bluuebunny/crossref_metadata_2025 huggingface dataset:
Provider Perceptions Regarding Cardiopulmonary Resuscitation in Surgical Patients With Frailty
Authors: Allen Matthew B. , Reich Amanda J. , Collins Patrick , Chahal Karen , Moustaqim-Barrette Maria , Bernacki Rachelle E. , Cooper Zara , Bader Angela M.
Published: January 2024

Objective:

To characterize the perceptions of surgeons, anesthesiologists, and geriatricians regarding perioperative cardiopulmonary resuscitation (CPR) in surgical patients with frailty.

Background:

The population of patients undergoing surgery is growing older and more frail. Despite a growing focus on goal-concordant care, frailty assessment, and debate regarding the appropriateness of CPR in patients with frailty, providers’ views regarding frailty and perioperative CPR are unknown.

Methods:

We performed qualitative thematic analysis of transcripts from semistructured interviews of anesthesiologists (8), surgeons (10), and geriatricians (9) who care for high-risk surgical patients at 2 academic medical centers in Boston, MA. The interview guide elicited clinicians’ understanding of frailty, approach to decision-making regarding perioperative CPR, and perceptions of perioperative CPR in frail surgical patients.

Results:

We identified 5 themes: (1) perceptions of perioperative CPR in patients with frailty vary by provider specialty, (2) judgments regarding the appropriateness of CPR in surgical patients with frailty are typically multifactorial and include patient goals, age, comorbidities, and arrest etiology, (3) resuscitation in patients with frailty is sometimes associated with moral distress, (4) biases, such as ableism and ageism, may skew clinicians’ perceptions of the appropriateness of perioperative CPR in patients with frailty, and (5) evidence to guide risk stratification for patients with frailty undergoing perioperative CPR is inadequate.

Conclusions:

Anesthesiologists, surgeons, and geriatricians offer different accounts of frailty’s relevance to judgments regarding CPR in surgical patients. Divergent views regarding frailty and perioperative CPR may impede efforts to deliver goal-concordant care and suggest a need for research to inform risk stratification, predict patient-centered outcomes, and understand the role of potential biases, such as ageism and ableism.
Carotid Revascularization is Associated with Improved Mood in Patients with Advanced Carotid Disease
Authors: Succar Bahaa , Chou Ying-hui , Hsu Chiu-Hsieh , Rapcsak Steven , Trouard Theodore , Zhou Wei
Published: January 2024

Objective:

To investigate the impact of carotid interventions on patients’ mental condition in patients with carotid stenosis.

Summary Background Data:

Ongoing research highlights the impact of carotid interventions on neurocognitive function in patients with advanced carotid atherosclerosis. However, data regarding the impact of carotid revascularization on mood is scarce.

Methods:

A total of 157 patients undergoing carotid revascularization were prospectively recruited. The primary outcome was depression, evaluated pre-operatively, and at 1-,6- and 12-month post-intervention using the long form of the geriatric depression scale (GDS-30) questionnaire. Other tests were also used to assess cognition at the respective timepoints. Statistical analyses were performed to assess the postoperative outcomes compared to baseline.

Results:

Baseline depression (GDS>9) was observed in 49(31%) subjects, whereas 108(69%) patients were not depressed (GDS≤9). The average pre-operative GDS score was 15.42 ± 4.40(14.2-16.7) and 4.28 ±2.9(3.7-4.8) in the depressed and non-depressed groups, respectively. We observed a significant improvement in GDS scores within the depressed group at 1-month (P=0.002), 6-months (P=0.027), and 1-year (P<0.001) post-intervention compared to preop, whereas the non-depressed group had similar post-op GDS scores at all time points compared to baseline. Significant improvement in measures of executive function was seen in non-depressed patients at all three timepoints whereas depressed patients showed an improvement at 1-year follow-up.

Conclusions:

Our study highlights improvement in mood among patients with advanced carotid disease who screened positive for depression at baseline. Further studies with larger sample sizes are warranted to investigate the association between depression, carotid disease, and carotid intervention.
Phase 1 trial of same day cytology to guide the use of HIPEC
Authors: Sugarbaker Paul H. , Deng Tom
Published: January 2024

Background:

Peritoneal metastases from gastrointestinal or gynecologic malignancy are a prominent part of the natural history of these diseases. Peritoneal metastases, if not effectively treated, will result in a decreased survival and cause an impaired quality of life. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment specifically designed to combat peritoneal metastases. A group of patients who, from a theoretical perspective, may benefit from HIPEC are those patients with a positive peritoneal cytology. In order to identify these patients at the time of a surgical intervention, a same day cytology is to be performed.

Materials and methods:

The result of this test is to be available at or before the completion of the cancer resection. If the cytology is positive, the patient immediately becomes a candidate for HIPEC. The HIPEC will be of maximal value if a complete cytoreduction, as judged by the surgeon, has been possible. This phase 1 trial is to demonstrate that the Surgical Oncology Service, the Department of Pathology, the Pharmacy and the Operating Room personnel can co-ordinate a phase 1 protocol to successfully complete the same day cytology with an efficient delivery of HIPEC. A standardized plan for consent, cytology collection, preparation of the specimen, reading of the specimen, reporting the results in a timely manner facilitates the administration of HIPEC in peritoneal cytology positive patients.

