bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting senescent hepatocytes using the thrombomodulin-PAR1 inhibitor vorapaxar ameliorates NAFLD progression
Authors: Maeso-Díaz Raquel , Du Kuo , Pan Christopher , Guy Cynthia D. , Oh Seh Hoon , Chen Tianyi , Wang Liuyang , Ko Dennis C. , Tang Linda , Dutta Rajesh K. , Jun Ji Hye , Suzuki Ayako , Abdelmalek Manal F. , Wang Xiao-Fan , Diehl Anna Mae
Published: April 2023

Background and Aims:

Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Senescing cells upregulate thrombomodulin–protease-activated receptor-1 (THBD-PAR1) signaling to remain viable. Vorapaxar blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH.

Approach and Results:

We evaluated the THBD-PAR1 pathway in liver biopsies from patients with NAFLD. Chow-fed mice were treated with viral vectors to overexpress p16 in hepatocytes and induce replicative senescence. Effects on the THBD-PAR1 axis and regenerative capacity were assessed; the transcriptome of p16-overexpressing hepatocytes was characterized, and we examined how conditioned medium from senescent but viable (dubbed “undead”) hepatocytes reprograms HSCs. Mouse models of NASH caused by genetic obesity or Western diet/CCl4 were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Inducing senescence upregulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR1 signaling with vorapaxar interrupts this process, reduces the burden of ‘undead’ senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress.

Conclusion:

The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.
Diagnostic strategies in adrenal insufficiency
Authors: Siampanopoulou Vasiliki , Tasouli Elisavet , Angelousi Anna
Published: April 2023

Purpose of review

Adrenal insufficiency (AI) is the clinical manifestation of deficient production of glucocorticoids with occasionally deficiency also in mineralocorticoids and adrenal androgens and constitutes a fatal disorder if left untreated. The aim of this review is to summarize the new trends in diagnostic methods used for determining the presence of AI.

Recent findings

Novel aetiologies of AI have emerged; severe acute respiratory syndrome coronavirus 2 infection was linked to increased frequency of primary AI (PAI). A new class of drugs, the immune checkpoint inhibitors (ICIs) widely used for the treatment of several malignancies, has been implicated mostly with secondary AI, but also with PAI. Salivary cortisol is considered a noninvasive and patient-friendly tool and has shown promising results in diagnosing AI, although the normal cut-off values remain an issue of debate depending on the technique used. Liquid chromatography–mass spectrometry (LC–MS/MS) is the most reliable technique although not widely available.

Our research has shown that little progress has been made regarding our knowledge on AI. Coronavirus disease 2019 and ICIs use constitute new evidence on the pathogenesis of AI. The short synacthen test (SST) remains the ‘gold-standard’ method for confirmation of AI diagnosis, although salivary cortisol is a promising tool.
Adolescent patient portals and concerns about confidentiality
Authors: Sethness Janis L. , Golub Sarah , Evans Yolanda N.
Published: April 2023

Purpose of review

To better understand confidentiality issues that arise from adolescent access to patient portals.

Recent findings

Studies have evaluated the views of teens, parents, providers, and institutional leadership on adolescent patient portals and the risks they pose to adolescent privacy. Additional investigations have shown that teen portal accounts are often inappropriately accessed by parents. Guidelines are needed to better inform the creation of secure teen patient portals. Adolescent providers and other medical staff should be aware of the information available on portals, how to ensure portals are being accessed appropriately, and the potential for confidentiality breaches that come with portal use. Medical organizations that offer portal access need to provide resources to adolescents and their families to improve understanding around the importance of confidential care and how to maintain confidentiality while still engaging meaningfully with the healthcare system through patient portals.

Adolescents realize the benefits portals may offer regarding improved understanding of their health conditions, communication with their providers, and autonomy in their healthcare decisions. However, confidentiality of patient portals is a major concern and a potential barrier to adolescent portal utilization. Adolescent providers should be aware of the limitations of portal systems and advocate for improved confidentiality functionality to ensure teens can access the benefits of patient portals without any harm.
A Simplified Version of the IASLC Grading System for Invasive Pulmonary Adenocarcinomas With Improved Prognosis Discrimination
Authors: Bossé Yohan , Gagné Andréanne , Althakfi Wajd A. , Orain Michèle , Couture Christian , Trahan Sylvain , Pagé Sylvain , Joubert David , Fiset Pierre O. , Desmeules Patrice , Joubert Philippe
Published: April 2023

