bluuebunny/crossref_metadata_2025 huggingface dataset:
Laparoscopic Large Hiatal Hernia Repair With RefluxStop: Outcomes of Six Months Follow-up in Thirty Patients
Authors: Fringeli Yannick , Linas Ioannis , Kessler Ulf , Zehetner Joerg
Published: February 2024

Objective:

The antireflux surgical technique with the RefluxStop device is one of the latest approaches to treating patients with gastroesophageal reflux disease (GERD). The aim of this study was to assess the safety and feasibility of laparoscopic hiatal hernia (HH) repair with the RefluxStop device in patients with GERD and concurrent large HH (≥4 cm).

Patients and Methods:

A retrospective chart review was performed for the first 30 patients with a large HH who consented and underwent HH surgery with the RefluxStop device. The operative technique and outcomes were evaluated to assess safety and feasibility, HH recurrence, dysphagia, and patient satisfaction.

Results:

Between May 2020 and April 2022, 30 patients underwent laparoscopic HH repair with the RefluxStop device. All patients had typical symptoms of GERD, such as heartburn and regurgitation, and 15 patients (50%) had preoperative dysphagia. Median HH size was 5 cm (interquartile range, 4 to 5). Median operating time was 56 minutes (interquartile range, 52 to 63), with no intra and postoperative complications related to the device. One patient required laparotomy due to adhesions and associated bleeding when accessing the abdomen. All patients had postoperative imaging (video fluoroscopy) on postoperative day 1 and at 3 months, confirming the correct location of the RefluxStop device. One patient (3.3%) needed postoperative balloon dilatation due to severe dysphagia. Reflux symptoms (heartburn and acid regurgitation) resolved significantly in all patients (P < 0.001) at 6 months. One episode of recurrence of HH (3.3%) occurred during the follow-up period of 6 months.

Conclusion:

This study demonstrates the short-term safety and feasibility of laparoscopic HH repair with the RefluxStop device in patients with large HH, with a low rate of postoperative dysphagia and subsequent improvement or resolution of reflux symptoms in all patients.
Transmission and Non-transmission of Melanoma From Deceased Solid Organ Donors to Transplant Recipients: Risks and Missed Opportunities
Authors: Rosales Brenda Maria , Hedley James , De La Mata Nicole , Cavazzoni Elena , Vajdic Claire M. , Thompson John F. , Kelly Patrick J. , Wyburn Kate , Webster Angela C.
Published: February 2024

Background.

Biovigilance concerns are in tension with the need to increase organ donation. Cancer transmission risk from donor to recipient may be overestimated, as non-transmission events are rarely reported. We sought to estimate melanoma transmission risk in deceased organ donation and identify missed opportunities for donation in an Australian cohort with high melanoma prevalence.

Methods.

We used a population-based approach and linked deceased organ donors, transplant recipients, and potential donors forgone, 2010–2018, with the Central Cancer Registry (CCR), 1976–2018. We identified melanomas using ICD-O-3 classification, assessed the probability of transmission, and compared suspected melanoma history in potential donors forgone with melanoma notifications in the CCR.

Results.

There were 9 of 993 donors with melanoma in CCR; 4 in situ low-risk and 5 invasive high-to-unacceptable risk. Four were unrecognized before donation. Of 16 transplant recipients at risk, we found 0 of 14 transmission events (2 recipients had insufficient follow-up). Of 35 of 3588 potential donors forgone for melanoma risk alone, 17 were otherwise suitable for donation; 6 of 35 had no melanoma in CCR, 2 of 35 had in situ melanomas and 9 of 35 had thin invasive melanomas (localized, ≤0.8 mm thickness).

Conclusions.

Our findings contribute to current evidence that suggests donors with melanomas of low metastatic potential may provide an opportunity to safely increase organ donation and so access to transplantation.
Effect of Behavioral Health Disorders on Surgical Outcomes in Cancer Patients
Authors: Katayama Erryk S , Woldesenbet Selamawit , Munir Muhammad Musaab , Endo Yutaka , Rawicz-Pruszyński Karol , Khan Muhammad Muntazir Mehdi , Tsilimigras Diamantis , Dillhoff Mary , Cloyd Jordan , Pawlik Timothy M
Published: February 2024

BACKGROUND:

Behavioral health disorders (BHDs) can often be exacerbated in the setting of cancer. We sought to define the prevalence of BHD among cancer patients and characterize the association of BHD with surgical outcomes.

STUDY DESIGN:

Patients diagnosed with lung, esophageal, gastric, liver, pancreatic, and colorectal cancer between 2018 and 2021 were identified within Medicare Standard Analytic Files. Data on BHD defined as substance abuse, eating disorder, or sleep disorder were obtained. Postoperative textbook outcomes (ie no complications, prolonged length of stay, 90-day readmission, or 90-day mortality), as well as in-hospital expenditures and overall survival were assessed.

RESULTS:

Among 694,836 cancer patients, 46,719 (6.7%) patients had at least 1 BHD. Patients with BHD were less likely to undergo resection (no BHD: 23.4% vs BHD: 20.3%; p < 0.001). Among surgical patients, individuals with BHD had higher odds of a complication (odds ratio [OR] 1.32 [1.26 to 1.39]), prolonged length of stay (OR 1.36 [1.29 to 1.43]), and 90-day readmission (OR 1.57 [1.50 to 1.65]) independent of social vulnerability or hospital-volume status resulting in lower odds to achieve a TO (OR 0.66 [0.63 to 0.69]). Surgical patients with BHD also had higher in-hospital expenditures (no BHD: $16,159 vs BHD: $17,432; p < 0.001). Of note, patients with BHD had worse long-term postoperative survival (median, no BHD: 46.6 [45.9 to 46.7] vs BHD: 37.1 [35.6 to 38.7] months) even after controlling for other clinical factors (hazard ratio 1.26 [1.22 to 1.31], p < 0.001).

