrease the spread of COVID-19.

Method

This is a systemic review study during which all studies which helped us answer the question, of how the use of ACEI and ARBs can affect the transmission of the COVID-19 virus, were analyzed and reviewed to draw a conclusion about clinical safety and requirements of ACEI and ARBs in COVID-19 patients.

Result

After a complete review of all the available data very conflicting results were found. Many studies showed an increase in the transmission of COVID-19 while others showed a decreased risk of COVID-19 transmission with ACEI and ARBs use. Both results were statistically significant.

Conclusion

With these conflicting results the question we started with comes up again. Should we or should we not use ACEI & ARBs with covid patients? What should be the best clinical response with the use of ACEI & ARBs if it modulates transmission? To answer these, one must look not only at the statistically significant results of studies but also at the disease progression without ACEI & ARBs treatment regimes. Due to the small amount of data, there is currently no clear conclusive evidence to suggest that ACE inhibitors either increase or decrease the risk of COVID-19 transmission or the severity of the disease. Thus, more and larger studies should be developed to find a concrete answer. Until that these medicines should not be discontinued as the morbidities of cardiovascular diseases are high, and the use of ACEI and ARBs is central to the treatment.
Performance of ChatGPT and GPT-4 on Neurosurgery Written Board Examinations
Authors: Ali Rohaid , Tang Oliver Y. , Connolly Ian D. , Zadnik Sullivan Patricia L. , Shin John H. , Fridley Jared S. , Asaad Wael F. , Cielo Deus , Oyelese Adetokunbo A. , Doberstein Curtis E. , Gokaslan Ziya L. , Telfeian Albert E.
Published: March 2023

Background

Interest surrounding generative large language models (LLMs) has rapidly grown. While ChatGPT (GPT-3.5), a general LLM, has shown near-passing performance on medical student board examinations, the performance of ChatGPT or its successor GPT-4 on specialized exams and the factors affecting accuracy remain unclear.

Objective

To assess the performance of ChatGPT and GPT-4 on a 500-question mock neurosurgical written boards examination.

Methods

The Self-Assessment Neurosurgery Exams (SANS) American Board of Neurological Surgery (ABNS) Self-Assessment Exam 1 was used to evaluate ChatGPT and GPT-4. Questions were in single best answer, multiple-choice format. Chi-squared, Fisher’s exact, and univariable logistic regression tests were employed to assess performance differences in relation to question characteristics.

Results

ChatGPT (GPT-3.5) and GPT-4 achieved scores of 73.4% (95% confidence interval [CI]: 69.3-77.2%) and 83.4% (95% CI: 79.8-86.5%), respectively, relative to the user average of 73.7% (95% CI: 69.6-77.5%). Question bank users and both LLMs exceeded last year’s passing threshold of 69%. While scores between ChatGPT and question bank users were equivalent (P=0.963), GPT-4 outperformed both (bothP<0.001). GPT-4 answered every question answered correctly by ChatGPT and 37.6% (50/133) of remaining incorrect questions correctly. Among twelve question categories, GPT-4 significantly outperformed users in each but performed comparably to ChatGPT in three (Functional, Other General, and Spine) and outperformed both users and ChatGPT for Tumor questions. Increased word count (odds ratio [OR]=0.89 of answering a question correctly per +10 words) and higher-order problem-solving (OR=0.40,P=0.009) were associated with lower accuracy for ChatGPT, but not for GPT-4 (bothP>0.005). Multimodal input was not available at the time of this study so, on questions with image content, ChatGPT and GPT-4 answered 49.5% and 56.8% of questions correctly based upon contextual context clues alone.

Conclusion

LLMs achieved passing scores on a mock 500-question neurosurgical written board examination, with GPT-4 significantly outperforming ChatGPT.
Age-specific findings on lifestyle and trajectories of cognitive function from the Korean Longitudinal Study of Aging
Authors: Lim Seungju , Yoo Eunyoung , Hong Ickpyo , Park Jihyuk
Published: March 2023

Background

There is a paucity of longitudinal studies in the literature which have investigated age-related differences in the relationship between lifestyle factors and cognitive decline. Thus, the purpose of this study was to investigate which lifestyle factors at baseline would slow the longitudinal rate of cognitive decline in young-old (55-64 years), middle-old (65-74 years), and old-old (75+ years) individuals.

Methods

We conducted an 11-year follow-up of 6189 older adults from the Korean Longitudinal Study of Aging, which is a cohort of community-dwelling older Koreans. Lifestyle factors including physical activity (PA), social activity (SA), smoking, and alcohol consumption were assessed at baseline. Cognitive function was measured at 2-year intervals over a duration of 11 years. Latent growth curve modeling (LGM) and multigroup analyses (MGA) were performed.

Results

The influence of lifestyle factors on the rate of cognitive decline differed by age. Smoking at baseline (−0.05, 95% CI −0.11 to −0.001, per study wave) accelerated the cognitive decline in young-old individuals while frequent SA participation at baseline (0.02, 95% CI 0.01 to 0.03, per study wave) decelerated the cognitive decline in middle-old individuals. None of the lifestyle factors in this study decelerated the cognitive decline in old-old individuals.