Dissemination:

Successful completion of these requirements is a positive result for this study and allows for future protocols to be generated. Successful completion of the same day cytology phase 1 protocol will allow the efficacy, safety, and efficiency of this plan of patient management to be evaluated.
Social Determinants of Outcomes Disparity among Pediatric Patients with Solid Tumor
Authors: Cochran Elizabeth D , Jacobson Jillian C , Nehrubabu Mithin , Qiao Jingbo , McCreery Sullivan , Chung Dai H
Published: January 2024

BACKGROUND:

Socioeconomic factors have a significant impact on healthcare outcomes. Metrics such as area deprivation index (ADI) are used to quantify the anticipated influence of these factors. Here, we sought to assess the impact of socioeconomic factors on clinical outcomes among pediatric patients with solid tumor in our region.

STUDY DESIGN:

We identified 3,863 pediatric patients who were diagnosed with a malignant solid tumor in the Texas Cancer Registry between 1995 and 2019. ADI was used to quantify socioeconomic determinants of health. These outcome variables were determined: stage of disease at diagnosis, time between diagnosis and treatment initiation, and overall mortality. Statistical analysis was performed using logistic regression, linear regression, Cox proportional hazards regression, and Kaplan–Meier survival curves.

RESULTS:

A total of 53.5% of patients were male and the average age at diagnosis was 4.5 years. Forty-seven percent of patients were White, 13.3% were Black, 36.2% were Hispanic, 1.7% were Asian, and other rare minority groups made up 1.8%. On multivariable analysis, increased risk of death was associated with Black race, rare minority race, residence in a border county, and increasing ADI score, with the risk of death at 5 years rising 4% with each increasing ADI point.

CONCLUSIONS:

Social determinants of health are associated with disparate outcomes among pediatric patients with solid tumor. Our results suggest that patients who are part of racial minority groups and those who reside in socioeconomically disadvantaged neighborhoods or regions near the Texas-Mexico border are at an increased risk of death. This information may be useful in strategizing outreach and expanding resources to improve outcomes in at-risk communities.
Judgment Errors in Surgical Care
Authors: Marsh Katherine M , Turrentine Florence E , Jin Ruyun , Schirmer Bruce D , Hanks John B , Davis John P , Schenk Worthington G , Jones R Scott
Published: January 2024

BACKGROUND:

Human error is impossible to eliminate, particularly in systems as complex as healthcare. The extent to which judgment errors in particular impact surgical patient care or lead to harm is unclear.

STUDY DESIGN:

The American College of Surgeons NSQIP (2018) procedures from a single institution with 30-day morbidity or mortality were examined. Medical records were reviewed and evaluated for judgment errors. Preoperative variables associated with judgment errors were examined using logistic regression.

RESULTS:

Of the surgical patients who experienced a morbidity or mortality, 18% (31 of 170) experienced an error in judgment during their hospitalization. Patients with hepatobiliary procedure (odds ratio [OR] 5.4 [95% CI 1.23 to 32.75], p = 0.002), insulin-dependent diabetes (OR 4.8 [95% CI 1.2 to 18.8], p = 0.025), severe COPD (OR 6.0 [95% CI 1.6 to 22.1], p = 0.007), or with infected wounds (OR 8.2 [95% CI 2.6 to 25.8], p < 0.001) were at increased risk for judgment errors.

CONCLUSIONS:

Specific procedure types and patients with certain preoperative variables had higher risk for judgment errors during their hospitalization. Errors in judgment adversely impacted the outcomes of surgical patients who experienced morbidity or mortality in this cohort. Preventing or mitigating errors and closely monitoring patients after an error in judgment is prudent and may improve surgical safety.
Clinical Validation of Computer-Aided Diagnosis Software for Preventing Retained Surgical Sponges
Authors: Kurisaki Ken , Soyama Akihiko , Hamauzu Shin , Yamada Masahiko , Yamaguchi Shun , Matsuguma Kunihito , Kerkhof Enzo , Fukuda Toru , Toya Ryo , Eguchi Susumu
Published: January 2024

BACKGROUND:

We previously reported the successful development of a computer-aided diagnosis (CAD) system for preventing retained surgical sponges with deep learning using training data, including composite and simulated radiographs. In this study, we evaluated the efficacy of the CAD system in a clinical setting.

STUDY DESIGN:

A total of 1,053 postoperative radiographs obtained from patients 20 years of age or older who underwent surgery were evaluated. We implemented a foreign object detection application software on the portable radiographic device used in the operating room to detect retained surgical sponges. The results of the CAD system diagnosis were prospectively collected.

RESULTS:

Among the 1,053 images, the CAD system detected possible retained surgical items in 150 images. Specificity was 85.8%, which is similar to the data obtained during the development of the software.

