bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy, Safety, and Tolerability of Centanafadine Sustained-Release Tablets in Adults With Attention-Deficit/Hyperactivity Disorder
Authors: Adler Lenard A. , Adams Julie , Madera-McDonough Jessica , Kohegyi Eva , Hobart Mary , Chang Denise , Angelicola Mark , McQuade Robert , Liebowitz Michael
Published: June 2022

Purpose/Background

Centanafadine is an inhibitor of norepinephrine, dopamine, and serotonin reuptake transporters under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD).

Methods/Procedures

Two phase 3 randomized, double-blind, placebo-controlled, parallel-group studies of 200 mg/d or 400 mg/d centanafadine sustained-release tablets versus placebo included adults (18–55 years of age) with a diagnosis of ADHD. The primary and key secondary efficacy endpoints were the change from baseline at day 42 in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score and the Clinical Global Impression–Severity of Illness Scale, respectively.

Findings/Results

Subjects randomized in study 1 (centanafadine 200 mg/d, n = 149; centanafadine 400 mg/d, n = 149; placebo, n = 148) and study 2 (centanafadine 200 mg/d, n = 145; centanafadine 400 mg/d, n = 143; placebo, n = 142) had moderate to severe ADHD (mean AISRS total score, 38.7 [SD, 6.8] across both studies). At day 42, statistically significant least-squares mean differences in AISRS total score were observed in favor of centanafadine versus placebo in study 1 (200 mg/d: −3.16, P = 0.019; 400 mg/d: −2.74, P = 0.039) and study 2 (200 mg/d: −4.01, P = 0.002; 400 mg/d: −4.47, P = 0.001). Effect sizes versus placebo were −0.28 for 200 mg/d and −0.24 for 400 mg/d in study 1 and −0.37 for 200 mg/d and −0.40 for 400 mg/d in study 2. The overall rate of treatment-emergent adverse events (TEAEs) was low, but there was a small increase in TEAE occurrence with increasing dose. Incidences of serious TEAEs and abuse potential–related AEs were low.

Implications/Conclusions

These are the first large-scale studies to demonstrate the efficacy and safety profiles of 200 mg/d and 400 mg/d centanafadine in adults with ADHD.
Observed Injury Rates Did Not Follow Theoretically Predicted Injury Risk Patterns in Professional Human Circus Artists
Authors: Shrier Ian , Mattiello Rita , Caron Melissa , Verhagen Evert , Steele Russell J.
Published: June 2022

Objective:

Identifying which types of athletes have increased injury risk (ie, predictive risk factors) should help develop cost-effective selective injury prevention strategies. Our objective was to compare a theoretical injury risk classification system developed by coaches and rehabilitation therapists, with observed injury rates in human circus acts across dimensions of physical stressors, acrobatic complexity, qualifications, and residual risks.

Design:

Descriptive epidemiological study.

Setting:

professional circus company.

Patients or Other Participants:

Human circus artists performing in routine roles between 2007 and 2017.

Assessment of Risk Factors:

Characteristics of circus acts categorized according to 4 different dimensions.

Main Outcome Measures:

Medical attention injury rates (injury requiring a visit to the therapist), time-loss injury rates (TL-1; injury resulting in at least one missed performance), and time-loss 15 injury rates (TL-15; injury resulting in at least 15 missed performances).

Results:

Among 962 artists with 1 373 572 performances, 89.4% (860/962) incurred at least one medical attention injury, 74.2% (714/962) incurred at least one TL-1 injury, and 50.8% (489/962) incurred at least one TL-15 injury. There were important inconsistencies between theoretical and observed injury risk patterns in each of the 4 dimensions for all injury definitions (medical attention, TL-1, and TL-15).

Conclusions:

Although theoretical classifications are the only option when no data are available, observed risk patterns based on injury surveillance programs can help identify artists who have a high (or low) theoretical risk but are nonetheless actually at low (or high) risk of injury, given their current roles. This will help develop more cost-effective selective injury prevention programs.
She came to me for care, why would I say no? Survey results of advanced practice nurses caring for transgender and gender diverse patients
Authors: Klotzbaugh Ralph , Hopwood Ruben , Spencer Gale
Published: June 2022

ABSTARCT

Background:

Literature has recognized deficient knowledge of transgender or gender diverse (TGD) patient needs that can negatively affect health care. Prior research on education has shown little progress responsive to TGD health care needs from nursing. Findings from this demonstrate some improvement, however slight. This study examined the education of family nurse practitioners (FNPs) providing care to TGD patients.

Purpose:

The purposes of this study were to describe the relationship between location of practice and TGD patient care and to identify emerging themes related to the care of TGD individuals.

Methods:

Surveys were sent to 3,500 FNPs. Surveys were completed by 356.

Results:

No significant results were found between location of practice and TGD patient care or between location of education and TGD curricular inclusion. Statistical significance was found between inclusion of TGD content and participants' year of graduation. Those graduating in or after 2011 were more likely to report receiving content. Themes emerged in four areas related to practice area, role, location, and education. This study highlights inadequacy of curricular inclusion of TGD health needs. Findings underscored ways FNPs sourced best practices to provide health care to TGD people.