Conclusion

Cognitive strategies through modifiable lifestyle factors such as smoking cessation in the young-old and frequent SA participation in the middle-old age groups may have great potential in preventing cognitive decline. Since the influence of lifestyle factors varies by age group, age-specific approaches are recommended for promoting cognitive health.

What is already known on this topic

Previous studies have shown that lifestyle factors are associated with cognitive decline in older adults. However, longitudinal population-based studies are scarce, and few studies have considered age differences based on the heterogeneity of the elderly population.

What this study adds

The results of the present study show a difference in the influence of lifestyle factors on the rate of cognitive decline with age. Smoking at baseline accelerated cognitive decline in the young-old (55-64 years) group, while frequent social activity participation at baseline decelerated in the middle-old (65-74 years) group. In the old-old group (75+ years), there were no lifestyle factors that could decelerate cognitive decline.

How this study might affect research, practice or policy

These results emphasize the importance of an age-specific modifiable lifestyle approach for promoting cognitive health in the elderly.
Modification of clinical indicators for differentiating stages of chronic HBV infection based on pathological changes in liver tissue
Authors: Li Wentao , Zhang Binhao , Zhu Jiansheng , Liu Junyan , Wang Qiupeng , Feng Jiang , Xing Tongjing
Published: March 2023

Objective

To screen and modify more accurate clinical and viral indicators for differentiating the different stages of chronic hepatitis B virus (HBV) infection based on liver histopathological changes.

Methods

The clinical and liver pathology data of chronic hepatitis B (CHB) patients undergoing liver biopsy were collected for retrospective analysis. The area under the curve (AUC) of the receiver operating characteristic (ROC) was used to evaluate the diagnostic value for differentiating the different stages of chronic HBV infection.

Results

A total of 118 patients who met the diagnostic and exclusion criteria were selected. There were significant differences among HBV DNA, hepatitis B surface antigen (HBsAg), HBeAg, HBcAb, and platelets (PLT) between the IT and IC stages. Platelets were significantly higher in patients with the IT stage of CHB than in patients with the IC stage, whereas HBcAb levels were directly reversed. Multivariate analysis showed that HBeAg independently correlated with the IT and IC stages. Univariate analysis showed that HBV DNA and HBsAg were quantified between the ICO and IR stages except for ALT. The cutoff value of HBeAg used to quantitatively differentiate between IT and IC was 1335 and the AUC was 0.921 (95% confidence interval (CI): 0.836 to 0.971).

Conclusions

The high levels of HBeAg rather than HBeAg positive might help to identify patients with the “true” IT stage. PLT and HBcAb are effective indicators for differentiating patients between the IT and IC stages of chronic HBV infection. HBV DNA of <20 IU/mL may be a more rational cutoff value for ICO patients.
Impact of Diabetes Mellitus on Myocardial Fibrosis in Patients with Hypertension: the REMODEL Study
Authors: Pua Chee Jian , Loo Germaine , Kui Michelle , Moy Wai Lun , Hii An-An , Lee Vivian , Chin Chee-Tang , Bryant Jennifer A , Toh Desiree-Faye , Lee Chi-Hang , Cook Stuart A , Richards A Mark , Le Thu-Thao , Chin Calvin WL
Published: March 2023

BACKGROUND

Compared to patients with hypertension only (HTN), those with hypertension and diabetes (HTN/DM) have worse prognosis. We aimed to characterize morphological differences between HTN and HTN/DM using cardiovascular magnetic resonance (CMR); and compare differentially expressed proteins associated with myocardial fibrosis using high throughput multiplex assays.

METHODS

Asymptomatic patients underwent CMR: 438 patients with HTN (60±8 years; 59% males) and 167 age- and sex-matched patients with HTN/DM (60±10 years; 64% males). Replacement myocardial fibrosis was defined as non-ischemic late gadolinium enhancement on CMR. Extracellular volume (ECV) fraction was used as a marker of diffuse myocardial fibrosis. A total of 184 serum proteins (Olink Target CVD II and III panels) were measured to identify unique signatures associated with myocardial fibrosis in all patients.

RESULTS

Despite similar left ventricular (LV) mass (P=0.344) and systolic blood pressure (P=0.086), patients with HTN/DM had increased concentricity and worse multi-directional strain (P<0.001 for comparison of all strain measures) compared to HTN only. Replacement myocardial fibrosis was present in 28% of patients with HTN/DM compared 16% of those with HTN (P<0.001). NT-proBNP was the only protein differentially upregulated in HTN patients with replacement myocardial fibrosis and independently associated with ECV. In patients with HTN/DM, GDF-15 was independently associated with replacement myocardial fibrosis and ECV. Ingenuity Pathway Analysis demonstrated a strong association between increased inflammatory response/immune cell trafficking and myocardial fibrosis in patients with HTN/DM.

CONCLUSIONS

Adverse cardiac remodeling was observed in patients with HTN/DM. The novel proteomic signatures and associated biological activities of increased immune and inflammatory response may partly explain these observations.