CONCLUSIONS:

The validation of a CAD system using deep learning in a clinical setting showed similar efficacy as during the development of the system. These results suggest that the CAD system can contribute to the establishment of a more effective protocol than the current standard practice for preventing the retention of surgical items.
Mycobacterium interjectum Causing Submandibular Lymphadenitis in a Child
Authors: Lin Sallie , Trieu Connie
Published: January 2024

Nontuberculous mycobacteria (NTM) commonly manifest as cervical lymphadenitis in immunocompetent children. Only a few species, such as Mycobacterium avium complex (MAC), cause infection in children. With recent advances in gene sequencing, Mycobacterium interjectum has been identified as a rare cause of adenitis in children, with at least 10 cases reported since 1993. Curative treatment for NTM lymphadenitis, particularly when caused by MAC, usually involves complete surgical excision of the affected lymph nodes. This case report highlights successful treatment of submandibular lymphadenitis caused by M. interjectum in a pediatric patient, despite multi-drug resistance in vitro.
Time-lapse mesoscopy of Candida albicans and Staphylococcus aureus dual-species biofilms reveals a structural role for the hyphae of C. albicans in biofilm formation
Authors: Baxter Katherine J. , Sargison Fiona A. , Fitzgerald J. Ross , McConnell Gail , Hoskisson Paul A.
Published: January 2024

Polymicrobial infection with Candida albicans and

Staphylococcus aureus

may result in a concomitant increase in virulence and resistance to antimicrobial drugs. This enhanced pathogenicity phenotype is mediated by numerous factors, including metabolic processes and direct interaction of

S. aureus

with C. albicans hyphae. The overall structure of biofilms is known to contribute to their recalcitrance to treatment, although the dynamics of direct interaction between species and how it contributes to pathogenicity is poorly understood. To address this, a novel time-lapse mesoscopic optical imaging method was developed to enable the formation of C. albicans/

S. aureus

whole dual-species biofilms to be followed. It was found that yeast-form or hyphal-form C. albicans in the biofilm founder population profoundly affects the structure of the biofilm as it matures. Different sub-populations of C. albicans and

S. aureus

arise within each biofilm as a result of the different C. albicans morphotypes, resulting in distinct sub-regions. These data reveal that C. albicans cell morphology is pivotal in the development of global biofilm architecture and the emergence of colony macrostructures and may temporally influence synergy in infection.
CoSpred: Machine learning workflow to predict tandem mass spectrum in proteomics
Authors: Xue Liang , Tiwary Shivani , Bordyuh Mykola , Jean-Beltran Pierre M , Stanton Robert
Published: January 2024

In mass spectrometry-based proteomics, the identification and quantification of peptides and proteins is usually done using database search algorithms or spectral library matching. The use of deep learning algorithms can help improve the identification rates of peptides and proteins through the generation of high-fidelity theoretical spectrum which can be used as the basis of a more complete spectral library than those presently available. Current methods focus on predicting only backbone ions, such as y- and b-ions. However, the inclusion of non-backbone ions is necessary to truly improve spectral library matching. Here we focus on providing a user-friendly machine learning workflow, which we callCompleteSpectrumPredictor (CoSpred). Using CoSpred users can create their own machine learning compatible training dataset and then train a Machine Learning model to predict both backbone and non-backbone ions. For the model a transformer encoder architecture is used to predict the complete MS/MS spectrum from a given peptide sequence. This model does not require background knowledge of fragment ion annotations or fragmentation rules. The model outputs the set of pairs (Mi,Ii) whereMiis the m/z (mass-to-charge ratio) of a peak in the spectrum andIiis the intensity of the peak. The model presented here for validation was trained on the dataset available in the MassIVE data repository and shows superior performance in terms of various metrics (e.g. precision/recall for mass, cosine similarity for peak intensity, etc) between the true and predicted spectra. Furthermore, CoSpred can be used to create custom models that allow for accurate spectrum prediction for different experimental conditions. In addition to the transformer model provided in the package, the code is built modularly to allow for alternate ML models to be easily “plugged in”. The CoSpred workflow (preprocessing->training->inference) provides a path for state-of-art ML capabilities to be more accessible to proteomics scientists.
TMC7 deficiency causes acrosome biogenesis defects and male infertility in mice
Authors: Wang Jing , Yin Yingying , Yang Lei , Qin Junchao , Wang Zixiang , Qiu Chunhong , Gao Yuan , Lu Gang , Gao Fei , Chen Zi-jiang , Zhang Xiyu , Liu Hongbin , Liu Zhaojian
Published: January 2024

Transmembrane channel-like (TMC) proteins are a highly conserved ion channel family consisting of eight members (TMC1–TMC8) in mammals. TMC1/2 are components of the mechanotransduction channel in hair cells, and mutations of TMC1/2 cause deafness in humans and mice. However, the physiological roles of other TMC proteins remain largely unknown. Here, we show thatTmc7is specifically expressed in the testis and that it is required for acrosome biogenesis during spermatogenesis.Tmc7−/−mice exhibited abnormal sperm head, disorganized mitochondrial sheaths, and reduced number of elongating spermatids, similar to human oligo-astheno-teratozoospermia. We further demonstrate that TMC7 is colocalized with GM130 at the cis-Golgi region in round spermatids. TMC7 deficiency leads to aberrant Golgi morphology and impaired fusion of Golgi-derived vesicles to the developing acrosome. Moreover, upon loss of TMC7 intracellular ion homeostasis is impaired and ROS levels are increased, which in turn causes Golgi and endoplasmic reticulum (ER) stress. Taken together, these results suggest that TMC7 is required to maintain pH and ion homeostasis, which is needed for acrosome biogenesis. Our findings unveil a novel role for TMC7 in acrosome biogenesis during spermiogenesis.
Gene expression differences associated with alcohol use disorder in human brain
Authors: Willis Caryn , White Julie D. , Minto Melyssa S. , Quach Bryan C. , Han Shizhong , Tao Ran , Shin Joo Heon , Deep-Soboslay Amy , Hyde Thomas M. , Mayfield R. Dayne , Webb Bradley T. , Johnson Eric O. , Kleinman Joel E. , Bierut Laura J. , Hancock Dana B.
Published: January 2024