Tumor grading enables better management of patients and treatment options. The International Association for the Study of Lung Cancer (IASLC) Pathology Committee has recently released a 3-tier grading system for invasive pulmonary adenocarcinoma consisting of predominant histologic patterns plus a cutoff of 20% of high-grade components including solid, micropapillary, and complex glandular patterns. The goal of this study was to validate the prognostic value of the new IASLC grading system and to compare its discriminatory performance to the predominant pattern–based grading system and a simplified version of the IASLC grading system without complex glandular patterns. This was a single-site retrospective study based on a 20-year data collection of patients that underwent lung cancer surgery. All invasive pulmonary adenocarcinomas confirmed by the histologic review were evaluated in a discovery cohort (n=676) and a validation cohort (n=717). The median duration of follow-up in the combined dataset (n=1393) was 7.5 years. The primary outcome was overall survival after surgery. The 3 grading systems had strong and relatively similar predictive performance, but the best parsimonious model was the simplified IASLC grading system (log-rank P=1.39E−13). The latter was strongly associated with survival in the validation set (P=1.1E−18) and the combined set (P=5.01E−35). We observed a large proportion of patients upgraded to the poor prognosis group using the IASLC grading system, which was attenuated when using the simplified IASLC grading system. In conclusion, we identified a histologic simpler classification for invasive pulmonary adenocarcinomas that outperformed the recently proposed IASLC grading system. A simplified grading system is clinically convenient and will facilitate widespread implementation.
Vial-splitting and Repackaging into Aliquot-specific Syringes: A Cost-effective and Waste-decreasing Strategy for Sugammadex
Authors: Amaya Sebastian , Kalsotra Sidhant , Tram Nguyen K. , Tobias Joseph D. , Olbrecht Vanessa A.
Published: April 2023

Introduction:

Sugammadex is a medication that may have cost considerations with the potential for waste of unused product in pediatric patients due to the vial size and its single-use limitation. Therefore, exploring the potential of vial-splitting for perioperative use may be beneficial.

Methods:

The study was a retrospective, quality improvement study using the electronic medical record to identify every sugammadex administration over the last five years in a tertiary care pediatric institution. We divided patients into groups depending on the dose of sugammadex administered. The cost of sugammadex was calculated under three scenarios: (1) only 200-mg vials available; (2) 100-mg aliquots available; and (3) 50-mg aliquots. We then calculated the total money spent per patient in the 3 scenarios.

Results:

31,063 patients received sugammadex over the study period, of whom 23.6% received 151–200 mg. The greatest percentage of patients received ≤50 mg (32.9%). The average cost per patient was $113.58, $81.61, and $68.83 if 200 mg, 100 mg, and 50 mg doses were available, respectively. Over the last 5 years, $1,390,110.13 could have been saved by having 50 and 100 mg aliquots available.

Conclusions:

Pediatric patients generally receive lower doses of sugammadex due to weight-based dosing, leading to increased waste and cost when using only 200-mg vials. Vial-splitting into smaller aliquots can significantly cut costs for healthcare centers and patients while decreasing waste.
Developing a Craniofacial Soft Tissue Anthropomorphic Database with Magnetic Resonance Imaging and Unbiased Diffeomorphic Registration
Authors: Villavisanis Dillan F , Khandelwal Pulkit , Zapatero Zachary D , Wagner Connor S , Blum Jessica D , Cho Daniel Y , Swanson Jordan W , Taylor Jesse A , Yushkevich Paul A , Bartlett Scott P
Published: April 2023

Introduction:

Objective assessment of craniofacial surgery outcomes in a pediatric population is challenging due to complexity of patient presentations, diversity of procedures performed, and rapid craniofacial growth. There is a paucity of robust methods to quantify anatomic measurements by age and objectively compare craniofacial dysmorphology and postoperative outcomes. Here the authors present data in developing a racially and ethnically sensitive anthropomorphic database, providing plastic and craniofacial surgeons with “normal” three-dimensional anatomic parameters to appraise and optimize aesthetic and reconstructive outcomes.

Methods:

Patients with normal craniofacial anatomy receiving head MRIs from 2008-2021 were included in this retrospective study. Images were used to construct composite (template) images with diffeomorphic image registration method using the Advanced Normalization Tools (ANTs) package. Composites were thresholded to generate binary three-dimensional segmentations used for anatomic measurements in Materalise Mimics.

Results:

High-resolution MRIs from 130 patients generated 12 composites from an average of ten MRI sequences each: four three-year-olds, four four-year-olds, and four five-year-olds (two male, two female, two black, and two white). The average head circumference of three-, four-, and five-year-old composites was 50.3 cm, 51.5 cm, and 51.7 cm, respectively, comparable with normative data published by the World Health Organization.

Conclusions:

Application of diffeomorphic registration-based image template algorithm to MRI is effective in creating composite templates to represent “normal” three dimensional craniofacial and soft tissue anatomy. Future research will focus on development of automated computational tools to characterize anatomic normality, generation of indices to grade preoperative severity, and quantification of postoperative results to reduce subjectivity bias.
A NOVEL RAT MODEL OF CONTRAST-INDUCED ACUTE KIDNEY INJURY BASED ON RENAL CONGESTION AND THE RENO-PROTECTION OF MITOCHONDRIAL FISSION INHIBITION
Authors: Yang Qiang , Hu Jiachang , Ning Yichun , Zhao Shuan , Chen Weize , Ren Ting , Zhang Di , Ding Xiaoqiang , Zou Jianzhou
Published: April 2023

