bluuebunny/crossref_metadata_2025 huggingface dataset:
Working Conditions and Racial and Ethnic Disparities in Self-rated Health
Authors: Whitley Margaret D. , Burgard Sarah A.
Published: April 2023

Objective

The aims of the study are to examine racial and ethnic differences in occupational physical demands, substantive complexity, time pressure, work hours, and establishment size and to assess whether working conditions contribute to racial and ethnic differences in self-rated health.

Methods

We used 2017 and 2019 Panel Study of Income Dynamics data for 8439 adults. Using path models, we examined working conditions among Black, Latino, and White workers and explored whether those conditions mediated racial and ethnic differences in incident poor self-rated health.

Results

Some working conditions disproportionately affected Black workers (high physical demands, low substantive complexity), Latino workers (low substantive complexity, small establishments), and White workers (time pressure). Time pressure predicted worse self-rated health; there was no evidence that the working conditions studied mediated racial/ethnic differences.

Conclusions

Working conditions vary by racial and ethnic group; some predict worse health.
Lipoprotein(a) is associated with premature coronary artery disease: a meta-analysis
Authors: Papathanasiou Konstantinos A. , Kazantzis Dimitrios , Rallidis Loukianos S.
Published: April 2023

Background

Lipoprotein(a) is associated with adverse cardiovascular outcomes and its association with premature coronary artery disease (pCAD) is underexamined. The primary aim of the study is to compare serum lipoprotein(a) levels between pCAD cases and controls.

Methods

We conducted a systematic review and the MEDLINE database, ClinicalTrials.gov, medRxiv and Cochrane Library were searched for studies evaluating lipoprotein(a) and pCAD. Standardized mean differences (SMD) of lipoprotein(a) in pCAD patients versus the controls were pooled by a random-effects meta-analysis. The presence of statistical heterogeneity was evaluated with the Cochran Q chi-square test and the quality of the included studies was assessed via the Newcastle-Ottawa Scale.

Results

A total of 11 studies were found eligible, reporting on the difference in lipoprotein(a) levels between pCAD patients and controls. Serum lipoprotein(a) concentration was found significantly increased in patients with pCAD (SMD = 0.97; 95% confidence intervals, 0.52–1.42; P < 0.0001; I
2 = 98%) as compared to controls. High statistical heterogeneity and relatively small case-control studies of moderate quality are the main limitations of this meta-analysis.

Conclusion

Lipoprotein(a) levels are significantly increased in patients with pCAD as compared to controls. Further studies are needed to clarify the clinical significance of this finding.
Tailored Nurse Support Program Promoting Positive Parenting and Family Preservation
Authors: Brown Samantha M. , McConnell Luke , Zelaya Alicia , Doran Mary , Swarr Vicki
Published: April 2023

Background

Public health nurse home visiting is a promising approach for addressing the complex needs of families at risk of child maltreatment. The Colorado Nurse Support Program advances service provision by using evidence-based practices to provide tailored assessment and intervention to low-income, primiparous, and multiparous families with children under 18 years of age identified as high risk by county human service systems.

Objectives

This study aimed to test the effects of the Nurse Support Program on child protective services case characteristics between Nurse Support Program families and a demographically comparable reference group of families and evaluate changes in parenting outcomes from pre- to postprogram involvement for Nurse Support Program families.

Methods

We used a matched comparison group quasi-experimental design in which families in the Nurse Support Program (n = 48) were compared to families (n = 150) who were identified using administrative data from Colorado’s Comprehensive Child Welfare Information System. Outcomes were child protective case characteristics (child protection referrals, open assessments, founded assessments, open cases, and children’s placement in out-of-home care) and parenting outcomes.

Results

Nurse Support Program families were less likely to have a child protection case opened or have their child placed in out-of-home care. There were no significant between-group differences in child protection referrals, open assessments, or founded assessments. Families in the Nurse Support Program showed improvements in parenting outcomes over time.