Excessive alcohol consumption is a leading cause of preventable death worldwide. Neurobiological mechanisms associated with alcohol use disorder (AUD) remain poorly understood. To further understand differential gene expression (DGE) associated with AUD, we compared deceased individuals with and without AUD across two human brain regions, nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC). Bulk RNA-seq data in both NAc and DLPFC from human postmortem brains (N ≥ 50 with AUD and ≥ 46 non-AUD) were analyzed for DGE using negative binomial regression adjusting for technical and biological covariates. The region-level results were meta-analyzed with a previously published, independent dataset (NNAc= 28 AUD, 29 non-AUD; NPFC= 66 AUD, 77 non-AUD). We further utilized these data to test for heritability enrichment of AUD-related phenotypes, gene co-expression networks, gene ontology enrichment, and drug repurposing. We identified 176 differentially expressed genes (DEGs; 12 in both regions, 78 only in NAc, 86 only in DLPFC) for AUD in our new dataset. By meta-analyzing with published data, we identified 476 DEGs (25 in both regions, 29 only in NAc, 422 only in PFC). Of these DEGs, we found 17 genes that were significant when looked up in GWAS of problematic alcohol use or drinks per week. Gene co-expression analysis showed both concordant and unique gene networks across brain regions. We also identified 29 and 436 drug compounds that target DEGs from our meta-analysis in NAc and DLPFC, respectively. This study identified robust AUD-associated DEGs, providing novel neurobiological insights into AUD and highlighting genes targeted by known drug compounds, generating opportunity for drug repurposing to treat AUD.
Multivariate Time-Lagged Multidimensional Pattern Connectivity (mvTL-MDPC) for EEG/MEG Functional Connectivity Analysis
Authors: Rahimi Setareh , Jackson Rebecca L. , Hauk Olaf
Published: January 2024

Multidimensional connectivity methods are critical to reveal the full pattern of complex interactions between brain regions over time. However, to date only bivariate multidimensional methods are available for time-resolved EEG/MEG data, which may overestimate connectivity due to the confounding effects of spurious and indirect dependencies. Here, we introduce a novel functional connectivity method which is both multivariate and multidimensional, Multivariate Time-lagged Multidimensional Pattern Connectivity (mvTL-MDPC), to address this issue in time-resolved EEG/MEG applications. This novel method extends its bivariate counterpart TL-MDPC to estimate how well patterns in an ROI 1 at time pointt1can be linearly predicted from patterns of an ROI 2 at time pointt2while partialling out the multivariate contributions from other brain regions. We compared the performance of mvTL-MDPC and TL-MDPC on simulated data designed to test their ability to identify true direct connections, using the Euclidean distance to the ground truth to measure goodness-of-fit. These simulations demonstrate that mvTL-MDPC produces more reliable and accurate results than the bivariate method. We therefore applied this method to an existing EEG/MEG dataset contrasting words presented in more or less demanding semantic tasks, to identify the dynamic brain network underlying controlled semantic cognition. As expected, mvTL-MDPC was more selective than TL-MDPC, identifying fewer connections, likely due to a reduction in the detection of spurious or indirect connections. Dynamic connections were identified between bilateral anterior temporal lobes, posterior temporal cortex and inferior frontal gyrus, in line with recent neuroscientific models of semantic cognition.
Impact of dendritic spine loss on excitability of hippocampal CA1 pyramidal neurons: a computational study of early Alzheimer disease
Authors: Tian Chengju , Reyes Isabel , Masurkar Arjun V.
Published: January 2024

Synaptic spine loss is an early pathophysiologic hallmark of Alzheimer disease (AD) that precedes overt loss of dendritic architecture and frank neurodegeneration. While spine loss signifies a decreased engagement of postsynaptic neurons by presynaptic targets, the degree to which loss of spines and their passive components impacts the excitability of postsynaptic neurons and responses to surviving synaptic inputs is unclear. Using passive multicompartmental models of CA1 pyramidal neurons (PNs), implicated in early AD, we find that spine loss alone drives a boosting of remaining inputs to their proximal and distal dendrites, targeted by CA3 and entorhinal cortex (EC), respectively. This boosting effect is higher in distal versus proximal dendrites and can be mediated by spine loss restricted to the distal compartment, enough to impact synaptic input integration and somatodendritic backpropagation. This has particular relevance to very early stages of AD in which pathophysiology extends from EC to CA1.
Spontaneous oxycodone withdrawal disrupts sleep, circadian, and electrophysiological dynamics in rats
Authors: Gulledge M , Carlezon WA , McHugh R Kathryn , Prerau M. , Chartoff EH
Published: January 2024