CLINICAL PERSPECTIVES

Myocardial fibrosis is a hallmark of heart failure and predicts worse cardiovascular outcomes in patients with hypertension. There is increasing interest to target the myocardial interstitium to improve diagnosis, risk stratification and to discover novel therapies. Our study demonstrates that myocardial fibrosis is a heterogeneous pathology resulting from cardiac disease-specific biology. In hypertensive patients, concomitant diabetes mellitus accelerates adverse cardiac remodeling. This observation endorses the importance to consider early risk stratification by imaging and/or biomarker profiling in these patients. Whether patients with hypertension and diabetes would derive incremental anti-fibrotic benefits from therapies targeting inflammation/immune activate require further investigations.
Ipsilateral restriction of chromosome movement along a centrosome, and apical-basal axis during the cell cycle
Authors: Cai Pingping , Casas Christian J. , Plancarte Gabriel Quintero , Hua Lisa L. , Mikawa Takashi
Published: March 2023

Little is known about how distance between homologous chromosomes are controlled during the cell cycle. Here, we show that the distribution of centromere components display two discrete clusters placed to either side of the centrosome and apical/basal axis from prophase to G1interphase. 4-Dimensional live cell imaging analysis of centromere and centrosome tracking reveals that centromeres oscillate largely within one cluster, but do not cross over to the other cluster. We propose a model of an axis-dependent ipsilateral restriction of chromosome oscillations throughout mitosis.
Single-cell transcriptome dataset of human and mousein vitroadipogenesis models
Authors: Li Jiehan , Jin Christopher , Gustafsson Stefan , Rao Abhiram , Wabitsch Martin , Park Chong Y. , Quertermous Thomas , Bielczyk-Maczynska Ewa , Knowles Joshua W.
Published: March 2023

Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on human and mouse adipogenesis, as well as on cell-to-cell variability in gene expression during this process.
Machine learning based gut microbiota pattern and response to fiber as a diagnostic tool for chronic inflammatory diseases
Authors: Boodaghidizaji Miad , Jungles Thaisa , Chen Tingting , Zhang Bin , Landay Alan , Keshavarzian Ali , Hamaker Bruce , Ardekani Arezoo
Published: March 2023

Gut microbiota has been implicated in the pathogenesis of multiple gastrointestinal (GI) and systemic metabolic and inflammatory disorders where disrupted gut microbiota composition and function (dysbiosis) has been found in multiple studies. Thus, human microbiome data has a potential to be a great source of information for the diagnosis and disease characteristics (phenotypes, disease course, therapeutic response) of diseases with dysbiotic microbiota community. However, multiple attempts to leverage gut microbiota taxonomic data for diagnostic and disease characterization have failed due to significant inter-individual variability of microbiota community and overlap of disrupted microbiota communities among multiple diseases. One potential approach is to look at the microbiota community pattern and response to microbiota modifiers like dietary fiber in different disease states. This approach is now feasible by availability of machine learning that is able to identify hidden patterns in the human microbiome and predict diseases. Accordingly, the aim of our study was to test the hypothesis that application of machine learning algorithms can distinguish stool microbiota pattern and microbiota response to fiber between diseases where overlapping dysbiotic microbiota have been previously reported. Here, we have applied machine learning algorithms to distinguish between Parkinson’s disease, Crohn’s disease (CD), ulcerative colitis (UC), human immune deficiency virus (HIV), and healthy control (HC) subjects in the presence and absence of fiber treatments. We have shown that machine learning algorithms can classify diseases with accuracy as high as 95%. Furthermore, machine learning methods applied to the microbiome data to predict UC vs CD led to prediction accuracy as high as 90%.
Distinct mesoscale cortical dynamics encode search strategies during spatial navigation
Authors: Surinach Daniel , Rynes Mathew L , Saxena Kapil , Ko Eunsong , Redish A David , Kodandaramaiah Suhasa B
Published: March 2023

Spatial navigation is a complex cognitive process that involves neural computations in distributed regions of the brain. Little is known about how cortical regions are coordinated when animals navigate novel spatial environments or how that coordination changes as environments become familiar. We recorded mesoscale calcium (Ca2+) dynamics across large swathes of the dorsal cortex in mice solving the Barnes maze, a 2D spatial navigation task where mice used random, serial, and spatial search strategies to navigate to the goal. Cortical dynamics exhibited patterns of repeated calcium activity with rapid and abrupt shifts between cortical activation patterns at sub-second time scales. We used a clustering algorithm to decompose the spatial patterns of cortical calcium activity in a low dimensional state space, identifying 7 states, each corresponding to a distinct spatial pattern of cortical activation, sufficient to describe the cortical dynamics across all the mice. When mice used serial or spatial search strategies to navigate to the goal, the frontal regions of the cortex were reliably activated for prolonged durations of time (> 1s) shortly after trial initiation. These frontal cortex activation events coincided with mice approaching the edge of the maze from the center and were preceded by temporal sequences of cortical activation patterns that were distinct for serial and spatial search strategies. In serial search trials, frontal cortex activation events were preceded by activation of the posterior regions of the cortex followed by lateral activation of one hemisphere. In spatial search trials, frontal cortical events were preceded by activation of posterior regions of the cortex followed by broad activation of the lateral regions of the cortex. Our results delineated cortical components that differentiate goal- and non-goal oriented spatial navigation strategies.
A Pvr–AP-1–Mmp1 signaling pathway is activated in astrocytes upon traumatic brain injury
Authors: Li Tingting , Shi Wenwen , Ho Margaret S. , Zhang Yong Q.
Published: March 2023