Contrast-induced acute kidney injury (CI-AKI) is a serious and common complication in patients receiving intravenous iodinated contrast medium (CM). Clinically, congestive heart failure is the most critical risk factor for CI-AKI and always leads to renal congestion for increased central venous pressure and fluid overload. Here, we aimed to investigate a novel CI-AKI rat model based on renal congestion. After the exploratory testing phase, we successfully constructed a CI-AKI rat model by inducing renal congestion by clamping the unilateral renal vein, removing the contralateral kidney, and a single tail vein injection of iohexol. This novel CI-AKI rat model showed elevated serum creatinine, urea nitrogen, and released tubular injury biomarkers (KIM-1 and NGAL), reduced glomerular filtration rate, and typical pathologic features of CM-induced tubular injury with extensive foamy degeneration, tubular edema, and necrosis. Electron microscopy and confocal laser scanning revealed excessive mitochondrial fission and increased translocation of Drp1 from the cytoplasm to the mitochondrial surface in tubular epithelial cells. As a Drp1 inhibitor, Mdivi-1 attenuated excessive mitochondrial fission and exerted reno-protection against CM injury. Simultaneously, Mdivi-1 alleviated oxidative stress, apoptosis, and inflammatory responses induced by CM toxicity. We concluded that renal congestion exacerbated CM toxicity and presented a novel CI-AKI rat model. Excessive mitochondrial fission plays a crucial role in CM reno-toxicity and is a promising target for preventing and treating CI-AKI.
Safe Implementation of a Next-Generation Surgical Robot
Authors: Soumpasis Ilias , Nashef Samer , Dunning Joel , Moran Paul , Slack Mark
Published: April 2023

Objective:

To present the first report of data from the Versius Surgical Registry, a prospective, multicenter data registry with ongoing collection across numerous surgical indications, developed to accompany the Versius Robotic Surgical System into clinical practice.

Background:

A data registry can be utilized to minimize risk to patients by establishing the safety and effectiveness of innovative medical devices and generating a thorough evidence base of real-world data.

Methods:

Surgical outcome data were collected and inputted through a secure online platform. Preoperative data included patient age, sex, body mass index, surgical history, and planned procedures. Intraoperative data included operative time, complications during surgery, conversion from robot-assisted surgery to an alternative surgical technique, and blood loss. Postoperative outcome data included length of hospital stay, complications following surgery, serious adverse events, return to the operating room, readmission to the hospital, and mortality within 90 days of surgery.

Results:

This registry analysis included 2083 cases spanning general, colorectal, hernia, gynecologic, urological, and thoracic indications. A considerable number of cases were recorded for cholecystectomy (n=539), anterior resection (n=162), and total laparoscopic hysterocolpectomy (n=324) procedures. The rates of conversion to an alternative technique, serious adverse events, and 90-day mortality were low for all procedures across all surgical indications.

Conclusions:

We report the large-scale analysis of the first 2083 cases recorded in this surgical registry, with substantial data collected for cholecystectomies, anterior resections, and total laparoscopic hysterectomies. The extensive surgical outcome data reported here provide real-world evidence for the safe implementation of the surgical robot into clinical practice.
Inpatient Skin-to-Skin Care Predicts 12-month Neurodevelopmental Outcomes in Very Preterm Infants
Authors: Lazarus Molly F. , Marchman Virginia A. , Brignoni-Pérez Edith , Dubner Sarah , Feldman Heidi M. , Scala Melissa , Travis Katherine E.
Published: April 2023

Objective

Limited research links hospital-based experiences of skin-to-skin (STS) care to longer-term neurodevelopmental outcomes in preterm children. The present study examined relations between inpatient STS and neurodevelopmental scores measured at 12 months in a sample of very preterm (VPT) infants.

Study Design and Methods

From a retrospective study review of medical records of 181 VPT infants (<32 weeks gestational age (GA)) we derived the STS rate, i.e., the total minutes of STS each infant received/day of hospital stay. We used scores on the Capute Scales from routine follow-up care at 12 months as the measure of neurodevelopmental outcome (n=181).

Results

Families averaged approximately 17 minutes/day of STS care (2 days/week, 70 minutes/session), although there was substantial variability. Variation in STS rate was positively associated with outcomes at 12 months corrected age (r= 0.25,p <.001). STS rate significantly predicted 6.2% unique variance in 12-month neurodevelopmental outcomes, after controlling for GA, socioeconomic status (SES), health acuity, and visitation frequency. A 20-minute increase in STS per day was associated with a 10-point increase (.67 SDs) in neurodevelopmental outcomes at 12 months. SES, GA, and infant health acuity did not moderate these relations.

Conclusion

VPT infants who experienced more STS during hospitalization demonstrated higher scores on 12-month assessments of neurodevelopment. Results provide evidence that STS care may confer extended neuroprotection on VPT infants through the first year of life.
Association between PM2.5 air pollution, temperature, and sunlight during different infectious stages with the case fatality of COVID-19 in the United Kingdom: a modeling study
Authors: Hossain M. Pear , Zhou Wen , Leung Marco Y. T. , Yuan Hsiang-Yu
Published: April 2023

Although the relationship between the environmental factors such as weather conditions and air pollution and COVID-19 case fatality rate (CFR) has been found, the impacts of these factors to which infected cases are exposed at different infectious stages (e.g., virus exposure time, incubation period, and at or after symptom onset) are still unknown. Understanding this link can help reduce mortality rates. During the first wave of COVID-19 in the United Kingdom (UK), the CFR varied widely between and among the four countries of the UK, allowing such differential impacts to be assessed.