Opioid dependence is defined by an aversive withdrawal syndrome upon drug cessation that can motivate continued drug-taking, development of opioid use disorder, and precipitate relapse. An understudied but common opioid withdrawal symptom is disrupted sleep, reported as both insomnia and daytime sleepiness. Despite the prevalence and severity of sleep disturbances during opioid withdrawal, there is a gap in our understanding of their interactions. The goal of this study was to establish an in-depth, temporal signature of spontaneous oxycodone withdrawal effects on the circadian composition of discrete sleep stages and the dynamic spectral properties of the electroencephalogram (EEG) signal in male rats. We continuously recorded EEG and electromyography (EMG) signals for 8 d of spontaneous withdrawal after a 14-d escalating-dose oxycodone regimen (0.5 - 8.0 mg/kg, 2×d; SC). During withdrawal, there was a profound loss and gradual return of circadian structure in sleep, body temperature, and locomotor activity, as well as increased sleep and wake fragmentation dependent on lights on/off. Withdrawal was associated with significant alterations in the slope of the aperiodic 1/f component of the EEG power spectrum, an established biomarker of arousal level. Early in withdrawal, NREM exhibited an acute flattening and return to baseline of both low (1-4 Hz) and high (15-50 Hz) frequency components of the 1/f spectrum. These findings suggest temporally dependent withdrawal effects on sleep, reflecting the complex way in which the allostatic forces of opioid withdrawal impinge upon sleep and circadian processes. These foundational data based on continuous tracking of nocturnal rhythms, sleep stage composition, and spectral EEG properties provide a detailed construct with which to form and test hypotheses on the mechanisms of opioid-sleep interactions.
Changes in neural progenitor lineage constituent during astrocytic differentiation of human iPSCs
Authors: Li Zongze , Cardo Lucia Fernandez , Rokicki Michal , Monzón-Sandoval Jimena , Volpato Viola , Wessely Frank , Webber Caleb , Li Meng
Published: January 2024

The regional specificity of stem cell-derived astrocytes is believed to be an important prerequisite for their application in disease modelling and cell-based therapies. Due to the lack of subtype-defining markers for astrocytes in different regions of the brain, the regional identity ofin vitro-derived astrocytes is often declared by the dominant positional characteristics of their antecedent neural progenitors, patterned to a fate of interest, with the assumption that the positional trait is preserved by the derived astrocytes via linear descent. Using a human induced pluripotent stem cell line designed for tracing derivatives of LMX1A+cells combined with a ventral midbrain induction paradigm, we show that astrocytes originating from LMX1A+progenitors can only be generated if these progenitors are purified prior to the astrocyte differentiation process, or their progenies are gradually lost to progenies of LMX1A-progenitors. This finding indicates that the lineage composition of iPSC-derived astrocytes may not accurately recapitulate the founder progenitor population. Using deep single-cell RNA sequencing, we identified distinct transcriptomic signatures in astrocytes derived from the LMX1A+progenitor cells. Our study highlights the need for rigorous characterization of pluripotent stem cell-derived regional astrocytes, and provides a resource for assessing LMX1A+ventral midbrain progenitor-derived human astrocytes.
MetaIBS - large-scale amplicon-based meta analysis of irritable bowel syndrome
Authors: Carcy Salomé , Ostner Johannes , Tran Viet , Menden Michael , Müller Christian L.
Published: January 2024

Background

Irritable Bowel Syndrome (IBS) is a chronic functional bowel disorder causing abdominal discomfort, as well as transit deregulation with constipation and/or diarrhea. The pathophysiology of IBS is poorly understood and believed to be multifactorial. The role of gut microbiota in IBS has been investigated in several case-control studies, in particular via 16S rRNA amplicon sequencing surveys. These studies, however, have not yet led to a consistent picture of significant changes in gut microbial compositions across health and disease. One key bottleneck is the modest cohort sizes of most individual studies and a high diversity of experimental, bioinformatics, and statistical analysis approaches across studies.

Results

We address these shortcomings by presenting MetaIBS, an open-access data repository and associated meta-analysis workflow of thirteen 16S rRNA amplicon datasets comprising both fecal matter and sigmoid biopsy samples spanning ∽2,500IBS and healthy individuals. MetaIBS includes a tailored computational framework that (i) enables coherentde novoprocessing and taxonomic assignments of the raw 16S rRNA amplicon reads across experimental protocols and sequencing technologies, and (ii) statistical workflows for visualization and analysis at different taxonomic ranks and data granularity. Our statistical meta-analysis shows that popular high-level microbiome summary statistics, including Firmicutes/Bacteroidota ratios or diversity indices, are insufficient for reliable discrimination between IBS patients and healthy controls. Fine-grained multi-method differential abundance and classification analysis, however, can identify sets of differentially abundant taxa that replicateacross multiple datasets, includingCoprococcus eutactusandAlistipes finegoldii.

Conclusions

MetaIBS provides a curated and reproducible data and (meta-)analysis resource for amplicon-based IBS research at unprecedented scale. MetaIBS allows assessing the heterogeneity of IBS cohorts across multiple experimental protocols, sample types, and IBS phenotypes. Our framework will likely contribute to more coherent insights into the role of the microbiome in IBS and the discovery of reliable microbial IBS biomarkers for follow-up functional and translational studies.
Intensive environmental sampling and whole genome sequence-based characterization ofListeriain small and medium sized dairy plants reveal opportunities for simplified and size-appropriate environmental monitoring strategies
Authors: Bolten Samantha , Lott Timothy T. , Ralyea Robert D. , Gianforte Anika , Trmcic Aljosa , Orsi Renato H. , Martin Nicole H. , Wiedmann Martin
Published: January 2024