CONCLUSIONS:

BHD was associated with lower likelihood to achieve a postoperative textbook outcome, higher expenditures, as well as worse prognosis. Initiatives to target BHD are needed to improve outcomes of cancer patients undergoing surgery.
ICTV Virus Taxonomy Profile: Kolmioviridae 2024
Authors: Kuhn Jens H. , Babaian Artem , Bergner Laura M. , Dény Paul , Glebe Dieter , Horie Masayuki , Koonin Eugene V. , Krupovic Mart , Paraskevopoulou Sofia , de la Peña Marcos , Smura Teemu , Hepojoki Jussi
Published: February 2024

Kolmioviridae is a family for negative-sense RNA viruses with circular, viroid-like genomes of about 1.5–1.7 kb that are maintained in mammals, amphibians, birds, fish, insects and reptiles. Deltaviruses, for instance, can cause severe hepatitis in humans. Kolmiovirids encode delta antigen (DAg) and replicate using host-cell DNA-directed RNA polymerase II and ribozymes encoded in their genome and antigenome. They require evolutionary unrelated helper viruses to provide envelopes and incorporate helper virus proteins for infectious particle formation. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Kolmioviridae, which is available at ictv.global/report/kolmioviridae.
Evaluating the effect of rapamycin treatment in Alzheimer's Disease and aging usingin vivoimaging: the ERAP phase IIa clinical study protocol
Authors: Svensson Jonas E. , Bolin Martin , Thor Daniel , Williams Pete A. , Brautaset Rune , Carlsson Marcus , Sörensson Peder , Marlevi David , Spin-Neto Rubens , Probst Monika , Hagman Göran , Morén Anton Forsberg , Kivipelto Miia , Plavén-Sigray Pontus
Published: February 2024

Background

Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and pre-clinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer’s disease have shown beneficial effects of rapamycin including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The “Evaluating rapamycin treatment in Alzheimer’s disease using positron emission tomography” (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer’s disease.

Methods

ERAP is a six month long, single-arm, open-label, phase IIa biomarker driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer’s disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [18F]FDG positron emission tomography. Secondary endpoints will be change in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function.

Discussion

The ERAP study is a clinical trial usingin vivoimaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer’s disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease modifying treatment in Alzheimer’s disease.

Trial Registration

ClinicalTrials.govIDNCT06022068, date of registration 2023-08-30
Pharmacodynamic evaluation of AUM001/tinodasertib, an oral inhibitor of mitogen-activated protein kinase (MAPK)-interacting protein kinase 1, 2 (MNK1/2) in preclinical models and tissues from a Phase 1 clinical study
Authors: Gan Bong Hwa , Lee Lay Hoon , Takeda Reika , Yasin Maryam , Teneggi Vincenzo , Ethirajulu Kantharaj , Yeo Pauline , Umrani Dhananjay , Pendharkar Vishal , Lim Darren Wan Teck , Li Greg , Lu Qingshu , Cao Yang , Nellore Ranjani , Blanchard Stephanie , Hentze Hannes , Novotny-Diermayr Veronica
Published: February 2024

Mitogen-activated protein kinase (MAPK) interacting kinase (MNK) inhibitors affect cap-dependent mRNA translation by blocking the phosphorylation of RNA-binding proteins such as the eukaryotic initiation factor 4E (eIF4E). Phosphorylation on serine (Ser) 209 of eIF4E causes hyperactivation and dysregulation of mRNA translation, which is a hallmark of numerous malignancies. AUM001/Tinodasertib (ETC-206) is a selective and potent oral kinase inhibitor of MNK1 and MNK2 (IC50of 64 and 86 nM, respectively), inducing dose-dependent inhibition of eIF4E phosphorylation on Ser209 (p-eIF4E) with an IC50of 0.8 µM in K562-eIF4E cells. In mice, single oral doses of ∼12.5 mg/kg led to rapid (1-2 h post-dose) ∼70% inhibition of p-eIF4E in different normal or tumor tissues at a plasma concentration of 8.6 μM. However, in peripheral blood mononuclear cells (PBMCs), obtained from human healthy volunteers (HVs) in a Ph1 study, single oral doses of 10 or 20 mg ETC-206 did not show inhibitory activity up to 12 h post-dose, instead ETC-206 caused a statistically significant (p=0.0037) p-eIF4E inhibition in PBMCs of 24% at 24 h post-dose with 10 mg, and an inhibition of ≥27 % up to 52% was seen in 11/14 subjects in the 20 mg group where ETC-206 plasma concentrations remained above the IC50for p-eIF4E (1.7 µM) for 30 h. While in mouse pharmacodynamic (PD) activity was also shown in tumor, skin, and hair follicles (HFs), in human tissues, PBMCs showed a trend for delayed PD inhibition and skin was not a suitable surrogate. Analysis of pharmacokinetic (PK) and PD relationships shown herein demonstrate excellent pharmaceutical properties of ETC-206 which has now advanced to Ph2 clinical trials (NCT05462236).
A new look at functional beta diversity
Authors: Ricotta Carlo , Pavoine Sandrine
Published: February 2024

The variability in species composition among a set of sampling sites, or beta diversity, is considered a key signature of the ecological processes that shape the spatial structure of species assemblages.