We developed a generalized linear mixed-effect model combined with distributed lag nonlinear models to estimate the odds ratio of the weather factors (i.e., temperature, sunlight, relative humidity, and rainfall) and air pollution (i.e., ozone,NO2,SO2,CO, PM10andPM2.5) using data between March 26, 2020 and May 12, 2020 in the UK. After retrospectively time adjusted CFR was estimated using back-projection technique, the stepwise model selection method was used to choose the best model based on Akaike information criteria (AIC) and the closeness between the predicted and observed values of CFR.

We found that the low temperature (8-11°C), prolonged sunlight duration (11-13hours) and increasedPM2.5(11-18μg/m3) after the incubation period posed a greater risk of death (measured by odds ratio (OR)) than the earlier infectious stages. The risk reached its maximum level when the low temperature occurred one day after (OR = 1.76; 95% CI: 1.10-2.81), prolonged sunlight duration 2-3 days after (OR = 1.50; 95% CI: 1.03-2.18) and increasedP.M2.5at the onset of symptom (OR =1.72; 95% CI: 1.30-2.26). In contrast, prolonged sunlight duration showed a protective effect during the incubation period or earlier.

After reopening, many COVID-19 cases will be identified after their symptoms appear. The findings highlight the importance of designing different preventive measures against severe illness or death considering the time before and after symptom onset.
A resampling-based approach to share reference panels
Authors: Cavinato Théo , Rubinacci Simone , Malaspinas Anna-Sapfo , Delaneau Olivier
Published: April 2023

For many genome-wide association studies, imputing genotypes from a haplotype reference panel is a necessary step. Over the past 15 years, reference panels have become larger and more diverse, leading to improvements in imputation accuracy. However, the latest generation of reference panels is subject to restrictions on data sharing due to concerns about privacy, limiting their usefulness for genotype imputation. In this context, we propose RESHAPE, a method that employs a recombination Poisson process on a reference panel to simulate the genomes of hypothetical descendants after multiple generations. This data transformation helps to protect against re-identification threats and preserves important data attributes, such as linkage disequilibrium (LD) patterns and, to some degree, Identity-By-Descent (IBD) sharing, allowing for genotype imputation. Our experiments on gold standard datasets show that simulated descendants up to eight generations can serve as reference panels without significantly reducing genotype imputation accuracy. We suggest that this specific type of data anonymization could be used to generate synthetic reference panels available under less restrictive data sharing policies.
SARS-CoV-2’s evolutionary capacity is mostly driven by host antiviral molecules
Authors: Lamb Kieran D. , Luka Martha M. , Saathoff Megan , Orton Richard , Phan My , Cotten Matthew , Yuan Ke , Robertson David L.
Published: April 2023

The COVID-19 pandemic has been characterised by sequential variant-specific waves shaped by viral, individual human and population factors. SARS-CoV-2 variants are defined by their unique combinations of mutations and there has been a clear adaptation to human infection since its emergence in 2019. Here we use machine learning models to identify shared signatures, i.e., common underlying mutational processes, and link these to the subset of mutations that define the variants of concern (VOCs). First, we examined the global SARS-CoV-2 genomes and associated metadata to determine how viral properties and public health measures have influenced the magnitude of waves, as measured by the number of infection cases, in different geographic locations using regression models. This analysis showed that, as expected, both public health measures and not virus properties alone are associated with the rise and fall of regional SARS-CoV-2 reported infection numbers. This impact varies geographically. We attribute this to intrinsic differences such as vaccine coverage, testing and sequencing capacity, and the effectiveness of government stringency. In terms of underlying evolutionary change, we used non-negative matrix factorisation to observe three distinct mutational signatures, unique in their substitution patterns and exposures from the SARS-CoV-2 genomes. Signatures 0, 1 and 3 were biased to C→T, T→C/A→G and G→T point mutations as would be expected of host antiviral molecules APOBEC, ADAR and ROS effects, respectively. We also observe a shift amidst the pandemic in relative mutational signature activity from predominantly APOBEC-like changes to an increasingly high proportion of changes consistent with ADAR editing. This could represent changes in how the virus and the host immune response interact, and indicates how SARS-CoV-2 may continue to accumulate mutations in the future. Linkage of the detected mutational signatures to the VOC defining amino acids substitutions indicates the majority of SARS-CoV-2’s evolutionary capacity is likely to be associated with the action of host antiviral molecules rather than virus replication errors.
Supplemental LED lighting improves plant growth without affecting biological control in a tri-trophic greenhouse system
Authors: Fraser Jessica L. , Abram Paul K. , Dorais Martine
Published: April 2023