Traumatic brain injury (TBI) caused by external mechanical forces is a major health burden worldwide, but the underlying mechanism in glia remains largely unclear. We report herein thatDrosophilaadults exhibit a defective blood-brain-barrier (BBB), elevated innate immune responses, and astrocyte swelling upon consecutive strikes with a high-impact trauma device. RNA sequencing (RNA-seq) analysis of these astrocytes revealed upregulated expression of genes encoding PDGF and VEGF receptor-related (Pvr, a receptor tyrosine kinase (RTK)), adaptor protein complex 1 (AP-1, a transcription factor complex of the c-Jun N-terminal Kinase (JNK) pathway) composed of Jun-related antigen (Jra) and kayak (kay), and matrix metalloproteinase 1 (Mmp1) following TBI. Interestingly, Pvr is both required and sufficient for AP-1 and Mmp1 upregulation, while knockdown of AP-1 expression in the background of Pvr overexpression in astrocytes rescued Mmp1 upregulation upon TBI, indicating that Pvr acts as the upstream receptor for the downstream AP-1–Mmp1 transduction. Moreover, dynamin-associated endocytosis was found to be an important regulatory step in downregulating Pvr signaling. Our results identify a new Pvr–AP-1–Mmp1 signaling pathway in astrocytes in response to TBI, providing potential targets for developing new therapeutic strategies of TBI.

Main Points

The study provided RNA-seq data of astrocytes following traumatic brain injury (TBI)

Genes involved in endocytic trafficking are upregulated in astrocytes after TBI

A new Pvr–AP-1–Mmp1 pathway is activated in astrocytes following TBI.

Inhibition of endocytosis in astrocytes upregulates the Pvr–AP-1–Mmp1 signaling.
Hip geometric parameters are associated with radiographic and clinical hip osteoarthritis: findings from a cross-sectional study in UK Biobank
Authors: Heppenstall SV , Ebsim R , Saunders FR , Lindner C , Gregory JS , Aspden RM , Harvey NC , Cootes T , Tobias JH , Frysz M , Faber BG
Published: March 2023

Objectives

To examine the extent to which geometric parameters derived from dual-energy x-ray absorptiometry (DXA) scans in the UK Biobank (UKB) study are related to hip osteoarthritis (HOA) independently of sex, age and body size.

Methods

Femoral neck width (FNW), diameter of the femoral head (DFH) and hip axis length (HAL) were derived automatically from left hip DXA scans in UKB using outline points placed around the hip by a machine-learning program. Correlations were calculated between geometric parameters, age, height, and weight. Logistic regression was used to examine the relationship of geometric parameters with radiographic hip osteoarthritis (rHOA), and hospital diagnosed HOA (HESOA), and Cox proportional hazards model to evaluate the relationship with total hip replacement (THR). Analyses were adjusted for sex, age, height, weight, and geometric parameters.

Results

Complete data were available for 40,312 participants. In age and sex-adjusted analyses, FNW, HAL and DFH were all related to increased risk of rHOA. Despite strong relationships between geometric parameters and body size, relationships between geometric parameters and HOA showed little attenuation after adjustment for height and weight. Following mutual adjustment, both HAL and FNW retained independent relationships with rHOA, while DFH was now protective. Only FNW was independently related to HESOA and THR.

Conclusion

Greater FNW and HAL were independently related to an increased risk of rHOA, whereas greater DFH appeared to be protective. Greater FNW was independently predictive of HESOA and THR. These results suggest DXA-derived geometric parameters, particularly FNW, could help to predict HOA and THR risk.
Efficacy and feasibility of Pharmacoscopy-guided treatment for acute myeloid leukemia patients that exhausted all registered therapeutic options
Authors: Schmid Jonas Andreas , Festl Yasmin , Severin Yannik , Bacher Ulrike , Kronig Marie-Noëlle , Snijder Berend , Pabst Thomas
Published: March 2023

Elderly or unfit patients with relapsed acute myeloid leukemia (AML) face a poor prognosis and are likely to rapidly exhaust all registered treatment options. Pharmacoscopy, an image-basedex vivodrug screening platform, has previously been suggested as a tool for treatment selection in AML. We used pharmacoscopy to generate personalized treatment recommendations for 30 relapse settings of 24 AML patients which exhausted all standard therapeutic options. We evaluated whether pharmacoscopy can be employed within the narrow timeframe available under an AML relapse setting, how often recommended regimens could be started and whether they provided durable clinical benefits. 17 of 30 screens (56.7%) resulted in patients receiving a recommended therapy, leading to promising trends in clinical response and survival. A drug regimen’s integrated pharmacoscopy score proved to be an excellent predictor of clinical response: Patients receiving a regimen with above-median scores showed significantly higher rates of complete remission (OR 3.01, p < 0.0005) and significantly longer overall survival (ratio 3.39, p < 0.006). We conclude that pharmacoscopy is an efficient and valuable tool for therapy selection in AML at relapse and propose concrete measures to further improve clinical implementation.
Hippocampal and amygdala subfield volumes in obsessive-compulsive disorder differ according to medication status
Authors: Ntwatwa Ziphozihle , Lochner Christine , Roos Annerine , Sevenoaks Tatum , van Honk Jack , Alonso Pino , Batistuzzo Marcelo C. , Choi Sunah , Hoexter Marcelo Q. , Kim Minah , Kwon Jun S. , Mataix-Cols David , Menchón José M. , Miguel Euripides C. , Nakamae Takashi , Phillips Mary L. , Soriano-Mas Carles , Veltman Dick J. , Groenewold Nynke A. , van den Heuvel Odile A. , Stein Dan J. , Ipser Jonathan
Published: March 2023