In this paper, we propose to decompose this variability into three additive components: i) the standard compositional similarity between individuals of the same species among sites, ii) the degree of functionaldissimilaritybetween individuals of distinct species among sites, and iii) the degree of functionalsimilaritybetween individuals of distinct species among sites. These three components can be used to portray the functional resemblance among sites on a ternary diagram.

The potential of this method is shown with real data on the functional turnover of Alpine species along a primary succession on glacial deposits in northern Italy.

Synthesis. With the resulting ternary diagram of ‘functional resemblance’ we can relate various aspects of taxonomic and functional variability among sites to community assembly processes more completely than just looking at individual components.
Evaluation of commonin vitroassays for the prediction of oral bioavailability and hepatic metabolic clearance in humans
Authors: Fagerholm Urban
Published: February 2024

Introduction

Intrinsic hepatic metabolic clearance (CLint) measured with human hepatocytes, apparent intestinal permeability (Papp) obtained using the Caco-2 model, unbound fraction in plasma (fu) and blood-to-plasma concentration ratio (Cbl/Cpl) are commonly used for predicting the hepatic clearance (CLH) and oral bioavailability (F) of drug candidates in humans. The primary objective was to select drugs whosein vitrohepatocyte CLint, Caco-2 Papp, fuand Cbl/Cplhave been measured in various laboratories and studies, and estimate correlation coefficients (R2) for predicted and observed F and log plasma CLH. Secondary aims were to estimate the laboratory/study variability and its impact on predictions and to compare results toin silicoand animal model-based predictions.

Materials and Methods

A literature search was done in order to find unbound hepatocyte CLint, (and corresponding predictedin vivoCLint), Caco-2 Papp, fuand Cbl/Cpldata. Compounds with multiple measurements for the four assays, without significantin vivosolubility/dissolution limitations and with knownin vivoCLHand F, were selected. Min, max and mean estimates were used in the analysis.

Results and Discussion

Thirty-two compounds with data (in total 561 estimates) produced by 21 major pharmaceutical companies and universities met the inclusion criteria. The predicted vs observed R2for log mean CLint, log mean CLHand mean F were 0.32, 0.08 and 0.20, respectively. Exclusion of atenolol increased the R2for CLHto 0.20. R2-values were considerably lower than those presented in many studies, which seems to be explained by selection bias (choosing favorable reference values). There was considerable interstudy variability for measured and predicted CLint(80- and 1,476-fold mean and max differences, respectively) and measured fu(6.6- and 50-fold mean and max differences, respectively). For F, higher predictive performance was found forin silico(Q2=0.58; head-to-head) and animalin vivomodels (R2=0.30).

Conclusion

The combination of data from many laboratories and the use of mean values resulted in reduced selection bias and predictive accuracy. Overall, the predictive accuracy (here R2) for log CLint, log CLHand F was low to moderately low (0.08-0.32). The halved R2compared to individual studies where high performance was demonstrated seems to be explained be selection bias (enabled by large data variability). Animalin vivomodels, and in particular,in silicomethodology, outperformedin vitromethodology for the prediction of F in man.
Perinatal Brain Injury Triggers Niche-Specific Changes to Cellular Biogeography
Authors: Tahmasian Nareh , Feng Min Yi , Arbabi Keon , Rusu Bianca , Cao Wuxinhao , Kukreja Bharti , Lubotzky Asael , Wainberg Michael , Tripathy Shreejoy J. , Kalish Brian T.
Published: February 2024

Preterm infants are at risk for brain injury and neurodevelopmental impairment due, in part, to white matter injury following chronic hypoxia exposure. However, the precise molecular mechanisms by which perinatal hypoxia disrupts early neurodevelopment are poorly understood. Here, we constructed a brain-wide map of the regenerative response to newborn brain injury using high-resolution imaging-based spatial transcriptomics to analyze over 1.3 million cells in a mouse model of chronic neonatal hypoxia. Additionally, we developed a new method for inferring condition-associated differences in cell type spatial proximity, enabling the identification of niche-specific changes in cellular architecture. We observed hypoxia-associated changes in region-specific cell states, cell type composition, and spatial organization. Importantly, our analysis revealed mechanisms underlying reparative neurogenesis and gliogenesis, while also nominating pathways that may impede circuit rewiring following perinatal hypoxia. Altogether, our work provides a comprehensive description of the molecular response to newborn brain injury.
Evoked Resonant Neural Activity Long-Term Dynamics can be Reproduced by a Computational Model with Vesicle Depletion
Authors: Sermon James J. , Wiest Christoph , Tan Huiling , Denison Timothy , Duchet Benoit
Published: February 2024

Subthalamic deep brain stimulation (DBS) robustly generates high-frequency oscillations known as evoked resonant neural activity (ERNA). Recently the importance of ERNA has been demonstrated through its ability to predict the optimal DBS contact in the subthalamic nucleus in patients with Parkinson’s disease. However, the underlying mechanisms of ERNA are not well understood, and previous modelling efforts have not managed to reproduce the wealth of published data describing the dynamics of ERNA. Here, we therefore aim to present a minimal model capable of reproducing the characteristics of the slow ERNA dynamics published to date. We make biophysically-motivated modifications to the Kuramoto model and fit its parameters to the slow dynamics of ERNA obtained from data. We further validate the model against experimental data from Parkinson’s disease patients by simulating variable stimulation and medication states, as well as the response of individual neurons. Our results demonstrate that it is possible to reproduce the slow dynamics of ERNA with a single neuronal population, and, crucially, with vesicle depletion as the key mechanism behind the ERNA frequency decay. We provide a series of predictions from the model that could be the subject of future studies for further validation.