Small and medium sized dairy processing plants (SMDPs) may face unique challenges with respect to controllingListeriain their processing environments, e.g., due to limited resources. The aim of this study was to implement and evaluate environmental monitoring programs (EMPs) forListeriacontrol in eight SMDPs in a ∼1-year longitudinal study; this included a comparison of pre-operation (i.e., after cleaning and sanitation and prior to production) and mid-operation (i.e., at least 4 h into production) sampling strategies. Among 2,072 environmental sponge samples collected across all plants, 272 (13%) were positive forListeria.Listeriaprevalence among pre- and mid-operation samples (15 and 17%, respectively), was not significantly different. Whole genome sequencing (WGS) performed on select isolates to characterizeListeriapersistence patterns revealed repeated isolation of closely relatedListeriaisolates (i.e., ≤20 high quality single nucleotide polymorphism [hqSNP] differences) in 5/8 plants over >6 months, suggestingListeriapersistence and/or re-introduction was relatively common among the SMDPs evaluated here. WGS furthermore showed that for 41 sites where samples collected pre- and mid- operation were positive forListeria,Listeriaisolates obtained were highly related (i.e., ≤10 hqSNP differences), suggesting that pre-operation sampling alone may be sufficient and more effective for detecting sites ofListeriapersistence. Importantly, our data also showed that only 1/8 plants showed a significant decrease inListeriaprevalence over 1 year, indicating continued challenges withListeriacontrol in at least some SMDPs. We conclude that options for simplifiedListeriaEMP programs (e.g., with a focus on pre-operation sampling, which allows for more rapid identification of likely persistence sites) may be valuable for improvedListeriacontrol in SMDPs.
Subthalamic nucleus activity dynamics preceding clinical manifestations in a progressive Parkinson’s disease model
Authors: Bertrand Mathilde , Chabardes Stephan , De Leiris Nicolas , Reboulet Ghislaine , Baudin Bruno , Bastin Julien , Piallat Brigitte
Published: January 2024

Background

Parkinson’s disease (PD) diagnosis relies on motor symptoms such as akinesia, rigidity, and tremor, which manifest late in the disease course, contributing to delayed diagnosis. However, cognitive, and limbic manifestations may precede motor symptoms, offering an earlier diagnostic opportunity, but their early kinetics require further characterization. Although high frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) significantly improves motor symptoms, it does not specifically address non-motor symptoms. Here, we aimed to correlate STN activity with the onset of motor, cognitive, and limbic symptoms of PD and propose specific STN-DBS paradigm to address both motor and non-motor symptoms.

Methods

Local field potentials of the STN were recorded in two non-human primates (Macaca fascicularis) performing a behavioral task assessing motor, cognitive, and limbic reward-related behaviors. A progressive model of PD, consisting of small injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.2-0.5mg/kg), was used to characterize behavior for several months until the onset of motor symptoms. Finally, when a stable parkinsonian syndrome was established, the behavioral effects of high- (HFS, 130Hz) and low- (LFS, 4Hz) frequency stimulations were investigated.

Results

After the first MPTP injections, we observed a progressive parkinsonian syndrome from stage 1, asymptomatic, to stage 3 with limbic, cognitive, and motor symptoms. Each stage was associated with specific changes in STN electrophysiological activity. Stage 1 was characterized by a decrease in the power of reward-related gamma/theta oscillations. Stage 2 featured an early decline in motivation and decreased theta-band activity during decision-making. Later, an increase in error on Switch trials was observed, illustrating the stage 2’, along with a decrease in beta-gamma power following movement. Finally, stage 3 was defined by an increase in motor response time while maintaining all the STN neuronal changes. In stage 3, HFS applied in dorsal STN improved motor reaction time, while LFS applied in ventral STN improved motivation.

Conclusion

Our results highlight a progressive timeline in the onset of behavioral parkinsonian manifestations, with limbic symptoms followed by cognitive and then motor symptoms. We identified specific electrophysiological biomarkers in the STN correlating with and preceding the onset of each symptom, providing insights into their pathophysiology. Finally, our results suggest that combined stimulation of HFS in the dorsal STN and LFS in the ventral STN may optimize STN-DBS outcomes, reducing both motor and non-motor symptoms.
Phenotypic screening of covalent compound libraries identifies chloromethyl ketone antibiotics and MiaA as a new target
Authors: Jin Yizhen , Jana Sadhan , Abbasov Mikail E. , Lin Hening
Published: January 2024

The emerging antibiotic resistance requires the development of new antibiotics working on novel bacterial targets. Here, we reported an antibiotic discovery workflow by combining the cysteine-reactive compound library phenotypic screening with activity-based protein profiling, which enables the rapid identification of lead compounds as well as new druggable targets in pathogens. Compounds featuring chloromethyl ketone scaffolds exhibited a notably high hit rate against both gram-negative and gram-positive bacterial strains, but not the more commonly used warheads such as acrylamide or chloroacetamide. Target identification of the lead compound, 10-F05, revealed that its primary targets inS. flexneriare FabH Cys112 and MiaA Cys273. We validated the target relevance through biochemical and genetic interactions. Mechanistic studies revealed modification of MiaA by 10-F05 impair substrate tRNA binding, leading to decreased bacterial stress resistance and virulence. Our findings underscore chloromethyl ketone as a novel antibacterial warhead in covalent antibiotic design. The study showcases that combining covalent compound library phenotypic screening with chemoproteomics is an efficient way to identify new drug targets as well as lead compounds, with the potential to open new research directions in drug discovery and chemical biology.