Discussion

Findings suggest that the Nurse Support Program is a successful public health nurse home-visiting approach to promote positive parenting and family preservation among families with complex needs. Implementing tailored public health nurse home-visiting programs, such as the Nurse Support Program, should continue to be evaluated and supported to mitigate the public health risk of child maltreatment.
Trusted Sources of Information and COVID-19 Vaccine Uptake in a Sample of Latinx Sexual and Gender Minorities in South Florida
Authors: Metheny Nicholas , Scott Dalton , Buch Juan , Fallon Stephen , Chavez Jennifer
Published: April 2023

Objective:

To examine factors associated with COVID-19 vaccine uptake in a sample of Latino/a/x sexual and/or gender minority (SGM) individuals in South Florida.

Design:

Data were collected via an online survey from March 2021 to August 2022, as part of the Community Engagement Alliance Against COVID-19 Disparities. A multivariate regression analysis was fit using completion of a COVID-19 vaccine regimen as the outcome. Key covariates included trusted sources of information (eg, doctor, media), COVID-19–related challenges (eg, accessing medication, transportation), and dominant wave of SARS-CoV-2 at the time of data collection.

Setting:

Miami-Dade and Broward counties, Florida.

Results:

White Latino/a/x, bachelor's educated respondents, and those with high levels of trust in community organizations had significantly greater odds of vaccination.

Conclusion:

Community organizations may be key to improving vaccine uptake among marginalized Latino/a/x SGM for COVID-19 and other emerging communicable diseases, such as meningitis and Mpox (monkeypox). The results of this study suggest that tailored public health messaging and additional funding for vaccine distribution are needed to better equip community organizations with the resources they need to serve this population.
Clinical characteristics and outcomes of inpatient falls during inpatient rehabilitation: a case-control study
Authors: Lee Se Won , Elsakr Carol , Ayutyanont Napatkamon , Lee Soohyoung , Oh-Park Mooyeon
Published: April 2023

Inpatient falls (IFs) have a significant impact on the outcomes of older patients during inpatient rehabilitation. A retrospective case-control study was conducted using data of 7,066 adults aged 55 years or older to evaluate significant predictors of IFs during inpatient rehabilitation (IR) and the association of IFs with discharge destination and length of stay (LOS). A stepwise logistic regression was used to model odds of IFs and home discharge with demographic and clinical characteristic variables and a multivariate linear regression to evaluate the association between IFs and LOS.

931 of 7,066 patients (13.18%) had IFs during IR. The group with IFs had longer LOS (14.22 ± 7.82 versus 11.85 ± 5.33 days, P < .0001) and a decreased proportion of home discharges when compared to the group without IFs. There were increased odds of IFs among patients with diagnoses of head injury, other injuries, a history of falls, dementia, a divorced marital status, and a use of laxatives or anticonvulsants. IFs were associated with an increased LOS (Coefficient 1.62, CI [1.19, 2.06]) and decreased odds of home discharge (OR 0.79, CI [0.65, 0.96]) after IR. This knowledge may be incorporated into strategies for reducing IFs during IR.
Identification of key breast features using a neural network: applications of machine learning in the clinical setting of Plastic Surgery
Authors: Kenig Nitzan , Monton Echeverria Javier , De la Ossa Luis
Published: April 2023

Introduction:

In Plastic Surgery, evaluation of breast symmetry is an important aspect of clinical practice. Computer programs have been developed for this purpose, but most of them require operator input. Artificial Intelligence has been introduced into many aspects of medicine. In Plastic Surgery, automated neural networks for breast evaluation could improve quality of care. In this work, we evaluate the identification of breast features, with an ad-hoc trained neural network.

Materials and Methods:

An ad-hoc convolutional neural network was developed on YOLOV3 platform to detect key features of the breast that are commonly used in Plastic Surgery for symmetry evaluation. The program was trained with 200 frontal photographs of patients who underwent breast surgery and was tested on 47 frontal images of patients who underwent breast reconstruction after suffering from breast cancer.