Author Summary

ERNA is a high amplitude response to stimulation of deep brain structures, with a frequency over twice that of the frequency of stimulation. While the underlying mechanisms of ERNA are still unclear, recent findings have demonstrated its importance as the best indicator of which stimulation contact to select for DBS therapy in patients with Parkinson’s disease. Previous modelling studies of ERNA focus on the immediate responses to stimulation (<200ms) and rely on interconnected neural structures and delays. Our work shows that the long-term (on the scale of one or more seconds) ERNA response to continuous stimulation can be modelled using a single neural structure. The proposed model also captures the long-term frequency and amplitude characteristics of ERNA with variable stimulation and medication paradigms. The key features of the model, in particular the depletion of vesicles carrying neurotransmitters between neurons by high-frequency stimulation, may provide insights into the underlying mechanisms of ERNA and inform future investigations into this neural response.
Dynamic Clinical Success Rates for Drugs in the 21st Century
Authors: Zhou Ying , Zhang Yintao , Chen Zhen , Huang Shijie , Li Yinghong , Fu Jianbo , Zhang Hongning , Zhao Donghai , Lian Xichen , Zhou Yuan , Shen Xinyi , Qiu Yunqing , Han Lianyi , Zhu Feng
Published: February 2024

In clinical drug development, two fundamental questions remain unanswered: what is the success rate of drugs in clinical trial? how does such rate change over time? Herein, a systematic analysis on the dynamic change of drugs’clinical success rates(ClinSRs) using data from 20,398 clinical trial pipelines of 9,682 unique molecular entities during the past two decades was presented. Our analysis discovered that ClinSRs had been declining since the beginning of 21st century, and hit the bottom in recent years even substantially lower than previous estimates. In-depth assessments further reported great variation among the ClinSRs of various diseases, developmental strategies, and drug modalities. A platform ‘ClinSR.org’ (http://ClinSR.idrblab.org/) was finally constructed online to enable the illustration of how ClinSR dynamically changes over time, automated update of ClinSR for the coming decade, and customized calculation of ClinSRs for any drug group of interest. In sum, this study met the critical demand for accurate, timely and persistent assessment of ClinSR, for now and the future, to aid pharmaceutical and economic decision making.
A Curated Compendium of Transcriptomic Data for the Exploration of Neocortical Development
Authors: Sonthalia Shreyash , Adkins Ricky S. , Orvis Joshua , Li Guangyan , Blanco Xoel Mato , Casella Alex , Liu Jinrui , Stein-O’Brien Genevieve , Caffo Brian , Hertzano Ronna , Mahurkar Anup , Gillis Jesse , Werner Jonathan , Ma Shaojie , Micali Nicola , Sestan Nenad , Rakic Pasko , Santpere Gabriel , Ament Seth A. , Colantuoni Carlo
Published: February 2024

Vast quantities of multi-omic data have been produced to characterize the development and diversity of cell types in the cerebral cortex of humans and other mammals. To more fully harness the collective discovery potential of these data, we have assembled gene-level transcriptomic data from 188 published studies of neocortical development, including the transcriptomes of ∼30 million single-cells, extensive spatial transcriptomic experiments and RNA sequencing of sorted cells and bulk tissues:nemoanalytics.org/landing/neocortex. Applying joint matrix decomposition (SJD) to mouse, macaque and human data in this collection, we defined transcriptome dynamics that are conserved across mammalian neurogenesis and which elucidate the evolution of outer, or basal, radial glial cells. Decomposition of adult human neocortical data identified layer-specific signatures in mature neurons and, in combination with transfer learning methods in NeMO Analytics, enabled the charting of their early developmental emergence and protracted maturation across years of postnatal life. Interrogation of data from cerebral organoids demonstrated that while broad molecular elements ofin vivodevelopment are recapitulatedin vitro, many layer-specific transcriptomic programs in neuronal maturation are absent. We invite computational biologists and cell biologists without coding expertise to use NeMO Analytics in their research and to fuel it with emerging data (carlocolantuoni.org).
The DREAM implant: A Lightweight, Modular and Cost-Effective Implant System for Chronic Electrophysiology in Head-fixed and Freely Behaving Mice
Authors: Schröder Tim , Taylor Robert , Abd El Hay Muad , Nemri Abdellatif , França Arthur , Battaglia Francesco , Tiesinga Paul , Schölvinck Marieke L. , Havenith Martha N.
Published: February 2024

Chronic electrophysiological recordings in rodents have significantly improved our understanding of neuronal dynamics and their behavioral relevance. However, current methods for chronically implanting probes present steep trade-offs between cost, ease of use, size, adaptability and long-term stability.

Introducing a lightweight, cost-effective probe implant system for chronic electrophysiology in rodents, optimized for ease of use, probe recovery, experimental versatility and compatibility with behavior.