Implications for Clinical Practice:

These findings provide additional support for the need to educate FNPs to reduce barriers for TGD persons in accessing affirming health care.
Characterization of Host-Pathogen-Device Interactions in Pseudomonas aeruginosa Infection of Breast Implants
Authors: Vuong Linh N. , Dorsey Denise , Obernuefemann Chloe , Pinkner Jerome , Walker Jennifer N. , Hultgren Scott , Myckatyn Terence M.
Published: June 2022

Background:

Pseudomonas aeruginosa accounts for 7 to 22 percent of breast implant–associated infections, which can result in reconstructive failures and explantation. Investigating host-pathogen-device interactions in mice and patient samples will improve the understanding of colonization mechanisms, for targeted treatments and clinical guidelines.

Methods:

Mice with and without implants were infected with PAO1 laboratory strain or BIP2 or BIP16 clinical strains and killed at 1 day or 7 days after infection to evaluate for colonization of implants and underlying tissues by means of colony-forming unit enumeration. Immunostaining was performed on mouse implants, human tissue expanders colonized by BIP2, and acellular dermal matrix colonized by BIP16.

Results:

Colonization of tissues and smooth implants by P. aeruginosa was strain-dependent: at 1 day after infection, all strains acutely infected tissues with and without implants with colonization levels reflecting growth rates of individual strains. At 7 days after infection, PAO1 caused colonization of approximately 105 colony-forming units/100 mg of tissue but required implant presence, whereas in mice infected with BIP2/BIP16, colony-forming units were below the limit of detection with or without implants. Immunofluorescence staining of mouse implants, however, demonstrated continued presence of BIP2 and BIP16. Staining showed co-localization of all strains with fibrinogen, collagen I, and collagen III on mouse and human samples.

Conclusions:

The trajectory of P. aeruginosa in breast implant–associated infections was strain-dependent, and strains could exhibit acute symptomatic or chronic asymptomatic colonization. With strains causing clinical symptoms, the presence of an implant significantly worsened infection. For asymptomatic colonizers, further studies investigating their long-term impacts, especially during periods of immunosuppression in hosts, are needed.
Acellular Dermal Matrix Favorably Modulates the Healing Response after Surgery
Authors: du Plessis Miriam I. , Cottler Patrick S. , Campbell Chris A.
Published: June 2022

When first described for breast reconstruction, the presence of acellular dermal matrices was associated with increased seroma formation and infection. However, clinical safety data have gradually improved with surgeon experience to an acceptable outcomes profile of acellular dermal matrix–assisted reconstruction when compared to submuscular implant coverage. In fact, acellular dermal matrix use potentially decreases capsular contracture rates and facilitates expansion for staged prepectoral breast reconstruction. Because of new regulatory requirements, the collection of unbiased, well-powered premarket approval data summarizing long-term clinical outcomes will be essential over the coming years to understand the clinical performance of acellular dermal matrix use in breast reconstruction. Currently, the authors can highlight the physiologic benefits of acellular dermal matrix use in breast reconstruction by evaluating the components of surgical wound healing that are favorably augmented by the implanted collagen substrate. Acellular dermal matrix takes advantage of the wound healing cascade to incorporate into the patient’s tissues—a process that requires a coordinated inflammatory infiltrate and angiogenesis. The presence of acellular dermal matrix augments and modulates the wound healing process to its advantage by simultaneously increasing the invasion of appropriate cellular constituents to facilitate expeditious healing and accelerate angiogenesis. In this article, the authors summarize the wound healing literature to demonstrate the mechanisms acellular dermal matrices use to biointegrate and the literature in which cellular constituents and soluble growth factors are up-regulated in the presence of acellular dermal matrix. Lastly, the authors use their experimental observations of acellular dermal matrix incorporation to corroborate the literature.
The Effects of a Prenatal Mindfulness Intervention on Infant Autonomic and Behavioral Reactivity and Regulation
Authors: Noroña-Zhou Amanda N. , Coccia Michael , Epel Elissa , Vieten Cassandra , Adler Nancy E. , Laraia Barbara , Jones-Mason Karen , Alkon Abbey , Bush Nicole R.
Published: June 2022

Objective

Maternal health and wellness during pregnancy are associated with long-term health outcomes in children. The current study examined whether infants of women who participated in a mindfulness-based intervention during pregnancy that reduced levels of stress and depression, increased physical activity, and improved glucose tolerance differed on biobehavioral markers of psychopathological and physical health risk compared with infants of women who did not.

Methods

Participants were 135 mother-infant dyads drawn from a racially and ethnically diverse, low-income sample experiencing high stress. The women participated in an intervention trial during pregnancy that involved assignment to either mindfulness-based intervention or treatment-as-usual (TAU). Infants of women from both groups were assessed at 6 months of age on sympathetic (preejection period), parasympathetic (respiratory sinus arrhythmia), and observed behavioral (negativity and object engagement) reactivity and regulation during the still face paradigm. Linear mixed-effects and generalized linear mixed-effects models were used to examine treatment group differences in infant outcomes.

Results

Relative to those in the intervention group, infants in the TAU group showed a delay in sympathetic activation and subsequent recovery across the still face paradigm. In addition, infants in the intervention group engaged in higher proportions of self-regulatory behavior during the paradigm, compared with the TAU group. No significant effect of intervention was found for parasympathetic response or for behavioral negativity during the still face paradigm.