Intro

Although it has been suggested that the hippocampus and amygdala (HA) are involved in the neurobiology of obsessive-compulsive disorder (OCD), volumetric findings have been inconsistent. Furthermore, the HA consist of heterogenous anatomic units with specific functions and cytoarchitecture, and little work has been undertaken on the volumetry of these subfields in OCD.

Methods

T1-weighted images from 381 patients with OCD and 338 healthy controls (HCs) from the OCD Brain Imaging Consortium were segmented to produce twelve hippocampal subfields and nine amygdala subfields using FreeSurfer 6.0. We assessed between-group differences in subfield volume using a mixed-effects model adjusted for age, quadratic effects of age, sex, site, and whole HA volume. Given evidence of confounding effects of clinical characteristics on brain volumes in OCD, we also performed subgroup analyses to examine subfield volume in relation to comorbid anxiety and depression, medication status, and symptom severity.

Results

Patients with OCD and HCs did not significantly differ in HA subfield volume. However, medicated patients with OCD had significantly smaller hippocampal dentate gyrus (pFDR=0.042,d=-0.26) and molecular layer (pFDR=0.042, d=-0.29) and larger lateral (pFDR=0.049,d=0.23) and basal (pFDR=0.049,d=0.25) amygdala subfields than HCs. Unmedicated patients had significantly smaller hippocampal CA1 (pFDR=0.016, d=-0.28) than HCs. No association was detected between any subfield volume and OCD severity.

Conclusion

Differences in HA subfields between OCD and HCs are dependent on medication status, in line with previous work on other brain volumetric alterations in OCD. This emphasizes the importance of considering psychotropic medication in neuroimaging studies of OCD.
The Intra-Host Evolutionary Landscape And Pathoadaptation Of PersistentStaphylococcus aureusIn Chronic Rhinosinusitis
Authors: Houtak Ghais , Bouras George , Nepal Roshan , Shaghayegh Gohar , Cooksley Clare , Psaltis Alkis James , Wormald Peter-John , Vreugde Sarah
Published: March 2023

Chronic rhinosinusitis (CRS) is a common chronic sinonasal mucosal inflammation associated withStaphylococcus aureusbiofilm and relapsing infections. This study aimed to determine rates ofS. aureuspersistence and pathoadaptation in CRS patients by investigating the genomic relatedness and antibiotic resistance/tolerance in longitudinally collectedS. aureusclinical isolates.

A total of 68S. aureusisolates were sourced from 34 CRS patients at least six months apart. Isolates were grown into 48-hour biofilms and tested for tolerance to antibiotics. A hybrid sequencing strategy was used to obtain high-quality reference-grade assemblies of all isolates. Single nucleotide variants (SNV) divergence in the core genome and sequence type clustering were used to analyse the relatedness of the isolate pairs. Single nucleotide and structural genome variations, plasmid similarity, and plasmid copy numbers between pairs were examined.

Our analysis revealed that 41% (14/34 pairs) ofS. aureusisolates were persisters, while 59% (20/34 pairs) were non-persisters. Persister isolates showed episode-specific mutational changes over time with a bias towards events in genes involved in adhesion to the host and mobile genetic elements such as plasmids, prophages, and insertion sequences. A significant increase in the copy number of conserved plasmids of persister strains (p<0.05) was seen, indicating a role of the “mobilome” in promoting persistence. This was accompanied by a significant increase in biofilm tolerance against all tested antibiotics (p<0.001), which was linked to a significant increase in biofilm biomass (p<0.05) over time, indicating a biofilm central pathoadaptive process in persisters. In conclusion, our study provides important insights into the mutational changes underlyingS. aureuspersistence in CRS patients highlighting pathoadaptive mechanisms inS. aureuspersisters culminating in increased biofilm biomass linked to an increase in plasmid copy number over time.
CA3 hippocampal synaptic plasticity supports ripple physiology during memory consolidation
Authors: Oussini Hajer El , Zhang Chun-Lei , François Urielle , Castelli Cecilia , Lampin-Saint-Amaux Aurélie , Lepleux Marilyn , Molle Pablo , Velez Legeolas , Dejean Cyril , Lanore Frédéric , Herry Cyril , Choquet Daniel , Humeau Yann
Published: March 2023