This protocol introduces a novel chronic probe implant system for mice called the DREAM (Dynamic, Recoverable, Economical, Adaptable and Modular), designed to overcome the trade-offs associated with currently available options. The system provides a lightweight, modular and cost-effective solution with standardized hardware elements that can be combined and implanted in straightforward steps and explanted safely for recovery and multiple re-use of probes, significantly reducing experimental costs.

The DREAM implant system integrates three hardware modules: (1) a microdrive that can carry all standard silicon probes, allowing experimenters to adjust recording depth across a travel distance of up to 7mm; (2) a 3D-printable, open-source design for a wearable Faraday cage covered in copper mesh for electrical shielding, impact protection and connector placement, and (3) a miniaturized head-fixation system for improved animal welfare and ease of use. The corresponding surgery protocol was optimized for speed (total duration: 2 hours), probe safety and animal welfare.

The resulting implants had minimal impact on animals’ behavioral repertoire, were easily applicable in freely moving and head-fixed contexts and delivered clearly identifiable spike waveforms and healthy neuronal responses for weeks of data collection post-implant. Infections and other surgery complications were extremely rare.

As such, the DREAM implant system is a versatile, cost-effective solution for chronic electrophysiology in mice, enhancing animal well-being, and enabling more ethologically sound experiments. Its design simplifies experimental procedures across various research needs, increasing accessibility of chronic electrophysiology in rodents to a wide range of research labs.
Intracellular Lactate Dynamics inDrosophilaGlutamatergic Neurons
Authors: Price Matthew S. , Rastegari Elham , Gupta Richa , Vo Katie , Moore Travis I. , Venkatachalam Kartik
Published: February 2024

Rates of lactate production and consumption reflect the metabolic state of many cell types, including neurons. Here, we investigate the effects of nutrient deprivation on lactate dynamics inDrosophilaglutamatergic neurons by leveraging the limiting effects of the diffusion barrier surrounding cells in culture. We found that neurons constitutively consume lactate when availability of trehalose, the glucose disaccharide preferred by insects, is limited by the diffusion barrier. Acute mechanical disruption of the barrier reduced this reliance on lactate. Through kinetic modeling and experimental validation, we demonstrate that neuronal lactate consumption rates correlate inversely with their mitochondrial density. Further, we found that lactate levels in neurons exhibited temporal correlations that allowed prediction of cytosolic lactate dynamics after the disruption of the diffusion barrier from pre-perturbation lactate fluctuations. Collectively, our findings reveal the influence of diffusion barriers on neuronal metabolic preferences, and demonstrate the existence of temporal correlations between lactate dynamics under conditions of nutrient deprivation and those evoked by the subsequent restoration of nutrient availability.
Mint/X11 PDZ domains from non-bilaterian animals recognize and bind CaV2 calcium channel C-terminiin vitro.
Authors: Harracksingh Alicia N , Singh Anhadvir , Mayorova Tatiana , Bejoy Brian , Hornbeck Jillian , Elkhatib Wassim , McEdwards Gregor , Gauberg Julia , Taha Abdul Rahman Walid , Islam Ishrat M , Erclik Ted , Currie Mark A , Noyes Marcus , Senatore Adriano
Published: February 2024

PDZ domain mediated interactions with voltage-gated calcium (CaV) channel C-termini play important roles in localizing membrane Ca2+signaling. The first such interaction was described between the scaffolding protein Mint-1 and CaV2.2 in mammals. In this study, we show through variousin silicoanalyses that Mint is an animal-specific gene with a highly divergent N-terminus but a strongly conserved C-terminus comprised of a phosphotyrosine binding domain, two tandem PDZ domains (PDZ-1 and PDZ-2), and a C-terminal auto-inhibitory element that binds and inhibits PDZ-1. In addition to CaV2 channels, most genes that interact with Mint are also deeply conserved including amyloid precursor proteins, presenilins, neurexin, and CASK and Veli which form a tripartite complex with Mint in bilaterians. Through yeast and bacterial 2-hybrid experiments, we show that Mint and CaV2 channels from cnidarians and placozoans interactin vitro, andin situhybridization revealed co-expression in dissociated neurons from the cnidarianNematostella vectensis. Unexpectedly, the Mint orthologue from the ctenophoreHormiphora californiensisstrongly binds the divergent C-terminal ligands of cnidarian and placozoan CaV2 channels, despite neither the ctenophore Mint, nor the placozoan and cnidarian orthologues, binding the ctenophore CaV2 channel C-terminus. Altogether, our analyses suggest that the capacity of Mint to bind CaV2 channels predates pre-bilaterian animals, and that evolutionary changes in CaV2 channel C-terminal sequences resulted in altered binding modalities with Mint.
Volume electron microscopy reveals 3D synaptic nanoarchitecture in postmortem human prefrontal cortex
Authors: Glausier Jill R. , Bouchet-Marquis Cedric , Maier Matthew , Banks-Tibbs Tabitha , Wu Ken , Ning Jiying , Melchitzky Darlene , Lewis David A. , Freyberg Zachary
Published: February 2024