Conclusions

Findings provide evidence that maternal participation in a short-term, group mindfulness-based intervention during pregnancy is associated with the early development of salutary profiles of biobehavioral reactivity and regulation in their infants. Because these systems are relevant for psychopathology and physical health, prenatal behavioral interventions may benefit two generations.
Prognostic Value of Different Computed Tomography Scoring Systems in Patients With Severe Traumatic Brain Injury Undergoing Decompressive Craniectomy
Authors: Zhao Zhi-Jie , Chen Di , Zhou Lai-Yang , Sun Zhao-Liang , Wang Bo-Cheng , Feng Dong-Fu
Published: June 2022

Objective

In this study, we investigate the preoperative and postoperative computed tomography (CT) scores in severe traumatic brain injury (TBI) patients undergoing decompressive craniectomy (DC) and compare their predictive accuracy.

Methods

Univariate and multivariate logistic regression analyses were used to determine the relationship between CT score (preoperative and postoperative) and mortality at 30 days after injury. The discriminatory power of preoperative and postoperative CT score was assessed by the area under the receiver operating characteristic curve (AUC).

Results

Multivariate logistic regression analysis adjusted for the established predictors of TBI outcomes showed that preoperative Rotterdam CT score (odds ratio [OR], 3.60; 95% confidence interval [CI], 1.13–11.50; P = 0.030), postoperative Rotterdam CT score (OR, 4.17; 95% CI, 1.63–10.66; P = 0.003), preoperative Stockholm CT score (OR, 3.41; 95% CI, 1.42–8.18; P = 0.006), postoperative Stockholm CT score (OR, 4.50; 95% CI, 1.60–12.64; P = 0.004), preoperative Helsinki CT score (OR, 1.44; 95% CI, 1.03–2.02; P = 0.031), and postoperative Helsinki CT score (OR, 2.55; 95% CI, 1.32–4.95; P = 0.005) were significantly associated with mortality. The performance of the postoperative Rotterdam CT score was superior to the preoperative Rotterdam CT score (AUC, 0.82–0.97 vs 0.71–0.91). The postoperative Stockholm CT score was superior to the preoperative Stockholm CT score (AUC, 0.76–0.94 vs 0.72–0.92). The postoperative Helsinki CT score was superior to the preoperative Helsinki CT score (AUC, 0.88–0.99 vs 0.65–0.87).

Conclusions

In conclusion, assessing the CT score before and after DC may be more precise and efficient for predicting early mortality in severe TBI patients who undergo DC.
Efficacy and Safety of Intravenous Golimumab in Ankylosing Spondylitis Patients With Early and Late Disease Through One Year of the GO-ALIVE Study
Authors: Deodhar Atul A. , Shiff Natalie J. , Gong Cinty , Hsia Elizabeth C. , Lo Kim Hung , Kim Lilliane , Xu Stephen , Reveille John D.
Published: June 2022

Background/Objective

This post hoc analysis assessed efficacy and safety of intravenous (IV) golimumab in ankylosing spondylitis (AS) patients with early disease (ED) versus late disease (LD).

Methods

The phase 3, double-blind, GO-ALIVE study randomized patients to IV golimumab 2 mg/kg at weeks 0 and 4 and then every 8 weeks through week 52, or placebo at weeks 0, 4, and 12 with crossover to IV golimumab at week 16. Clinical efficacy was assessed by ≥20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS20), ≥50% improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), and Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 (inactive disease). Using self-reported duration of inflammatory back pain (IBP), patients were grouped into quartiles: first = ED and fourth = LD. Descriptive statistics summarized efficacy and safety findings through 1 year.

Results

Early disease patients (n = 60) were ~10 years younger and had shorter median AS (IBP) symptom duration (2–3 years) versus LD patients (n = 52; 21–24 years). At week 16, numerically higher proportions of golimumab- than placebo-treated patients achieved ASAS20 (ED: 71% vs. 32%; LD: 67% vs. 21%), BASDAI 50 (ED: 40% vs. 12%; LD: 33% vs. 7%), and ASDAS <1.3 (ED: 17% vs. 4%; LD 8% vs. 0%) regardless of IBP duration. Efficacy was durable through 1 year of treatment; however, response rates were numerically higher in patients with ED versus LD. Through week 60, adverse events and serious adverse events, respectively, were reported by 46% and 3% of ED patients and 61% and 2% of LD patients.

Conclusion

Prompt diagnosis of AS and early treatment with IV golimumab may yield more robust improvements in disease activity.
Language exposure and brain myelination in early development
Authors: Fibla Laia , Forbes Samuel H. , McCarthy Jordan , Mee Kate , Magnotta Vincent , Deoni Sean , Cameron Donnie , Spencer John P.
Published: June 2022

The language environment to which children are exposed has an impact on later language and cognitive abilities as well as on brain development; however, it is unclear how early such impacts emerge. This study investigates the effects of children’s early language environment and socioeconomic status (SES) on brain structure in infancy at both 6 and 30 months of age. We used magnetic resonance imaging (MRI) to quantify concentrations of myelin in specific fiber tracts in the brain. Our central question was whether Language ENvironment Analysis (LENA) measures from in-home recording devices and SES measures of maternal education and family income predicted myelin concentrations over development. Results show relationships between amount of in-home adult input and myelination in the white matter tracts most associated with language. Right hemisphere regions also show an association with SES, with older children from a higher SES background who were exposed to more adult input showing greater concentrations of myelin in language-related areas. We discuss these results in relation with the current literature and implications for future language research and intervention.