Consolidation of recent memory depends on hippocampal activities during resting periods that immediately follows the memory encoding. There, Slow Save Sleep phases appear as privileged periods for memory consolidation as hosting the ripple activities, which are fast oscillations generated within the hippocampus whose inactivation leads to memory impairment. If a strong correlation exists between these replays of recent experience and the persistence of behavioural adaptations, the mobilisation, the localization and the importance of synaptic plasticity events in this process is largely unknown. To question this issue, we used cell-surface AMPAR immobilisation to block post-synaptic LTP within the hippocampal region at various steps of the memory process. 1- Our results show that hippocampal synaptic plasticity is engaged during the consolidation but is dispensable during the encoding or recall of a working memory based spatial memory task. 2- Blockade of plasticity during sleep leads to apparent forgetting of the encoded rule. 3-In vivorecordings of ripple activities during resting periods show a strong impact of AMPAR immobilization solely, prominent when a rule has been recently encoded. 4-In situexamination of the interplay between AMPAR mobility, hippocampal plasticity and spontaneous ripple activities pointed that post-synaptic plasticity at CA3-CA3 recurrent synapses support ripple generation. As crucial results were reproduced using another AMPARM blockade strategy, we propose that after rule encoding, post-synaptic AMPAR mobility at CA3 recurrent synapses support the generation of ripples necessary for rule consolidation.
Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer
Authors: Freshour Sharon L. , Chen Timothy H.P. , Fisk Bryan , Shen Haolin , Mosior Matthew , Skidmore Zachary L. , Fronick Catrina , Bolzenius Jennifer K. , Griffith Obi L. , Arora Vivek K. , Griffith Malachi
Published: March 2023

To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4+ T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4+ T cell depletion. Functional analysis showed that knocking outIFNgR1in endothelial cells inhibited treatment response. Together, these results indicated that IFN-g signaling in endothelial cells is a key mediator of ICB induced anti-tumor activity.
Ultrasound neuromodulation of an anti-inflammatory pathway at the spleen produces sustained improvement of experimental pulmonary hypertension
Authors: Zafeiropoulos Stefanos , Ahmed Umair , Bekiaridou Alexandra , Mughrabi Ibrahim T , Jayaprakash Naveen , Saleknezhad Nafiseh , Chadwick Chrystal , Daytz Anna , Sato Izumi , Atish-Fregoso Yemil , Carroll Kaitlin , Al-Abed Yousef , Fudim Marat , Puleo Christopher , Giannakoulas George , Nicolls Mark , Diamond Betty , Zanos Stavros
Published: March 2023

Background

Inflammation is pathogenically implicated in pulmonary arterial hypertension (PAH); however, it has not been adequately targeted therapeutically. We investigated whether neuromodulation of an anti-inflammatory neuroimmune pathway involving the splenic nerve using noninvasive, focused ultrasound stimulation of the spleen (sFUS) can improve experimental pulmonary hypertension (PH).

Methods

PH was induced in rats either by SU5416 (20 mg/kg SQ) injection, followed by 21 (or 35) days of hypoxia (SuHx model), or by monocrotaline (60 mg/kg IP) injection (MCT model). Animals were randomized to receive either daily, 12-min-long sessions of sFUS or sham stimulation, for 14 days. Catheterizations, echocardiography, indices of autonomic function, lung and heart histology and immunohistochemistry, spleen flow cytometry and lung single-cell-RNA sequencing were performed after treatment to assess the effects of sFUS.

Results

Splenic denervation right before induction of PH results in a more severe phenotype. In both SuHx and MCT models of PH, sFUS treatment reduces right ventricular (RV) systolic pressure by 25-30% compared to sham therapy, without affecting systemic pressure, and improves RV function and autonomic indices. sFUS reduces wall thickness, apoptosis, and proliferation in small pulmonary arterioles, suppresses CD3+ and CD68+ cell infiltration in lungs and RV fibrosis and hypertrophy and lowers brain natriuretic peptide. Beneficial effects persist for weeks after sFUS discontinuation and are more robust with early and longer treatment. Splenic denervation abolishes sFUS therapeutic benefits. sFUS partially normalizes CD68+ and CD8+ T-cells cell counts in the spleen and downregulates several inflammatory genes and pathways in nonclassical and classical monocytes, and macrophages in the lung. Differentially expressed genes in those cell types are significantly enriched for human PAH-associated genes.

Conclusions

sFUS causes dose-dependent, sustained improvement of hemodynamic, autonomic, laboratory and pathological manifestations in two models of experimental PH. Mechanistically, sFUS normalizes immune cell populations in the spleen and downregulates inflammatory genes and pathways in the lung, many of which are relevant in human disease.
Learning to learn: Single session acquisition of new rules by freely-moving mice
Authors: Levi Amir , Aviv Noam , Stark Eran
Published: March 2023

Learning from examples and adapting to new rules are fundamental attributes of human cognition. However, it is unclear what conditions allow for fast and successful learning, especially in non-human subjects. To determine how rapidly freely-moving mice can learn a new rule, we designed a two-alternative forced-choice visual discrimination paradigm in which the rules governing the task can change between sessions. We find that experienced animals can learn a new rule after being exposed to only five training and three testing trials. The propensity for single session learning improves over time and is accurately predicted based on animal experience and rule difficulty. After establishing procedural learning of a paradigm, mice continuously improve their performance on new rules. Thus, mice learn to learn.
A meta-analysis of liver microbiome in beef and dairy cattle using metatranscriptome sequencing reads
Authors: Park Tansol , Li Wenli , Zanton Geoffrey
Published: March 2023