Synaptic function is directly reflected in quantifiable ultrastructural features using electron microscopy (EM) approaches. This coupling of synaptic function and ultrastructure suggests thatin vivosynaptic function can be inferred from EM analysis ofex vivohuman brain tissue. To investigate this, we employed focused ion beam-scanning electron microscopy (FIB-SEM), a volume EM (VEM) approach, to generate ultrafine-resolution, three-dimensional (3D) micrographic datasets of postmortem human dorsolateral prefrontal cortex (DLPFC), a region with cytoarchitectonic characteristics distinct to human brain. Synaptic, sub-synaptic, and organelle measures were highly consistent with findings from experimental models that are free from antemortem or postmortem effects. Further, 3D neuropil reconstruction revealed a unique, ultrastructurally-complex, spiny dendritic shaft that exhibited features characteristic of heightened synaptic communication, integration, and plasticity. Altogether, our findings provide critical proof-of-concept data demonstrating thatex vivoVEM analysis is an effective approach to inferin vivosynaptic functioning in human brain.
Discovery of the First-in-class G9a/GLP PROTAC Degrader
Authors: Velez Julia , Han Yulin , Yim Hyerin , Yang Peiyi , Deng Zhijie , Park Kwang-su , Kabir Md , Kaniskan H. Ümit , Xiong Yan , Jin Jian
Published: February 2024

Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and non-catalytic oncogenic functions of G9a/GLP. As such, G9a/GLP catalytic inhibitors have displayed limited anticancer activity. Here, we report the discovery of the first-in-class G9a/GLP proteolysis targeting chimera (PROTAC) degrader,10(MS8709), as a potential anticancer therapeutic.10induces G9a/GLP degradation in a concentration-, time, and ubiquitin-proteasome system (UPS)-dependent manner, does not alter the mRNA expression of G9a/GLP and is selective for G9a/GLP over other methyltransferases. Moreover,10displays superior cell growth inhibition to the parent G9a/GLP inhibitor UNC0642 in prostate, leukemia, and lung cancer cells and has suitable mouse pharmacokinetic properties forin vivoefficacy studies. Overall,10is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.

Graphical Abstract
Cerebrovascular reactivity dispersion as a new biomarker of recent stroke symptomatology in moyamoya
Authors: Han Caleb , Richerson Wesley T. , Garza Maria , Rodeghier Mark , Mishra Murli , Davis L. Taylor , Fusco Matthew , Chitale Rohan , Shiino Shuhei , Jordan Lori C. , Donahue Manus J.
Published: February 2024

Background

Moyamoya disease (MMD) is a non-atherosclerotic intracranial steno-occlusive condition placing patients at high risk for ischemic stroke. Direct and indirect surgical revascularization can improve blood flow in MMD; however, randomized trials demonstrating efficacy have not been performed and biomarkers of parenchymal hemodynamic impairment are needed to triage patients for interventions and evaluate post-surgical efficacy. We test the hypothesis that hypercapnia-induced maximum cerebrovascular reactivity (CVRMAX) and the more novel indicator cerebrovascular reactivity (CVR) response time (CVRDELAY), both assessed from time-regression analyses of non-invasive hypercapnic imaging, correlate with recent focal ischemic symptoms.

Methods

Hypercapnic reactivity medical resonance imaging (blood oxygenation level-dependent; echo time=35ms; spatial resolution=3.5×3.5×3.5mm) and catheter angiography assessments of cortical reserve capacity and vascular patency, respectively, in MMD participants (n=73) were performed in sequence. Time regression analyses were applied to quantify CVRMAXand CVRDELAY. Symptomatology information for each hemisphere (n=109) was categorized into symptomatic (ischemic symptoms within six months) or asymptomatic (no history of ischemic symptoms) and logistic regression analysis assessed the association of CVR metrics with ischemic symptoms after controlling for age and sex.

Results

Symptomatic hemispheres displayed lengthened CVRDELAY(p<0.001), which was more discriminatory between hemispheres than CVRMAX(p=0.037). CVRDELAY(p<0.001), but not CVRMAX(p=0.127), was found to be sensitively related to age in asymptomatic tissue (0.33-unit increase/year); age-dependent normative ranges are presented to enable quantitative assessment of patient-specific impairment. Furthermore, the area under the receiver operating characteristic curves shows that CVRDELAYpredicts ischemic symptoms (p<0.001), whereas CVRMAXdoes not (p=0.056).

Conclusion

Findings support that CVR metrics are uniquely altered in hemispheres with recent ischemic symptoms, motivating the investigation of CVR as a surrogate of ischemic symptomatology and treatment efficacy.
Psychological status of medical students and interns in the wake of the armed conflict of April 2023 in Sudan. A cross-sectional study
Authors: Abdulhamid Salaheddin M. , Almokdad Faris Kh. , Ahmed Razan J. Q. , Elbashir Rawah M. A. M. , Suleiman Yousif Ali Ahmed ,   SudaMedReCollab group
Published: February 2024

The ongoing civil war in Sudan of April 2023 has erupted as two belligerent groups vie for the position of ruler in the country, resulting in severe detrimental effects throughout the population, from deaths to property losses to severe deterioration of the already strained infrastructures of the country, to the sheer psychological trauma from observing and suffering the ongoing dramatic events. A subgroup is the medical students and interns in Sudan, who suffered direct losses in every regard, from sheer psychological distress to deaths, with material losses and career disruptions. We believe this is a group that should be paid due attention. This study aims to determine whether certain elements can be viewed as correlates of the psychological disorders we expect to see prevalent and their prevalences.