Significance Statement

This is the first study to look at how brain myelination is impacted by language input and socioeconomic status early in development. We find robust relationships of both factors in language-related brain areas at 30 months of age.
Prognostic value of serum MMP-9 level in acute ischemic stroke patient
Authors: Nayak Amit R. , Muley Swapnil S. , Kashyap Rajpal S. , Lande Neha H. , Kabra Dinesh P. , Singh Lokendra R. , Daginawala Hatim F.
Published: June 2022

Purpose

MMP-9 is reported to be a marker of severity and worse outcome after stroke. Despite the above information, there are very few studies based on the evaluation of role of follow-up estimation of serum MMP-9 in acute ischemic stroke (AIS) patients. The purpose of this study was to evaluate the role of follow-up estimation of serum MMP-9 in the prognosis of AIS patients. MMP-9 levels were also compared with reported biomarkers viz. Neuron-Specific Enolase (NSE), Glial specific protein (S100ββ) and Inter-α-trypsin inhibitor heavy chain 4 (ITIH4).

Materials/methods

MMP-9, NSE, and S-100ββ were measured in serum samples collected at admission and expired/discharge time of AIS patients (n=48) using commercially available ELISA kits. ITIH4 was measured using Indirect ELISA protocol.

Results

MMP-9 at admission (3639 ±1471) and discharged/expired (3707 ±1268) was significantly higher (p<0.05) in AIS patients as compared to healthy control subjects (749 ±302). Expired patients showed significantly (p<0.05) higher MMP-9 as compared to survivors. Similarly, follow-up MMP-9 at discharge was higher in AIS patients who expired within one year (75%; 3/4). The observed values of MMP-9 significantly correlates (p<0.05) with NSE (r=0.452), S-100ββ (r=0.452) and ITIH4 (r=-0.2027).

Conclusions

Follow-up measurement of serum MMP-9 may help to predict both short term and long term mortality in AIS patients.
COVID-19 is not an Independent Cause of Death
Authors: Castro Marcia C , Gurzenda Susie , Turra Cassio M , Kim Sun , Andrasfay Theresa , Goldman Noreen
Published: June 2022

The COVID-19 pandemic has had overwhelming global impacts with deleterious social, economic, and health consequences. To assess the COVID-19 death toll researchers have estimated declines in 2020 life expectancy at birth. Because data are often available only for COVID-19 deaths, the risks of dying from COVID-19 are assumed to be independent of those from other causes. We explore the soundness of this assumption based on data from the US and Brazil, the countries with the largest number of reported COVID-19 deaths. We use three methods. One estimates the difference between 2019 and 2020 life tables and therefore does not require the assumption of independence. The other two assume independence to simulate scenarios in which COVID-19 mortality is added to 2019 death rates or is eliminated from 2020 rates. Our results reveal that COVID-19 is not independent of other causes of death. The assumption of independence can lead to either an overestimate (Brazil) or an underestimate (US) of the decline in e0, depending on how the number of other reported causes of death changed in 2020.
TheGBAvariant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines
Authors: Smith Laura. J. , Bolsinger Magdalena. M. , Chau Kai-Yin. , Gegg Matthew. E. , Schapira Anthony. H. V.
Published: June 2022

Sequence variants or mutations in theGBAgene are numerically the most important risk factor for Parkinson disease (PD). TheGBAgene encodes for the lysosomal hydrolase enzyme, glucocerebrosidase (GCase).GBAmutations often reduce GCase activity and lead to impairment of the autophagy-lysosomal pathway, which is important in the turnover of alpha-synuclein, accumulation of which is a key pathological hallmark of PD. Although the E326K variant is one of the most commonGBAvariants associated with PD, there is limited understanding of its biochemical effects. We have characterised homozygous and heterozygous E326K variants in human fibroblasts. We found that E326K variants did not cause significant loss of GCase protein or activity, endoplasmic reticulum (ER) retention or ER stress, in contrast to the L444PGBAmutation. This was confirmed in human dopaminergic SH-SY5Y neuroblastoma cell lines over-expressing GCase with either E326K or L444P protein. Despite no loss of GCase activity, a significant increase of insoluble alpha-synuclein aggregates in E326K and L444P mutants was observed. Notably, SH-SY5Y over-expressing E326K demonstrated a significant increase in lipid droplet number under basal conditions, which was exacerbated following treatment with the fatty acid oleic acid. Similarly, a significant increase in lipid droplet formation following lipid loading was observed in heterozygous and homozygous E326K fibroblasts. In conclusion, the work presented here demonstrates that the E326K mutation behaves differently to common loss of functionGBAmutations, however lipid dyshomeostasis and alpha-synuclein pathology is still evident.
H4K20me1 plays a dual role in transcriptional regulation during regeneration and axis patterning ofHydra
Authors: Gungi Akhila , Pal Mrinmoy , Saha Shagnik , Galande Sanjeev
Published: June 2022

The evolution of the first body axis in the animal kingdom and an extensive ability to regenerate makesHydra, a Cnidarian, an excellent model system for understanding the underlying epigenetic mechanisms. We identify that SETD8 is critical for regeneration due to its interaction with β-catenin to fine-tune the underlying gene regulatory network. Its target histone mark, H4K20me1, colocalizes with transcriptional activation machinery locally at the β-catenin bound TCF/LEF binding sites on the promoters of head-associated genes, marking an epigenetic activation node. Contrastingly, genome-wide analysis of the H4K20me1 occupancy revealed a negative correlation with transcriptional activation. We propose H4K20me1 as a general repressive histone mark in Cnidaria and describe its dichotomous role in transcriptional regulation inHydra.
Single molecule studies characterize the kinetic mechanism of tetrameric p53 binding to different native response elements
Authors: Suwita Johannes P. , Voong Calvin K. , Ly Elina , Goodrich James A. , Kugel Jennifer F.
Published: June 2022