Graphic Abstract
Reanalysis of published histological data can help to characterize neuronal death after Spinal Cord Injury
Authors: Amezcua Pablo Ruiz , Barranco Nadia Ibáñez , Reigada David , Novillo Algaba Irene , Soto Altea , Barreda-Manso M. Asunción , Galdeano Teresa Muñoz- , Maza Rodrigo M. , Esteban Francisco J. , Nieto Díaz Manuel
Published: January 2024

Spinal cord injury (SCI) is a disabling disorder of the spinal cord resulting from trauma or disease. Neuronal death is a central event in the pathophysiology of spinal cord injury. Despite its importance and the large number of research studies carried out, we only have a fragmentary vision of the process focused on the specific targets of each study. It is our opinion that the research community has accumulated enough information which may be reanalyzed with novel tools to get a much more detailed, integrated vision of neuronal death after SCI. This work embeds this vision by creating NeuroCluedo, an open data repository to store and share images as well as the results from their analysis. We have employed this repository to upload the raw and processed images of spinal cord sections from a mouse model of moderate contusive SCI (Reigada et al., 2015) and used this information to: compare manual-, threshold-, and neuronal network-based neuron identifications; and to explore neuronal death at the injury penumbra 21 days after injury and the neuroprotective effects of the anti-apoptotic drug ucf-101. The results from these analyses i) indicate that the three identification methods yield coherent estimates of the total number of neurons per section; ii) identified the neural network as the optimal method, even in spinal sections with major artifacts and marked autofluorescence associated with spinal damage; iii) characterize neuronal distribution among Rexed laminae in the mice T11; iv) reveal that neuronal death distributes through all the gray matter in the penumbrae sections closer to the injury epicenter but concentrate in the intermediate region in sections located farther away; and that v) antiapoptotic effects of UCF-101 are highest in the intermediate region of the gray substance of the caudal segments closest to the injury epicenter. All methods and results, including raw and processed images, software, macros, and scripts, together with all data matrixes and results have been deposited and documented in the Open Science Framework (OSF) repository Neurocluedo (https://osf.io/n32z9/).
EXO1-mediated ssDNA gap expansion is essential for ATR activation and to maintain viability in BRCA1-deficient cells
Authors: García-Rodríguez Néstor , Domínguez-Pérez María del Carmen , Huertas Pablo
Published: January 2024

DNA replication faces challenges from DNA lesions originated from endogenous or exogenous sources of stress, leading to the accumulation of single-stranded DNA (ssDNA) that triggers the activation of the ATR checkpoint response. To complete genome replication in the presence of damaged DNA, cells employ DNA damage tolerance mechanisms that operate not only at stalled replication forks but also at ssDNA gaps originated by repriming of DNA synthesis downstream of lesions. Here, we demonstrate that human cells accumulate post-replicative ssDNA gaps following replicative stress induction. These gaps, initiated by PrimPol repriming and expanded by the long-range resection factors EXO1 and DNA2, constitute the principal origin of the ssDNA signal responsible for ATR activation upon replication stress, in contrast to stalled forks. Furthermore, we show that EXO1-deficient cells exhibit marked sensitivity to translesion synthesis inhibition, a distinctive characteristic of mutations in proteins essential for repairing ssDNA gaps via template switching, such as BRCA1/2. Strikingly, EXO1 loss results in synthetic lethality when combined with BRCA1 deficiency, but not BRCA2. Indeed, BRCA1-deficient cells become addicted to the overexpression ofEXO1 DNA2orBLM. This dependence on long-range resection unveils a new vulnerability of BRCA1-mutant tumors, shedding light on potential therapeutic targets for these cancers.
Interaction of adenylate cyclase CyaC with regulators Smc01817 and Clr ofSinorhizobium meliloti: cAMP as an ON/OFF trigger in sensor-regulator complexes?
Authors: Klein Robin , Wissig Juliane , Küllmer Katharina , Unden Gottfried
Published: January 2024

The symbiotic bacteriumSinorhizobium meliloticontains a large number of adenylate cyclases (AC) for the control of different life styles. ACs produce cyclic AMP (cAMP) as a secondary messenger. Earlier, the redox responsive membrane-intrinsic AC CyaC has been shown to produce a trimeric signalling complex CyaC×CycR×cAMP-Clr. Here, use of the bacterial two-hybrid system BACTH showed that the LysR-type transcriptional regulator Smc01817 interactsin vivowith CyaC and the general cAMP-regulator Clr, suggesting the formation of a sensor-regulator complex CyaC×Smc01817×cAMP-Clr. Therefore, formation of sensor-regulator complexes from ACs and transcriptional regulators seems to be a means inS. melilotito setup specific signalling routes in a background with a large number of signalling routes applying the same signalling molecule (cAMP). Use of caged cAMP allows to address a specific signalling route and set of regulators, which is at variance with the classical role of cAMP as a diffusing secondary messenger.
Development of blood-cerebrospinal fluid barrier model expressing pharmaceutically important transporters
Authors: Majerova Petra , Khiratkar Krutika , James Kevin , Olesova Dominika , Vegh Jozef , Kovac Andrej
Published: January 2024