An online cross-sectional study was undertaken using several sampling methods to reach as far as we possibly could under the circumstances, with a structured questionnaire containing items divided between demographics, what we perceive to be factors, and scales (PHQ-9, GAD-7, AIS-8, and ITQ). The Survey was conducted from September 11thto 30th, 2023, resulting in 7306 responses, of which 665 were excluded. A sample of 6641 were included, of which 2370 (35.7%) were males and 4271 (64.3%) were females. We found prevalences of 33.7% for depression, 22.4% for anxiety, 13.6% for PTSD, and 59.5% for Insomnia, correlating with several factors, noted to impact the psychological health of our sample. Our findings suggest the need for purposeful, directed interventions to mitigate the impact of this conflict, and all that may follow.
Development and Application of Natural Language Processing on Unstructured Data in Hypertension: A Scoping Review
Authors: Ye Jiancheng , He Lu , Hai Jiarui , Xu Chengqi , Ding Sirui , Beestrum Molly
Published: February 2024

Background

Hypertension is a global health concern with a vast body of unstructured data, such as clinical notes, diagnosis reports, and discharge summaries, that can provide valuable insights. Natural Language Processing (NLP) has emerged as a powerful tool for extracting knowledge from unstructured data. This scoping review aims to explore the development and application of NLP on unstructured clinical data in hypertension, synthesizing existing research to identify trends, gaps, and underexplored areas for future investigation.

Methods

We conducted a systematic search of electronic databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ACM Digital Library, and IEEE Xplore Digital Library, to identify relevant studies published until the end of 2022. The search strategy included keywords related to hypertension, NLP, and unstructured data. Data extraction included study characteristics, NLP methods, types of unstructured data sources, and key findings and limitations.

Results

The initial search yielded 951 articles, of which 45 met the inclusion criteria. The selected studies spanned various aspects of hypertension, including diagnosis, treatment, epidemiology, and clinical decision support. NLP was primarily used for extracting clinical information from unstructured electronic health records (EHRs) documents and text classification. Clinical notes were the most common sources of unstructured data. Key findings included improved diagnostic accuracy and the ability to comprehensively identify hypertensive patients with a combination of structured and unstructured data. However, the review revealed a lack of more advanced NLP techniques used in hypertension, generalization of NLP outside of benchmark datasets, and a limited focus on the integration of NLP tools into clinical practice.

Discussion

This scoping review highlights the diverse applications of NLP in hypertension research, emphasizing its potential to transform the field by harnessing valuable insights from unstructured data sources. There is a need to adopt and customize more advanced NLP for hypertension research. Future research should prioritize the development of NLP tools that can be seamlessly integrated into clinical settings to enhance hypertension management.

Conclusion

NLP demonstrates considerable promise in gleaning meaningful insights from the vast expanse of unstructured data within the field of hypertension, shedding light on diagnosis, treatment, and the identification of patient cohorts. As the field advances, there is a critical need to promote the use and development of advanced NLP methodologies that are tailored to hypertension and validated on real-world unstructured data.
Neuromodulatory effects on synchrony and network reorganization in networks of coupled Kuramoto oscillators
Authors: Aktay Sinan , Sander Leonard M. , Zochowski Michal
Published: February 2024

Neuromodulatory processes in the brain can critically change signal processing on a cellular level leading to dramatic changes in network level reorganization. Here, we use coupled non-identical Kuramoto oscillators to investigate how changes in the shape of phase response curves from Type 1 to Type 2, mediated by varying ACh levels, coupled with activity dependent plasticity may alter network reorganization. We first show that when plasticity is absent, the Type 1 networks, as expected, exhibit asynchronous dynamics with oscillators of the highest natural frequency robustly evolving faster in terms of their phase dynamics. At the same time, the Type 2 networks synchronize, with oscillators locked so that the ones with higher natural frequency have a constant phase lead as compared to the ones with lower natural frequency. This relationship establishes a robust mapping between the frequency and oscillators’ phases in the network, leading to structure/frequency mapping when plasticity is present. Further we show that while connection plasticity can produce stable synchrony (so called splay states) in Type 1 networks, the structure/frequency reorganization observed in Type 2 networks is not present.
Neural pathways and computations that achieve stable contrast processing tuned to natural scenes
Authors: Gür Burak , Ramirez Luisa , Cornean Jacqueline , Thurn Freya , Molina-Obando Sebastian , Ramos-Traslosheros Giordano , Silies Marion
Published: February 2024

Natural scenes are highly dynamic, challenging the reliability of visual processing. Yet, humans and many animals perform accurate visual behaviors, whereas computer vision devices struggle with changing environments. How does animal vision achieve this? Here, we reveal the algorithms and mechanisms of rapid luminance gain control inDrosophila,resulting in stable visual processing. We identify the dendrites of specific third order neurons, Tm1 and Tm9, as the site of luminance gain control. The circuitry further involves neurons with wide-field properties, matching computational predictions that local spatial pooling can drive optimal contrast processing in natural scenes where light conditions change rapidly. Experiments and theory argue that a spatially pooled luminance signal achieves luminance gain control via divisive normalization. This process relies on shunting inhibition using the glutamate-gated chloride channel GluClα. Our work describes computationally, algorithmically, and mechanistically, how visual circuits robustly process visual information in dynamically changing, natural scenes.
Decoding Musical Valence And Arousal: Exploring The Neural Correlates Of Music Evoked Emotions And The Role Of Expressivity Features
Authors: Sayal Alexandre , Guedes Ana Gabriela , Almeida Inês , Pereira Daniela Jardim , Lima César , Panda Renato , Paiva Rui Pedro , Sousa Teresa , Castelo-Branco Miguel , Bernardino Inês , Direito Bruno
Published: February 2024