The transcriptional activator p53 is a tumor suppressor protein that controls cellular pathways important for cell fate decisions, including cell cycle arrest, senescence, and apoptosis. It functions as a tetramer by binding to specific DNA sequences known as response elements (REs) to control transcription via interactions with co-regulatory complexes. Critical for understanding how p53 regulates gene expression is unraveling the fundamental mechanisms by which it binds to REs. Toward this goal we have used an in vitro single molecule fluorescence approach to quantify the dynamic binding of tetrameric p53 to five native REs in real time under equilibrium conditions. We found little evidence of dimer/DNA complexes as intermediates to the formation or dissociation of p53 tetramer/DNA complexes; however, tetramer/DNA complexes can exchange dimers at some REs. Determining rate constants for association and dissociation revealed two kinetically distinguishable populations of tetrameric p53/RE complexes. For the less stable population, the rate constants for dissociation were larger at REs closest to consensus, showing the more favorable binding sequences form the least kinetically stable complexes. Together our real time measurements provide insight into mechanisms with which tetrameric p53 forms complexes on different native REs.
GWANN: Implementing deep learning in genome wide association studies
Authors: Ashkenazy Nimrod , Feder Martin , Shir Ofer M. , Hübner Sariel
Published: June 2022

Motivation

Genome wide association studies (GWAS) are extensively used across species to identify genes that underlie important traits. Most GWAS methods apply modifications and extensions to a linear regression model in order to detect significant associations between genetic variation and a trait. Despite their popularity, these statistical models tend to suffer from high false positive rates, especially when utilized on large variant datasets or complex demographic scenarios. To overcome this, aggressive statistical corrections are applied which frequently diminish true associations.

Results

Here we consider a deep learning approach, and present an implementation of a convolutional neural network (CNN) to identify genetic variation that is associated with a trait of interest. To exploit the strength of CNNs in visual recognition, the genotype information is represented as an image, which enables the model to correctly classify genetic variants with respect to the trait, even when a population structure is present. Our proposed approach was implemented in a package called GWANN which exhibited solid performance. Overall, GWANN outperformed popular GWAS tools on both simulated and real datasets, and enabled the identification of association signals with increased sensitivity and speed.

Availability and implementation

The package is available at: https://github.com/hubner-lab/GWANN
Development and Application of a Novel Simple Sequence Repeat Mining Algorithm Based on Regular Expression
Authors: Jia Zhenguo , Geng Ruimei , Wu Xiuming , Chen Shuai , Tong Ying , Yang Aiguo , Luo Chenggang , Ren Min
Published: June 2022

Simple sequence repeats (SSRs) are molecular genetic markers that are powerful tools in genomics studies; SSR markers are routinely mined as a part of genetic workflows. Here, we developed a novel SSR mining algorithm based on regular expression that can reduce the complexity of commonly used SSR mining software. We used the following SSR mining regular expression: ({i, j}?) (\1) {k}, where i and j denote the minimum and maximum lengths of the motifs of the SSR sequence, respectively, and k is the minimum number of repeat motifs. From this SSR mining algorithm, we developed an SSR sequence analysis software (named “regexSSRw”) that is capable of mining eligible SSR loci from FASTA format sequences; regexSSRw can be accessed at https://github.com/renm79/rgxSSRw. This SSR mining algorithm can aid a range of applications, from being used by programmers in the development of SSR mining software to being implemented by scholars into their SSR marker workflow.
OmicSelector: automatic feature selection and deep learning modeling for omic experiments
Authors: Stawiski Konrad , Kaszkowiak Marcin , Mikulski Damian , Hogendorf Piotr , Durczyński Adam , Strzelczyk Janusz , Chowdhury Dipanjan , Fendler Wojciech
Published: June 2022

A crucial phase of modern biomarker discovery studies is selecting the most promising features from high-throughput screening assays. Here, we present the OmicSelector - Docker-based web application and R package that facilitates the analysis of such experiments. OmicSelector provides a consistent and overfitting-resilient pipeline that integrates 94 feature selection approaches based on 25 distinct variable selection methods. It identifies and then ranks the best feature sets using 11 modeling techniques with hyperparameter optimization in hold-out or cross-validation. OmicSelector provides classification performance metrics for proposed feature sets, allowing researchers to choose the overfitting-resistant biomarker set with the highest diagnostic potential. Finally, it performs GPU-accelerated development, validation, and implementation of deep learning feedforward neural networks (up to 3 hidden layers, with or without autoencoders) on selected signatures. The application performs an extensive grid search of hyperparameters, including balancing and preprocessing of next-generation sequencing (e.g. RNA-seq, miRNA-seq) oraz qPCR data. The pipeline is applicable for determining candidate circulating or tissue miRNAs, gene expression data and methylomic, metabolomic or proteomic analyses. As a case study, we use OmicSelector to develop a diagnostic test for pancreatic and biliary tract cancer based on serum small RNA next-generation sequencing (miRNA-seq) data. The tool is open-source and available at https://biostat.umed.pl/OmicSelector/
Biocompatible polymeric microparticles serve as novel and reliable vehicles for exogenous hormone manipulations in passerines
Authors: Mahr Katharina , Anzengruber Maria , Hellerschmid Anna , Slezaceck Julia , Hoi Herbert , Subbiahdoss Guruprakash , Gabor Franz , Lendvai Ádám Z.
Published: June 2022