Artificial lighting, including light-emitting diode (LED) illumination, is increasingly being optimized in protected agricultural systems to maximize plant yield and quality. However, it may also cause other top-down and bottom-up effects in these relatively simple ecological communities that also include insect pests and their natural enemies. While some effects of LED lighting on insects have been demonstrated to date, it is not known how they influence biological control of insect pests in practice. To examine potential top-down and bottom-up impacts of LED illumination on greenhouse biological control with parasitoids, we studied the effects of artificially lengthened days on a tri-trophic system in cages and in a greenhouse. We grew plants under a 12-hour photoperiod of white-supplemented light with 6 hours of additional 1) white light or 2) red and blue light, or 3) with no additional light. We exposed the plants to the pest aphidMyzus persicae(Hemiptera : Aphididae) with or without its parasitoid waspAphidius matricariae(Hymenoptera : Braconidae), or to no insects. The 18-hour light treatments increased mean plant dry mass by 127% compared with the 12-hour control without affecting the aphid’s population density or the parasitoid’s biological control efficacy under relatively low light conditions. This suggests that insect communities in protected agriculture can be resilient to even drastic changes in their light environment, and that adjusting crop lighting in a manner that affects plant growth does not necessarily compromise biological control’s effectiveness.
Responses of globally important phytoplankton species to olivine dissolution products and implications for carbon dioxide removal via ocean alkalinity enhancement
Authors: Hutchins David A. , Fu Fei-Xue , Yang Shun-Chung , John Seth G. , Romaniello Stephen J. , Andrews M. Grace , Walworth Nathan G.
Published: April 2023

Anthropogenic greenhouse gas emissions are leading to global temperature increases, ocean acidification, and significant ecosystem impacts. Given current emissions trajectories, the IPCC reports indicate that rapid abatement of CO2emissions and development of carbon dioxide removal (CDR) strategies are needed to address legacy and difficult to abate emissions sources. These CDR methods must efficiently and safely sequester gigatons of atmospheric CO2. Coastal Enhanced Weathering (CEW) via the addition of the common mineral olivine to coastal waters is one promising approach to enhance ocean alkalinity for large-scale CDR. As olivine weathers, it releases several biologically active dissolution products, including alkalinity, trace metals, and the nutrient silicate. Released trace metals can serve as micronutrients but may also be toxic at high concentrations to marine biota including phytoplankton that lie at the base of marine food webs. We grew six species representing several globally important phytoplankton species under elevated concentrations of olivine dissolution products via a synthetic olivine leachate (OL) based on olivine elemental composition. We monitored their physiological and biogeochemical responses, which allowed us to determine physiological impacts and thresholds at elevated olivine leachate concentrations, in addition to individual effects of specific constituents. We found both positive and neutral responses but no evident toxic effects for two silicifying diatoms, a calcifying coccolithophore, and three cyanobacteria. In both single and competitive co-cultures, silicifiers and calcifiers benefited from olivine dissolution products like iron and silicate or enhanced alkalinity, respectively. The non-N2-fixing picocyanobacterium could use synthetic olivine-derived iron for growth, while N2-fixing cyanobacteria could not. However, other trace metals like nickel and cobalt supported cyanobacterial growth across both groups. Growth benefits to phytoplankton groupsin situwill depend on species-specific responses and ambient concentrations of other required nutrients. Results suggest olivine dissolution products appear unlikely to cause negative physiological effects for any of the phytoplankton examined, even at high concentrations, and may support growth of particular taxa under some conditions. Future studies can shed light on long-term eco-evolutionary responses to olivine exposure and on the potential effects that marine microbes may in turn have on olivine dissolution rates and regional biogeochemistry.
Alpha and SSVEP power outperform Gamma power in capturing Attentional Modulation in Human EEG
Authors: Das Aritra , Nandi Nilanjana , Ray Supratim
Published: April 2023

The effect of visual attention has been extensively studied using various techniques such as macaque neurophysiology that yields spikes and local field potential (LFP), and human electro/magneto encephalogram (EEG/MEG). Attention typically suppresses power at low frequencies such as alpha band (8-12 Hz) and increases power in gamma band (>30 Hz) in brain signals. In addition, EEG studies often use flickering stimuli that produce a specific measure called steady-state visually evoked potential (SSVEP), whose power also increases with attention. However, effectiveness of these various neural measures in capturing attentional modulation is unknown since the stimuli and task paradigms vary widely across these studies. In a recent macaque neurophysiology study with flickering stimuli, we found that the effect of attention was more salient in the gamma band and beyond of the LFP, compared to alpha or SSVEP. To compare this with human EEG, we designed an orientation change detection task where we presented both static and counterphasing stimuli of matched difficulty levels to male (N=15) and female (N=11) subjects, allowing us to compare attentional modulation of various measures under similar conditions. We report two main results. First, attentional modulation was comparable for SSVEP and alpha. Second, non-foveal stimuli produced weak gamma despite various stimulus optimizations and showed a negligible effect of attention although full-screen gratings showed robust gamma activity. Our results are useful for brain-machine-interfacing studies where suitable features depending on recording modality are used for decoding attention, and also provide clues about the spatial scales of neural mechanisms underlying attention.