Results:

the program was successfully able to detect key features in 97.74% of cases. The boundaries of the breast in 94/94 of cases, the nipple-areolar complex in 94/94 of cases and the suprasternal notch in 41/47 of cases. Mean time of detection was 0,52 seconds.

Conclusions:

The ad-hoc neural network was successful at localizing key breast features, with a total detection rate of 97.74%. Neural Networks and machine learning have a potential of improving the evaluation of breast symmetry in the field of Plastic Surgery, by automated and quick detection of features used by surgeons in practice. More studies and development are needed to further the knowledge in this area.
A Characterization of Pediatric Craniofacial Injuries from Children’s Toys
Authors: Treger Dylan , Plotsker Ethan , Thaller Seth R.
Published: April 2023

Introduction:

Playing with toys contributes significantly to the cognitive, physical, and social development of children. Certain toys, unfortunately, carry the potential for serious craniofacial injury. There is a gap in the literature regarding the comprehensive assessment of toy-related craniofacial injuries. By studying mechanisms of injury and ensuing trauma, our goal is to encourage innovative design and educate caregivers, health care workers, and the Consumer Product Safety Commission on risk mitigation and prevention.

Methods and Materials:

The National Electronic Injury Surveillance System Database was queried to analyze toy-related craniofacial injuries that occurred in children (ages 0–10) between 2011 and 2020.

Results:

Approximately 881,000 injuries occurred over a 10-year span. Children ages 1 to 5 sustained most injuries, peaking at age 2 (16.3%). Males were injured 1.95 times more frequently than females. Injured sites included the face (43.7%), head (29.7%), mouth (13.5%), ears (6.9%), and eyes (6.2%). The top diagnoses were lacerations (40.4%), foreign bodies (16.2%), internal injuries (15.8%), and contusions (15.8%). The most common causes were scooters (13%), balls (6.9%), toy vehicles excluding riding toys (6.3%), building sets (4.4%), and tricycles (3%).

Discussion:

This study identifies toys that most frequently cause craniofacial injuries in children. These results provide new information about types of play that should be supervised, and this data helps anticipate injury profiles seen in emergency settings. Future research should study why the products identified are strongly associated with injuries, so safety features can be optimized and designs appropriately altered.
A Prospective Clinical Trial to Evaluate Mesothelin as a Biomarker for the Clinical Management of Patients with Esophageal Adenocarcinoma
Authors: Byun Alexander J. , Grosser Rachel A. , Choe Jennie K. , Rizk Nabil P. , Tang Laura H. , Molena Daniela , Tan Kay See , Restle David , Cheema Waseem , Zhu Amy , Gerdes Hans , Markowitz Arnold J. , Bains Manjit S. , Rusch Valerie W. , Jones David R. , Adusumilli Prasad S.
Published: April 2023

Objective:

We conducted a prospective trial (NCT01393483) to investigate the utility of serum soluble mesothelin related peptide (SMRP) and tumor mesothelin expression in the management of esophageal adenocarcinoma (ADC).

Summary Background Data:

Clinical management of esophageal ADC is limited by a lack of accurate evaluation of tumor burden, treatment response and disease recurrence. Our retrospective data showed that tumor mesothelin and its serum correlate, SMRP, are overexpressed and associated with poor outcomes in patients with esophageal ADC.

Methods:

Serum SMRP and tumoral mesothelin expression from 101 patients with locally advanced esophageal ADC were analyzed prior to induction chemoradiation (pre-treatment) and at the time of resection (post-treatment), as a biomarker for treatment response, disease recurrence and overall survival (OS).