The administration of exogenous hormones emerged as an essential tool for field studies in endocrinology. However, working with wild animals remains challenging because under field conditions, not every available method meets the necessary requirements. Achieving a sustained elevation in hormone levels while simultaneously minimising handling time and invasiveness of the procedure is a difficult task in field endocrinology. Facing this challenge, we have investigated the suitability of biocompatible polymeric microparticles, a novel method for drug administration, as a tool to manipulate hormones in small songbirds. We chose the insulin-like growth factor -1 (IGF-1) as the target hormone because it receives great interest from the research community due to its important role in shaping life-history traits. Moreover, its short half-life and hydrophilic properties imply a major challenge in finding a suitable method to achieve a sustained, systemic long-term release. To study the release kinetics, we injected either IGF-1 loaded polylactic-co-glycolic acid (PLGA) microparticles or dispersion medium (control group) in the skin pocket of the interscapular region of captive bearded reedlings (Panurus biarmicus). We collected blood samples for 7 consecutive days plus an additional sampling period after two weeks and complemented these with an in vitro experiment. Our results show that in vitro, PLGA microparticles allowed a stable IGF-1 release for more than 15 days, following a burst release at the beginning of the measurement. In vivo, the initial burst was followed by a drop to still elevated levels in circulating IGF-1 until the effect vanished by 16 days post-treatment. This study is the first to describe PLGA-microparticles as a novel tool for exogenous hormone administration in a small passerine. We suggest that this method is highly suitable to achieve the systemic long-term release of hydrophilic hormones with a short half-life and reduces overall handling time, as it requires only one subcutaneous injection.
Development of neonatal brain functional centrality and alterations associated with preterm birth
Authors: Fenn-Moltu Sunniva , Fitzgibbon Sean P , Ciarrusta Judit , Eyre Michael , Cordero-Grande Lucilio , Chew Andrew , Falconer Shona , Gale-Grant Oliver , Harper Nicholas , Dimitrova Ralica , Vecchiato Katy , Fenchel Daphna , Javed Ayesha , Earl Megan , Price Anthony N , Hughes Emer , Duff Eugene P , O’Muircheartaigh Jonathan , Nosarti Chiara , Arichi Tomoki , Rueckert Daniel , Counsell Serena , Hajnal Joseph V , Edwards A David , McAlonan Grainne , Batalle Dafnis
Published: June 2022

Formation of the functional connectome in early life underpins future learning and behaviour. However, our understanding of how the functional organisation of brain regions into interconnected hubs (centrality) matures in the early postnatal period is limited, especially in response to factors associated with adverse neurodevelopmental outcomes such as preterm birth. We characterised voxel-wise functional centrality (weighted degree) in 366 neonates from the Developing Human Connectome Project. We tested the hypothesis that functional centrality matures with age at scan in term-born babies and is disrupted by preterm birth. Finally, we asked whether neonatal functional centrality predicts general neurodevelopmental outcomes at 18 months. We report an age-related increase in functional centrality predominantly within visual regions and decrease within motor and auditory regions in term-born infants. Preterm-born infants scanned at term equivalent age had higher functional centrality predominantly within visual regions and lower measures in motor regions. Functional centrality was not related to outcome at 18 months old. Thus, preterm birth appears to affect functional centrality in regions undergoing substantial development during the perinatal period. Our work raises the question of whether these alterations are adaptive or disruptive, and whether they predict neurodevelopmental characteristics that are more subtle or emerge later in life.
Proactive inhibition of goal-directed movements involves explicit changes to movement planning
Authors: Pickavance John P. , Mon-Williams M. , Mushtaq Faisal , Morehead J. Ryan
Published: June 2022

Inhibition can be implemented reactively, withholding movement in response to a stop-signal, or by proactive changes to movement planning when a stop-signal is expected. Previous studies have typically employed simple button presses, finding proactive delays to movement onset when a stop-signal might appear. Here, we consider inhibition in the context of more complex, goal-directed movements, such as the swing of a bat. Thus, we observe two additional dimensions of movement planning under proactive control, movement duration and end-point error. We found, in addition to onset delay, movements were briefer and arrived later when a stop-signal might appear. This challenges a classical theoretical dichotomy, suggesting proactive inhibition is underlay by both response suppression and delayed facilitation. Moreover, participants were aware of delays to onset and arrival, but reported magnitudes were smaller than observed. This suggests proactive inhibition operates as an explicitly retrievable compensatory strategy whose finer details are implicitly tuned.
Dissociation of CED-4 from CED-9 upon EGL-1 binding: Molecular mechanism of linear apoptotic pathway inCaenorhabditis elegans
Authors: Reddy C. Narendra , Sankararamakrishnan Ramasubbu
Published: June 2022