Significance Statement

Various neural measures such as alpha and gamma band power or SSVEP power capture signatures of visual attention. A systematic comparison of their effectiveness in capturing attentional modulation is important for understanding different neural computations underlying attention and for developing brain-machine-interfaces (BMIs) that can decode the focus of attention. Since stimulus configuration and task paradigms vary widely across visual attention studies, we recorded all the relevant neural signals during an attention task under similar stimulus and behavioral conditions in human EEG. In contrast to invasive recordings in which gamma outperforms other measures, our results show that in human EEG, attentional modulation of alpha and SSVEP are comparable, and non-foveal stimuli produce weak gamma which is not well modulated by attention.
Dynamical BLUP modeling of reaction norm evolution, accommodating changing environments, overlapping generations, and multivariate data
Authors: Ergon Rolf
Published: April 2023

For theoretical studies, reaction norm evolution in a changing environment can be modeled by means of the multivariate breeder’s equation, with the reaction norm parameters treated as traits in their own right. This is, however, not a feasible approach for use of field data, where the intercept and slope values are not available. An alternative approach is to use infinite-dimensional characters and smooth covariance function estimates found by, i.e., random regression. This is difficult because of the need to find for example polynomial basis functions that fit the data reasonably well over time, and because reaction norms in multivariate cases are correlated, such that they cannot be modeled independently.

Here, I present an alternative approach based on a multivariate linear mixed model of any order, with dynamical incidence and residual covariance matrices that reflect the changing environment. From such a mixed model follows a dynamical BLUP model for prediction of the individual reaction norm parameter values at any given parent generation, and for updating of the mean reaction norm parameter values from generation to generation by means of Robertson’s secondary theorem of natural selection. This will, e.g., make it possible to disentangle the microevolutionary and plasticity components in climate change responses. The BLUP model incorporates the additive genetic relationship matrix in the usual way, and overlapping generations can easily be accommodated.

Parameters are assumed to be known and constant, but it is discussed how they can be estimated by means of a prediction error method. The identifiability by use of field or laboratory data containing environmental, phenotypic, fitness, and additive genetic relationship data, is an important feature of the proposed model.
Multi-scale Effects of Habitat Loss and the Role of Trait Variation
Authors: Bagawade Rishabh , van Benthem Koen J. , Wittmann Meike J.
Published: April 2023

Habitat loss (HL) is a major cause of species extinctions. Although effects of HL beyond the directly impacted area have been previously observed, they are not very well understood, especially in an eco-evolutionary context. To start filling this gap, we study a two-patch deterministic consumer-resource model, with one of the patches experiencing loss of resources. Our model allows foraging and mating within a patch as well as between patches. We then introduce heritable variation in consumer traits to investigate eco-evolutionary dynamics and compare results with constant or no trait variation scenarios. Our results show that HL indeed reduces consumer densities in the neighboring patch, but when the resources are overexploited, HL in one patch can increase the consumer densities in the neighbouring patch. Yet at the landscape scale, the effect of HL on consumer densities is consistently negative. In presence of HL, patch isolation has positive effects on consumer density in the patch experiencing HL and mostly negative effects on the neighbouring patch. The landscape level pattern depends on which of these effects are dominant at the local scale. Evolution always increased resistance of consumers in the affected patch to HL, with varied effects at the landscape level. Finally, we also show a possibility of landscape level consumer extinction due to HL in a local patch when the cross-patch dependence is high, and foraging and mating preferences are coupled. Eco-evolutionary dynamics can rescue consumers from such extinction in some cases if their death rates are sufficiently small. Our findings show that HL at a local scale can affect the neighbouring patch and the landscape as a whole, and that heritable trait variation can provide some resistance against HL. We thus suggest joint consideration of multiple spatial scales and trait variation when assessing and predicting the impacts of HL.
Caenorhabditis elegansmodels for striated muscle disorders caused by missense variants of humanLMNA
Authors: Gregory Ellen F. , Kalra Shilpi , Brock Trisha , Bonne Gisèle , Luxton G.W. Gant , Hopkins Christopher , Starr Daniel A.
Published: April 2023

Striated muscle laminopathies caused by missense mutations in the nuclear lamin geneLMNAare characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict whichLMNAvariants are pathogenic and to understand their physiological effects lags behind variant discovery. We createdCaenorhabditis elegansmodels for striated muscle laminopathies by introducing pathogenic humanLMNAvariants and variants of unknown significance at conserved residues within thelmn-1gene. Severe missense variants reduced fertility and/or motility inC. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele,lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we establishedC. elegansavatars for striated muscle laminopathies and identifiedLMNAvariants that offer insight into lamin mechanisms during normal development.

Author summary

Muscular dystrophy is a progressive muscle-wasting disorder that eventually leads to cardiac disease. Mutations in theLMNAgene, which encodes an intermediate filament protein involved in the structure and organization of the nucleus, is a common but poorly understood cause of this disease. How variants across the breadth ofLMNAcontribute to mechanistic cellular defects that lead to disease is poorly understood, leading to hurdles in diagnosing disease and developing treatments. We found that by introducing amino acid substitutions found in patients with striated muscle disorders caused byLMNAinto the conservedlmn-1gene of the nematodeC. elegans, we could rapidly test the function of these variants to better understand their roles. We found that variants modeling diseases that involve both skeletal and cardiac muscle in humans were the most pathogenic inC. elegans, typically affecting both viability and movement, while those that modeled cardiac disease alone had less deleterious effects inC. elegans. Furthermore, we uncovered molecular mechanisms for how lamins interact with other nuclear envelope proteins to carry out their cellular functions. Thus, our newC. elegansmodels can be used to diagnose and predict the severity of new variants of humanLMNAas well as better understanding the molecular mechanisms of lamins in normal development.
Myelodysplastic syndromes disable support of human hematopoietic stem and progenitor cells by CD271, VCAM- 1 and CD146 expressing marrow niche cells
Authors: Kawano Yuko , Kawano Hiroki , Ghoneim Dalia , Fountaine Thomas J. , Byun Daniel K , LaMere Mark W. , Mendler Jason H. , Ho Tzu-Chieh , Salama Noah A. , Frisch Benjamin J. , Myers Jason R. , Hussein Siba El , Ashton John M. , Azadniv Mitra , Liesveld Jane L. , Kfoury Youmna , Scadden David T. , Becker Michael W. , Calvi Laura M.
Published: April 2023