The gut-liver axis is at the forefront of host-microbial interactions given the proximity of liver to the gut and connection via portal circulation. In recent years, many studies in human and mouse models have demonstrated the existence of a significant microbial community embedded in diverse tissue types, including blood and liver. Yet, in cattle, the rumen microbiome has been the primary focus. The liver microbiome and its metabolic role in host health and performance remain largely unexplored. While there has been considerable work focusing on the liver of diseased cattle, the objective of this study was to evaluate, through meta-analysis, the commensal liver microbiome in various cattle breeds. To our knowledge, this is the first study in which a core liver microbiome has been described in cattle without overt liver disease. We discovered abundant microbial taxa in the liver, varying by host age, species, and developmental stage. Eight bacterial phyla (Actinobacteria, Bacteroidetes, Cyanobacteria, Deinococcus-Thermus, Firmicutes, Fusobacteria, Proteobacteria, and Tenericutes) were found to be the core microbial taxa, representing almost half of the total liver bacterial population. Additionally, we identified several KEGG pathways with significant association with cattle age. This study provides a baseline knowledge of the liver microbiome as identified by metatranscriptome sequencing in cattle. Besides finding the microbial taxa previously reported by studies using DNA-based, 16S rRNA amplicon sequencing methods, this study identified several core phyla that have not been reported in cattle liver, highlighting the improved sensitivity or ability in detecting microbes by RNA-over DNA-based methods.
Transcriptional Biomarker Discovery Towards Building A Load Stress Reporting System for EngineeredEscherichia coliStrains
Authors: Huang Yiming , Wipat Anil , Bacardit Jaume
Published: March 2023

Foreign proteins are produced by inserting synthetic constructs into host bacteria in biotechnology applications. This process can cause resource competition between synthetic circuits and host cells, placing a metabolic burden on the host cells which may result load stress and detrimental physiological changes. Consequently, the host bacteria can experience slow growth, while the synthetic system may suffer from suboptimal function and reduced productivity. To address this issue, we developed machine learning strategies to select a minimal number of genes that could serve as biomarkers for the design of load stress reporters. We identified pairs of biomarkers that showed discriminative capacity to detect the load stress states induced in 41 engineeredE. colistrains. These biomarker genes are mainly involved in Envelope stress response, Ion transport, Energy production and conversion.
SQ3370, the first clinical click chemistry-activated cancer therapeutic, shows safety in humans and translatability across species
Authors: Srinivasan Sangeetha , Yee Nathan A. , Zakharian Michael , Alečković Maša , Mahmoodi Amir , Nguyen Tri-Hung , Mejía Oneto José M.
Published: March 2023

Background

SQ3370 is the first demonstration of the Click Activated Protodrugs Against Cancer (CAPAC™) platform that uses click chemistry to activate drugs directly at tumor sites, maximizing therapeutic exposure. SQ3370 consists of a tumor-localizing biopolymer (SQL70) and a chemically-attenuated doxorubicin (Dox) protodrug SQP33; the protodrug is activated upon clicking with the biopolymer at tumor sites. Here, we present data from preclinical studies and a Phase 1 dose-escalation clinical trial in adult patients with advanced solid tumors (NCT04106492) demonstrating SQ3370’s activation at tumor sites, safety, systemic pharmacokinetics (PK), and immunological activity.

Methods

Treatment cycles consisting of an intratumoral or subcutaneous injection of SQL70 biopolymer followed by 5 daily intravenous doses of SQP33 protodrug were evaluated in tumor-bearing mice, healthy dogs, and adult patients with solid tumors.

Results

SQL70 effectively activated SQP33 at tumor sites, resulting in high Dox concentrations that were well tolerated and unachievable by conventional treatment. SQ3370 was safely administered at 8.9x the veterinary Dox dose in dogs and 12x the conventional Dox dose in patients, with no dose-limiting toxicity reported to date. SQ3370’s safety, toxicology, and PK profiles were highly translatable across species. SQ3370 increased cytotoxic CD3+and CD8+T-cells in patient tumors indicating T-cell-dependent immune activation in the tumor microenvironment.

Conclusions

SQ3370, the initial demonstration of click chemistry in humans, enhances the safety of Dox at unprecedented doses and has the potential to increase therapeutic index. Consistent safety, toxicology, PK, and immune activation results observed with SQ3370 across species highlight the translatability of the click chemistry approach in drug development.