We have established and optimized a protocol for the high-yield isolation of primary epithelial cells from rat choroid plexus. The addition of cytosine arabinoside suppressed the growth of contaminating cells, and epithelial culture was grown into a confluent impermeable monolayer within 5-6 days after seeding. To form anin vitroblood-CSF barrier, epithelial cells were plated on inverted coated polycarbonate support of Transwell inserts. Morphologically, the polarized cells remained cuboidal in shape and expressed TJ proteins at a high rate. The filter-grown monolayers displayed transendothelial resistance (TEER) values in the range of 160 to 180 Ω × cm2and remained at this level for 3 days, indicating the persistent formation of continuous TJs. The cells were able to secrete cerebrospinal fluid (CSF) actively. Epithelial cells showed expression of selective influx and efflux transporters. To conclude, our BCSFB model exhibits tight, functional barrier characteristics and shows the functional expression of the pharmaceutically important influx/efflux transporters. The recent model is suitable forin vitroinvestigations of BCSFB and routine pre-clinical drug discovery.
Molecular Cloning and Biochemical Characterisation of a Novel Acidic Laminarinase Derived from Jermuk Hot Spring Metagenome
Authors: Paloyan Ani , Karapetyan Mariam , Grigoryan Hasmik , Krüger Anna , Burkhardt Christin , Antranikian Garabed
Published: January 2024

Laminarinase, an enzyme with a specific affinity for laminarin—a complex polysaccharide found in the cell walls of brown algae and select marine organisms—was investigated in this study. We cloned and characterised a gene encoding a putative glycoside hydrolase family 16 (GH16) laminarinase from the Jermuk hot spring metagenome by heterologous expression inEscherichia coli. The resulting product, named Jermuk-LamM, represents a novel endo-1,3-β-D-glucanase (EC 3.2.1.39) with only 48.1 % amino acid sequence similarity to previously characterised GH16 family members catalogued in the NCBI database. To date, this stands as the sole described endo-1,3-β-D-glucanase within theMarinimicrobiaphylum.

Jermuk-LamM, identified as an acidic laminarinase, exhibits robust enzymatic activity at pH 5.0 and a temperature of 55 °C, maintaining its function for a duration of at least 7 hours. Notably, this enzyme effectively catalyses the hydrolysis of both soluble and insoluble (1,3)-β-D-glucans, as well as (1,3;1,4)-β-D-glucans, displaying a pronounced preference for laminarin. The specificity of Jermuk-LamM lies in its cleavage of 1,3-β-D-glucosidic linkages, yielding monosaccharides, disaccharides, and oligosaccharides. These breakdown products hold the potential for conversion into energy carriers, including alcohols, methane, and hydrogen.

The enzyme’s exceptional specific activities, coupled with its resistance to various additives, render Jermuk-LamM a promising candidate for various industrial applications, encompassing the realms of biofuel and pharmaceutical production.
Perturbing nuclear glycosylation in the mouse preimplantation embryo slows down embryonic growth
Authors: Formichetti Sara , Chitnavis Urvashi , Sadowska Agnieszka , Liu Na , Boskovic Ana , Boulard Matthieu
Published: January 2024

The only known form of intracellular protein glycosylation (O-GlcNAc) is reversible and has been mapped on thousands of cytoplasmic and nuclear proteins, including RNA polymerase II, transcription factors and chromatin modifiers. The O-GlcNAc modification is catalyzed by a single enzyme known as O-GlcNAc Transferase (OGT), that is required for mammalian early development. Remarkably, the regulatory function of protein O-GlcNAcylation in the embryo as well as the embryonic O-GlcNAc proteome remain unknown. Here, we devised a new method to enzymatically remove O-GlcNAc from preimplantation embryonic nuclei, where it accumulates coincidently with embryonic genome activation (EGA). Unexpectedly, the depletion of nuclear O-GlcNAc to undetectable levels has no impact on EGA, but dampens the transcriptional activation of the translational machinery, and triggers a spindle checkpoint response. These molecular alterations were phenotypically associated with a developmental delay starting from early cleavage stages and persisting after embryo implantation, establishing a novel link between nuclear glycosylation and embryonic growth.
Transcranial Photobiomodulation on the Left Prefrontal Cortex Enhances Mandarin Chinese L1 and L2 Complex Sentence Processing Performances
Authors: Yang Mingchuan , Liu Yang , Yue Zhaoqian , Yang Guang , Jiang Xu , Cai Yimin , Zhang Yuqi , Yang Xiujie , Li Dongwei , Chen Luyao
Published: January 2024

This study investigated the causal effect of transcranial photobiomodulation (tPBM) over the left prefrontal cortex (LPFC) on syntactically complex Mandarin Chinese first language (L1) and second language (L2) sentence processing performances. Two (L1 and L2) groups of participants (thirty per group) were recruited to receive the double-blind, sham-controlled tPBM intervention, followed by the sentence processing, the verbal working memory (WM), and the visual WM tasks. Results revealed a consistent pattern for both groups: (a) tPBM enhanced sentence processing performance but not verbal WM and visual WM performance; (b) Participants with lower sentence processing performances under sham tPBM benefited more from active tPBM. Taken together, the current study substantiated that tPBM enhanced L1 and L2 sentence processing ability directly without verbal WM interference, and would serve as a promising and cost-effective noninvasive brain stimulation (NIBS) tool for future applications on upregulating the human language faculty.

Highlights

The first study that applies tPBM to (complex) sentence processing.

tPBM enhances sentence processing performances in both Mandarin L1 & L2 speakers.

tPBM directly enhances sentence processing without the interference of verbal WM.

A causal role of LPFC for sentence processing through active tPBM.

Opening up the promising application prospect for tPBM on sentence processing.