Mesenchymal stem/stromal cells (MSCs) within the bone marrow microenvironment (BMME) support normal hematopoietic stem and progenitor cells (HSPCs). However, the heterogeneity of human MSCs has limited the understanding of their contribution to clonal dynamics and evolution to myelodysplastic syndromes (MDS). We combined three MSC cell surface markers, CD271, VCAM-1 (Vascular Cell Adhesion Molecule-1) and CD146, to isolate distinct subsets of human MSCs from bone marrow aspirates of healthy controls (Control BM). Based on transcriptional and functional analysis, CD271+CD106+CD146+(NGFR+/VCAM1+/MCAM+/Lin-;NVML) cells display stem cell characteristics, are compatible with murine BM- derived Leptin receptor positive MSCs and provide superior support for normal HSPCs. MSC subsets from 17 patients with MDS demonstrated shared transcriptional changes in spite of mutational heterogeneity in the MDS clones, with loss of preferential support of normal HSPCs by MDS-derived NVML cells. Our data provide a new approach to dissect microenvironment-dependent mechanisms regulating clonal dynamics and progression to MDS.
Adolescent morphine exposure impairs cognitive flexibility in female but not male mice
Authors: Wakhlu Aditii , Engelhardt Annabel , Anderson Eden M. , Grafelman Elaine , Ouimet Abbigail , Hearing Matthew C.
Published: April 2023

Use of prescription opioids continues to rise, especially in adolescent individuals. As adolescence is a critical development window for higher order cognitive functions, thus opioid exposure during this period may have significant long-lasting effects on cognitive function and predisposition individuals to be at greater risk of developing opioid use later in life. Here, we examine previously explored effects of opioid exposure during adolescence on affect-related behavior, motivation, and cognitive flexibility. We find that a two-week exposure to non-contingent morphine during adolescence (i.e., post-weaning) does not alter performance in an elevated plus maze, forced swim test, or motivation for appetitive reward in male or female mice when tested during adolescence or adulthood. Examination of how adolescent morphine impacts cognition revealed impairments in visual-based discriminative learning and cognitive flexibility in female but not male mice, as assessed using an operant-based attentional set-shifting task. Unexpectedly, deficits in discriminative learning are observed when testing occurred during adolescence but not adulthood, whereas impaired performance in the extradimensional shift remained impaired into adulthood. The data indicate that opioid exposure during adolescence has a greater impact on cognitive function in female mice and that these deficits may be more widespread during acute withdrawal periods, while deficits in flexibility more enduring.
Astrocytic LRRK2 Controls Synaptic Connectivity via Regulation of ERM Phosphorylation
Authors: Wang Shiyi , Baumert Ryan , Séjourné Gabrielle , Bindu Dhanesh Sivadasan , Dimond Kylie , Sakers Kristina , Vazquez Leslie , Moore Jessica , Tan Christabel Xin , Takano Tetsuya , Rodriguez Maria Pia , Soderling Scott H. , La Spada Albert R. , Eroglu Cagla
Published: April 2023

Astrocytes, a major glial cell type of the brain, regulate synapse numbers and function. However, whether astrocyte dysfunction can cause synaptic pathologies in neurological disorders such as Parkinson’s Disease (PD) is unknown. Here, we investigated the impact of the most common PD-linked mutation in the leucine-rich repeat kinase 2 (LRRK2) gene (G2019S) on the synaptic functions of astrocytes. We found that both in human and mouse cortex, the LRRK2 G2019S mutation causes astrocyte morphology deficits and enhances the phosphorylation of the ERM proteins (Ezrin, Radixin, and Moesin), which are important components of perisynaptic astrocyte processes. Reducing ERM phosphorylation in LRRK2 G2019S mouse astrocytes restored astrocyte morphology and corrected excitatory synaptic deficits. Using anin vivoBioID proteomic approach, we found Ezrin, the most abundant astrocytic ERM protein, interacts with the Autophagy-Related 7 (Atg7), a master regulator of catabolic processes. The Ezrin/Atg7 interaction is inhibited by Ezrin phosphorylation, thus diminished in the LRRK2 G2019S astrocytes. Importantly, Atg7 function is required to maintain proper astrocyte morphology. These studies reveal an astrocytic molecular mechanism that could serve as a therapeutic target in PD.
A hybridin silico/in-cell controller for microbial bioprocesses with process-model mismatch
Authors: Ohkubo Tomoki , Soma Yuki , Sakumura Yuichi , Hanai Taizo , Kunida Katsuyuki
Published: April 2023