Music can convey basic emotions, such as joy and sadness, and more complex ones, such as tenderness or nostalgia. Its effects on emotion regulation and reward have attracted much attention in cognitive and affective neuroscience. Understanding the neural correlates of music-evoked emotions may guide the development of neurorehabilitation interventions based on music. Here, we used fMRI to examine the relationship between the classification of music excerpts regarding perceived valence and arousal and their neural correlates. Twenty participants were scanned while listening to 96 musical excerpts, which were classified beforehand into four categories as a function of valence (positive vs. negative) and arousal (high vs. low). Differences in valence and arousal modulated activity in cortical regions, most noticeably the music-specific subregions of the auditory cortex, but also in the thalamus and regions of the reward network such as the amygdala. Using multivoxel pattern analysis, we created a computational model able to decode the valence and arousal of the music excerpts significantly above chance. We further explored how a set of musical features relate to brain activity in valence-, arousal-, reward-, and auditory-related ROIs. The results emphasize the differential involvement of musical features in the brain, notably expressive features such as Vibrato and Tonal and Spectral dissonance in valence, arousal, and reward brain networks, while a broader set of features modulate sensory auditory networks. Using ecologically valid music stimuli, we contribute to the definition of the neural substrates of music listening and evoked emotions. Moreover, the definition of the musical features that modulate specific brain networks paves the way to developing novel music-based neurorehabilitation strategies.
MVComp toolbox: MultiVariate Comparisons of brain MRI features accounting for common information across metrics
Authors: Tremblay Stefanie A , Alasmar Zaki , Pirhadi Amir , Carbonell Felix , Iturria-Medina Yasser , Gauthier Claudine J , Steele Christopher J
Published: February 2024

Multivariate approaches have recently gained in popularity to address the physiological unspecificity of neuroimaging metrics and to better characterize the complexity of biological processes underlying behavior. However, commonly used approaches are biased by the intrinsic associations between variables, or they are computationally expensive and may be more complicated to implement than standard univariate approaches. Here, we propose using the Mahalanobis distance (D2), an individual-level measure of deviation relative to a reference distribution that accounts for covariance between metrics. To facilitate its use, we introduce an open-source python-based tool for computing D2 relative to a reference group or within a single individual: the MultiVariate Comparison (MVComp) toolbox. The toolbox allows different levels of analysis (i.e., group-or subject-level), resolutions (e.g., voxel-wise, ROI-wise) and dimensions considered (e.g., combining MRI metrics or WM tracts). Several example cases are presented to showcase the wide range of possible applications of MVComp and to demonstrate the functionality of the toolbox. The D2 framework was applied to the assessment of white matter (WM) microstructure at 1) the group-level, where D2 can be computed between a subject and a reference group to yield an individualized measure of deviation. We observed that clustering applied to D2 in the corpus callosum yields parcellations that highly resemble known topography based on neuroanatomy, suggesting that D2 provides an integrative index that meaningfully reflects the underlying microstructure. 2) At the subject level, D2 was computed between voxels to obtain a measure of (dis)similarity. The loadings of each MRI metric (i.e., its relative contribution to D2) were then extracted in voxels of interest to showcase a useful option of the MVComp toolbox. These relative contributions can provide important insights into the physiological underpinnings of differences observed. Integrative multivariate models are crucial to expand our understanding of the complex brain-behavior relationships and the multiple factors underlying disease development and progression. Our toolbox facilitates the implementation of a useful multivariate method, making it more widely accessible.
A mediating framework in resting-state connectivity between the medial prefrontal cortex and anterior cingulate in mild cognitive impairment
Authors: Huang Yiyuan Teresa , Yan Sui-Hing , Chuang Yi-Fang , Shih Yao-Chia , Huang Yan-Siang , Liu Yi-Chien , Kao Scott Shyh-Chang , Chiu Yen-Ling , Fan Yang-Teng
Published: February 2024

Mild cognitive impairment (MCI) is recognized as the prodromal phase of dementia, a condition that can be either maintained or reversed through timely medical interventions to prevent cognitive decline. Considerable studies using functional magnetic resonance imaging (fMRI) have indicated that altered activity in the medial prefrontal cortex (mPFC) serves as an indicator of various cognitive stages of aging. However, the impacts of intrinsic functional connectivity in the mPFC as a mediator on cognitive performance in individuals with and without MCI have not been fully understood. In this study, we recruited 42 MCI patients and 57 healthy controls, assessing their cognitive abilities and functional brain connectivity patterns through neuropsychological evaluations and resting-state fMRI, respectively. The MCI patients exhibited poorer performance on multiple neuropsychological tests compared to the healthy controls. At the neural level, functional connectivity between the mPFC and the anterior cingulate cortex (ACC) was significantly weaker in the MCI group and correlated with multiple neuropsychological test scores. The result of the mediation analysis further demonstrated that functional connectivity between the mPFC and ACC notably mediated the relationship between the MCI and semantic working memory. These findings suggest that altered mPFC-ACC connectivity may have a plausible causal influence on cognitive decline and provide implications for early identifications of neurodegenerative diseases and precise monitoring of disease progression.