Many steps in programmed cell death are evolutionarily conserved across different species. TheCaenorhabditis elegansproteins CED-9, CED-4 and EGL-1 involved in apoptosis are respectively homologous to anti-apoptotic Bcl-2 proteins, Apaf-1 and the “BH3-only” pro- apototic proteins in mammals. In the linear apoptotic pathway ofC.elegans, EGL-1 binding to CED-9 leads to the release of CED-4 from CED-9/CED-4 complex. The molecular events leading to this process are not clearly elucidated. While the structures of CED-9 apo, CED- 9/EGL-1 and CED-9/CED-4 complexes are known, the CED-9/CED-4/EGL-1 ternary complex structure is not yet determined. In this work, we modeled this ternary complex and performed molecular dynamics simulations of six different systems involving CED-9. CED-9 displays differential dynamics depending upon whether it is bound to CED-4 and/or EGL-1. CED-4 exists as an asymmetric dimer (CED4a and CED4b) in CED-9/CED-4 complex. CED-4a exhibits higher conformational flexibility when simulated without CED-4b. Principal Component Analysis revealed that the direction of CED-4a’s winged-helix domain motion differs in the ternary complex. Upon EGL-1 binding, majority of non-covalent interactions involving CARD domain in the CED-4a-CED-9 interface have weakened and only half of the contacts found in the crystal structure between α/β domain of CED4a and CED-9 are found to be stable. Additional stable contacts in the ternary complex and differential dynamics indicate that winged-helix domain may play a role in CED-4a’s dissociation from CED-9. This study has provided a molecular level understanding of potential intermediate states that are likely to occur at the time of CED-4a’s release from CED-9.
In-text citation error rate as a scientometric tool for evaluating accuracy and weighing evidence
Authors: Lee Derek E.
Published: June 2022

Scientists are fallable and biased, but accuracy can be assessed through empirical analysis of published work that quantifies in-text citation (or quotation) errors. In scientific conflicts, it can be difficult for outsiders to know whose evidence or interpretation to trust. In-text citation error rate can assist decision- and policy-making bodies, as well as the courts when conflicts reach the judicial branch of government, by quantifying absolute and relative accuracy of scientists presenting scientific evidence. I propose the use of in-text citation error rates as a scientometric tool to quantify the accuracy of an author’s work. In-text citation error rates in excess of an established overall mean (e.g., 11% for minor errors and 7% for major errors in ecology), or differences in in-text citation error rates between opposing groups of scientists could be used to reveal excessive inaccuracies in an author or group. The spotted owl (Strix occidentalis) has been at the center of a multi-decadal conflict caused by competition among people over forest resources, with scientific experts representing opposing stakeholders often presenting conflicting evidence. I applied the in-text citation error rate tool to important papers in the spotted owl and forest fire debate and found evidence of greater error rates in works on one side of this debate. In-text citation error rate can be an effective tool for quantifying accuracy among scientists.
Immune-mediated Tubule Atrophy Promotes Acute Kidney Injury to Chronic Kidney Disease Transition
Authors: Xu Leyuan , Guo Jiankan , Moledina Dennis G. , Cantley Lloyd G.
Published: June 2022

Incomplete repair after acute kidney injury (AKI) is associated with progressive loss of tubular cell function and development of chronic kidney disease (CKD). Here, we compared mice subjected to either unilateral ischemia-reperfusion kidney injury with contralateral nephrectomy (IRI/CL-NX, in which tubule repair predominates) or unilateral IRI with contralateral kidney intact (U-IRI, in which fibrosis and atrophy predominates) to investigate the mechanism(s) underlying transition to CKD following AKI. The initial injury and early recruitment and activation of macrophages, dendritic cells (DCs), neutrophils, and T cells were similar through day 7 but markedly diverged afterwards between the two models. By day 14, kidneys subjected to U-IRI had greater numbers of macrophages with higher expression of Ccl2, Ccl7, Ccl8, Ccl12, and Cxcl16. These chemokines correlated with a second wave of Ccr1-positive neutrophils and Cxcr6-positive T cells, resulting in a proinflammatory milieu, accompanied by increased expression of tubular cell injury, oxidative stress and major histocompatibility complex genes. This second wave of immune dysfunction led to a distinct profile of tubule injury with morphologic kidney atrophy and a decreased proportion of differentiated tubule cells. Combined depletion of neutrophils and T cells beginning on day 5 after U-IRI was found to reduce tubular cell loss and the associated kidney atrophy. In kidney biopsy samples from patients with AKI, the number of interstitial T cells and neutrophils negatively correlated with 6-month recovery of GFR. Together, our findings demonstrate that macrophage persistence after AKI promotes a T cell- and neutrophil-mediated proinflammatory milieu that leads to progressive tubule damage.
Automated protein-protein structure prediction of the T cell receptor-peptide major histocompatibility complex
Authors: Rollins Zachary A. , Curtis Matthew B. , Faller Roland , George Steven C.
Published: June 2022