The optimization of bioprocess inputs using mathematical models is widely practiced. However, the mismatch between model prediction and the actual process [called process-model mismatch (PMM)] is problematic; when a large PMM exists, the process inputs optimized using the mathematical model in advance are no longer optimal for the actual process. In this study, we propose a hybrid control system that combines model-based optimization (in silicofeedforward controller) and feedback controllers using synthetic genetic circuits integrated into cells (in-cell feedback controller) – which we named the hybridin silico/in-cell controller (HISICC) – as a solution to this PMM issue. As a proof of concept for HISICC, we constructed a mathematical model of an engineeredEscherichia colistrain for the isopropanol production process that was previously developed. This strain contains an in-cell feedback controller, and its combination with anin silicocontroller can be regarded as an example of HISICC. We demonstrated the robustness of HISICC against PMM by comparing the strain with another strain with no in-cell feedback controller in simulations assuming PMM of various magnitudes.
GALBA: Genome Annotation with Miniprot and AUGUSTUS
Authors: Brůna Tomáš , Li Heng , Guhlin Joseph , Honsel Daniel , Herbold Steffen , Stanke Mario , Nenasheva Natalia , Ebel Matthis , Gabriel Lars , Hoff Katharina J.
Published: April 2023

The Earth Biogenome Project has rapidly increased the number of available eukaryotic genomes, but most released genomes continue to lack annotation of protein-coding genes. In addition, no transcriptome data is available for some genomes. Various gene annotation tools have been developed but each has its limitations. Here, we introduce GALBA, a fully automated pipeline that utilizes miniprot, a rapid protein- to-genome aligner, in combination with AUGUSTUS to predict genes with high accuracy. Accuracy results indicate that GALBA is particularly strong in the annotation of large vertebrate genomes. We also present use cases in insects, vertebrates, and a previously unannotated land plant. GALBA is fully open source and available as a docker image for easy execution with Singularity in high-performance computing environments. Our pipeline addresses the critical need for accurate gene annotation in newly sequenced genomes, and we believe that GALBA will greatly facilitate genome annotation for diverse organisms.
Formation of Ba3Nb0.75Mn2.25O9-6H during thermochemical reduction of Ba4NbMn3O12-12R
Authors: Strange Nicholas A. , Bell Robert T. , Park James Eujin , Stone Kevin H. , Coker Eric N. , Ginley David S.
Published: April 2023

The resurgence of interest in hydrogen-related technologies has stimulated new studies aimed at advancing lesser-developed water-splitting processes, such as solar thermochemical hydrogen production (STCH). Progress in STCH has been largely hindered by a lack of new materials able to efficiently split water at a rate comparable to ceria under identical experimental conditions. BaCe0.25Mn0.75O3 (BCM) recently demonstrated enhanced hydrogen production over ceria and has the potential to further our understanding of two-step thermochemical cycles. A significant feature of the 12R hexagonal perovskite structure of BCM is the tendency to, in part, form a 6H polytype at high temperatures and reducing environments (i.e., during the first step of the thermochemical cycle), which may serve to mitigate degradation of the complex oxide. An analogous compound, namely BaNb0.25Mn0.75O3 (BNM) with a 12R structure was synthesized and displays nearly complete conversion to the 6H structure under identical reaction conditions as BCM. The structure of the BNM-6H polytype was determined from Rietveld refinement of synchrotron powder X-ray diffraction data and is presented within the context of the previously established BCM-6H structure.
Syntheses, crystal structures and Hirshfeld surface analyses of four molecular salts of amitriptynol
Authors: Vinaya  , Anil Kumar Haleyur G. , Mohan Kumar Thaluru M. , Lakshmana Beliyaiah , Basavaraju Yeriyur B. , Yathirajan Hemmige S. , Parkin Sean
Published: April 2023

The syntheses and crystal structures of four salts of amitriptynol (C20H25NO) with different carboxylic acids are described. The salts formed directly from solutions of amitriptyline (which first hydrolysed to amitriptynol) and the corresponding acid in acetonitrile to form amitriptynolium [systematic name: (3-{2-hydroxytricyclo[9.4.0.03,8]pentadeca-1(11),3,5,7,12,14-hexaen-2-yl}propyl)dimethylazanium] 4-methoxybenzoate monohydrate, C20H26NO+·C8H7O3
−·H2O, (I), amitriptynolium 3,4-dimethoxybenzoate trihydrate, C20H26NO+·C9H9O4
−·3H2O, (II), amitriptynolium 2-chlorobenzoate, C20H26NO+·C7H4ClO2
−, (III), and amitriptynolium thiophene-2-carboxylate monohydrate, C20H26NO+·C5H3O2S−·H2O, (IV). Compound (III) crystallizes with two cations, two anions and six water molecules in the asymmetric unit. The different conformations of the amitriptynolium cations are determined by the torsion angles in the dimethylamino-propyl chains and the –CH2–CH2- bridge between the benzene rings in the tricyclic ring system, and are complicated by disorder of the bridging unit in II and III. The packing in all four salts is dominated by N—H...O and O—H...O hydrogen bonds. Hirshfeld surface analyses show that the amitriptynolium cations make similar inter-species contacts, despite the distinctly different packing in each salt.