Trial registration

NCT04106492; 7 September 2019
Paradoxical activation of a type VI secretion system (T6SS) phospholipase effector by its cognate immunity protein
Authors: Jensen Steven J. , Ruhe Zachary C. , Williams August F. , Nhan Dinh Q. , Garza-Sánchez Fernando , Low David A. , Hayes Christopher S.
Published: March 2023

Type VI secretion systems (T6SS) deliver cytotoxic effector proteins into target bacteria and eukaryotic host cells. Antibacterial effectors are invariably encoded with cognate immunity proteins that protect the producing cell from self-intoxication. Here, we identify transposon insertions that disrupt thetliimmunity gene ofEnterobacter cloacaeand induce auto-permeabilization through unopposed activity of the Tle phospholipase effector. This hyper-permeability phenotype is T6SS-dependent, indicating that the mutants are intoxicated by Tle delivered from neighboring sibling cells rather than by internally produced phospholipase. Unexpectedly, an in-frame deletion oftlidoes not induce hyper-permeability because Δtlinull mutants fail to deploy active Tle. Instead, the most striking phenotypes are associated with disruption of thetlilipoprotein signal sequence, which prevents immunity protein localization to the periplasm. Immunoblotting reveals that most hyper-permeable mutants still produce Tli, presumably from alternative translation initiation codons downstream of the signal sequence. These observations suggest that cytosolic Tli is required for the activation and/or export of Tle. We show that Tle growth inhibition activity remains Tli-dependent when phospholipase delivery into target bacteria is ensured through fusion to the VgrG β-spike protein. Together, these findings indicate that Tli has distinct functions depending on its subcellular localization. Periplasmic Tli acts as a canonical immunity factor to neutralize incoming effector proteins, while a cytosolic pool of Tli is required to activate the phospholipase domain of Tle prior to T6SS-dependent export.
Cisinteractions in theIrf8locus regulate stage-dependent enhancer activation
Authors: Liu Tian-Tian , Ou Feiya , Belk Julia A. , Bagadia Prachi , Anderson David A. , Durai Vivek , Yao Winnie , Satpathy Ansuman T. , Murphy Theresa L. , Murphy Kenneth M.
Published: March 2023

Individual elements within a superenhancer can act in a cooperative or temporal manner, but the underlying mechanisms remain obscure. We recently identified anIrf8superenhancer, within which different elements act at distinct stages of type 1 classical dendritic cell (cDC1) development. The +41-kbIrf8enhancer is required for pre-cDC1 specification, while the +32-kbIrf8enhancer acts to support subsequent cDC1 maturation. Here, we found that compound heterozygous Δ32/Δ41 mice, lacking the +32- and +41-kb enhancers on different chromosomes, show normal pre-cDC1 specification but, surprisingly, completely lack mature cDC1 development, suggestingcisdependence of the +32-kb enhancer on the +41-kb enhancer. Transcription of the +32-kbIrf8enhancer-associated long noncoding RNA (lncRNA) Gm39266 is also dependent on the +41-kb enhancer. However, cDC1 development in mice remained intact when Gm39266 transcripts were eliminated by CRISPR/Cas9-mediated deletion of lncRNA promoters and when transcription across the +32-kb enhancer was blocked by premature polyadenylation. We showed that chromatin accessibility and BATF3 binding at the +32-kb enhancer were dependent on a functional +41-kb enhancer located incis. Thus, the +41-kbIrf8enhancer controls the subsequent activation of the +32-kbIrf8enhancer in a manner that is independent of associated lncRNA transcription.
Genetic cold cases: lessons from solving complex congenital limb disorders
Authors: Andrey Guillaume , Duboule Denis
Published: March 2023

Congenital genetic disorders affecting limb morphology in humans and other mammals are particularly well described, due to both their rather high frequencies of occurrence and the ease of their detection when expressed as severe forms. In most cases, their molecular and cellular etiology remained unknown long after their initial description, often for several decades, and sometimes close to a century. Over the past 20 yr, however, experimental and conceptual advances in our understanding of gene regulation, in particular over large genomic distances, have allowed these cold cases to be reopened and, eventually, for some of them to be solved. These investigations led not only to the isolation of the culprit genes and mechanisms, but also to the understanding of the often complex regulatory processes that are disturbed in such mutant genetic configurations. Here, we present several cases in which dormant regulatory mutations have been retrieved from the archives, starting from a historical perspective up to their molecular explanations. While some cases remain open, waiting for new tools and/or concepts to bring their investigations to an end, the solutions to others have contributed to our understanding of particular features often found in the regulation of developmental genes and hence can be used as benchmarks to address the impact of noncoding variants in the future.
The special thing of clubs in the German football Bundesliga – about the legal forms of the clubs and the resulting consequences
Authors: Ingerfurth Stefan
Published: March 2023

Purpose

Also due to the “50+1 rule”, which exists in the German football Bundesliga and was introduced to regulate competition, clubs with a wide variety of legal forms participate. The aim of this article is to explain the consequences of the rule, the dominance of nonprofit organisations in German football and to contribute to the discussion on whether other football leagues should follow this model.

Design/methodology/approach

The study looks at the German Bundesliga with its special 50+1 rule. With reference to stakeholder theory, the management challenges of participants in the Bundesliga are elaborated.

Findings

There are still clubs that participate as purely nonprofit associations, even though from an organisational point of view there are some arguments against this legal form. Due to the 50+1 rule, a nonprofit association has the majority of decision-making powers in each participating organisation. The goals desired by the 50+1 rule, such as “maintaining football as a common good” and at the same time “competitive balance”, do not seem to be achieved.

Originality/value

The article shows that regulation in the leagues appears to make sense and, in the case of the German Bundesliga, has led to participants with different legal forms. However, it also shows that the 50+1 rule is also associated with opposing goals that cannot be achieved in equal measure.