T Cell Receptor (TCR) recognition of a peptide-major histocompatibility complex (pMHC) is a crucial component of the adaptive immune response. The identification of therapeutically relevant TCR-pMHC pairs is a significant bottleneck in the implementation of TCR-based immunotherapies but may be augmented by computational methodologies. The ability to computationally design TCRs to target a specific pMHC will require an automated integration of next-generation sequencing, protein-protein structure prediction, molecular dynamics (MD), and TCR ranking. We present a generic pipeline to evaluate patient-specific, sequence-based TCRs to a target pMHC. Using the three most frequently expressed TCRs from 16 colorectal cancer patients, we predicted the protein-protein structure of the TCRs to the target CEA peptide-MHC using Modeller and ColabFold. Then, these TCR-pMHC structures were compared by performing an automated molecular dynamics equilibration. ColabFold generates starting configurations that require, on average, a ~2.5X reduction in simulation time to equilibrate TCR-pMHC structures compared to Modeller. In addition, the structural differences between Modeller and ColabFold are demonstrated by an increase in root mean square deviation (~0.20 nm) between clusters of equilibrated configurations, which can impact the number of hydrogen bonds and Lennard-Jones contacts between the TCR and pMHC. Finally, we identify a TCR ranking criteria that may be used to prioritize TCRs for evaluation of in vitro immunogenicity.
Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma
Authors: Sessions Dane T. , Kim Kee-Beom , Kashatus Jennifer A. , Churchill Nikolas , Park Kwon-Sik , Mayo Marty W. , Sesaki Hiromi , Kashatus David F.
Published: June 2022

Oncogenic KRas activates mitochondrial fission through Erk-mediated phosphorylation of the mitochondrial fission GTPase Drp1. Drp1 deletion inhibits tumorigenesis of KRas-driven pancreatic cancer, but the role of mitochondrial dynamics in other Ras-driven malignancies is poorly defined. Here we demonstrate that in vitro and in vivo growth of KRas-driven lung adenocarcinoma is unaffected by deletion of Drp1, but inhibited by deletion of Opa1, the GTPase that regulates inner membrane fusion and promotes proper cristae morphology. Mechanistically, Opa1 knockout induces loss of electron transport chain (ETC) complex I assembly and activity that inhibits tumor cell proliferation through loss of NAD+ regeneration. Simultaneous inactivation of Drp1 and Opa1 restores cristae morphology, complex I activity and cell proliferation indicating that mitochondrial fission activity drives ETC dysfunction induced by Opa1 knockout. Our results support a model in which mitochondrial fission events disrupt cristae structure and tumor cells with hyperactive fission activity require Opa1 activity to maintain ETC function.
SVDquintets: a New Tool for Species Tree Inference
Authors: Richards A.
Published: June 2022

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Species tree inference is complicated by the fact that different segments have the genome can have evolutionary histories that differ from each other and from the evolutionary history of the species as a whole. One source of this mismatch is incomplete lineage sorting (ILS), which is commonly modeled by the multispecies coalescent process. Here we derive site pattern probabilities under the multispecies coalescent model, the Jukes-Cantor substitution model, and a relaxed molecular clock for five species at a time. As a result, we can demonstrate that the rank results that form the theoretical basis for SVDQuartets also appear to hold for sets of five species. Based on this, we have developed a new species tree inference algorithm: SVDquintets. Comparison with SVDQuartets shows improved species tree inference under a variety of simulated data settings.
Mapping genomic regulation of kidney disease and traits through high-resolution and interpretable eQTLs
Authors: Han Seong Kyu , McNulty Michelle T. , Benway Christopher J. , Wen Pei , Greenberg Anya , Onuchic-Whitford Ana C. ,   NEPTUNE, Wilson Parker C. , Humphreys Benjamin D. , Wen Xiaoquan , Han Zhe , Lee Dongwon , Sampson Matthew G.
Published: June 2022

Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes and contribute to fine-mapped loci discovered via genome-wide association studies (GWAS). Efforts to maximize their accuracy are ongoing. Using 240 glomerular (GLOM) and 311 tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered 5,371 GLOM and 9,787 TUBE eQTLs by incorporating kidney single-nucleus open chromatin data and transcription start site distance as an “integrative prior” for Bayesian statistical fine mapping. The use of an integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller numbers of variants in credible sets with greater confidence, (2) increased enrichment of partitioned heritability for GWAS of two kidney traits, (3) an increased number of variants colocalized with the GWAS loci, and (4) enrichment of computationally predicted functional regulatory variants. A subset of variants and genes were validated experimentally in vitro and using a Drosophila nephrocyte model. More broadly, this study demonstrates that tissue-specific eQTL maps informed by single-nucleus open chromatin data have enhanced utility for diverse downstream analyses.
Abdominal movements in insect flight reshape the role of non-aerodynamic structures for flight maneuverability I: Model predictive control for flower tracking
Authors: Bustamante Jorge , Ahmed Mahad , Deora Tanvi , Fabien Brian , Daniel Thomas L.
Published: June 2022

Research on insect flight control has focused primarily on the role of wings. Yet abdominal deflections during flight can potentially influence the dynamics of flight. This paper assesses the role of airframe deformations in flight, and asks to what extent the abdomen contributes to flight maneuverability. To address this, we use a combination of both a Model Predictive Control (MPC)-inspired computational inertial dynamics model, and free flight experiments in the hawkmoth, Manduca sexta. We explored both underactuated (i.e. number of outputs are greater than the number of inputs) and fully actuated (equal number of outputs and inputs) systems. Using metrics such as the non-dimensionalized tracking error and cost of transport to evaluate flight performance of the inertial dynamics model, we show that fully actuated simulations minimized the tracking error and cost of transport. Additionally, we tested the effect of restricted abdomen movement on free flight in live hawkmoths by fixing a carbon fiber rod over the thoracic-abdomen joint. Moths with a restricted abdomen performed worse than sham treatment moths. This study finds that abdominal motions contribute to flight control and maneuverability. Such motions of non-aerodynamic structures, found in all flying taxa, can inform the development of multi-actuated micro air vehicles.