Results:

Pre- and post-treatment serum SMRP was ≥1 nM in 49% and 53%, and pre- and post-treatment tumor mesothelin expression was >25% in 35% and 46% of patients, respectively. Pre-treatment serum SMRP was not significantly associated with tumor stage (P=0.9), treatment response (radiologic response, P=0.4; pathologic response, P=0.7) or recurrence (P=0.229). Pre-treatment tumor mesothelin expression was associated with OS (HR, 2.08; 95% CI, 1.14-3.79; P=0.017) but had no statistically significant association with recurrence (P=0.9). 3-year OS of patients with pre-treatment tumor mesothelin expression of ≤25% was 78% (95% CI, 68-89%), compared to 49% (95% CI, 35-70%) among those with >25%.

Conclusions:

Pre-treatment tumor mesothelin expression is prognostic of OS for patients with locally advanced esophageal ADC, whereas serum SMRP is not a reliable biomarker for monitoring treatment response or recurrence.
Use of multiplex PCR in pleural effusion: Is it necessary to change the paradigm of culture-based methods?
Authors: Londono-Ruiz Juan Pablo , Vargas-Garcia Andrea , Cardenas-Muller Adriana , Bejarano-Quintero Ana Maria , Mantilla Maria Ximena , Gutierrez-Tobar Ivan Felipe
Published: April 2023

The microbiological diagnosis of pleural effusion is largely based on classical microbiology methods, but these methods have a high rate of false negative results. Some previous studies have shown improved diagnostic performance for pathogens such as S. pneumoniae using molecular biology methods. We present the use of a Multiplex-PCR platform (BIOFIRE® FILMARRAY® Pneumonia Panel) for the etiological diagnosis of pleural effusion in pediatric pneumonia. We present a case series of 17 pleural fluid samples that were processed by culture-based microbiology and molecular biology methods. We document an increase in pathogen detection compared to culture-based methods. Additionally, the detection of viral pathogens in the pleural effusion was found, which are an important cause of pneumonia in pediatrics.
The conformational landscape of a serpin N-terminal subdomain facilitates folding and in-cell quality control
Authors: Kaur Upneet , Kihn Kyle C. , Ke Haiping , Kuo Weiwei , Gierasch Lila M. , Hebert Daniel N. , Wintrode Patrick L. , Deredge Daniel , Gershenson Anne
Published: April 2023

Many multi-domain proteins including the serpin family of serine protease inhibitors contain non-sequential domains composed of regions that are far apart in sequence. Because proteins are translated vectorially from N-to C-terminus, such domains pose a particular challenge: how to balance the conformational lability necessary to form productive interactions between early and late translated regions while avoiding aggregation. This balance is mediated by the protein sequence properties and the interactions of the folding protein with the cellular quality control machinery. For serpins, particularly α1-antitrypsin (AAT), mutations often lead to polymer accumulation in cells and consequent disease suggesting that the lability/aggregation balance is especially precarious. Therefore, we investigated the properties of progressively longer AAT N-terminal fragments in solution and in cells. The N-terminal subdomain, residues 1-190 (AAT190), is monomeric in solution and efficiently degraded in cells. More ý-rich fragments, 1-290 and 1-323, form small oligomers in solution, but are still efficiently degraded, and even the polymerization promoting Siiyama (S53F) mutation did not significantly affect fragment degradation.In vitro,the AAT190 region is among the last regions incorporated into the final structure. Hydrogen-deuterium exchange mass spectrometry and enhanced sampling molecular dynamics simulations show that AAT190 has a broad, dynamic conformational ensemble that helps protect one particularly aggregation prone ý-strand from solvent. These AAT190 dynamics result in transient exposure of sequences that are buried in folded, full-length AAT, which may provide important recognition sites for the cellular quality control machinery and facilitate degradation and, under favorable conditions, reduce the likelihood of polymerization.
Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress
Authors: Rodrigues RS , Moreira JB , Vaz SH , Barateiro A , Paulo SL , Mateus JM , Lourenço DM , Ribeiro FF , Loureiro-Campos E , Bielefeld P , Fernandes A , Sebastião AM , Pinto L , Fitzsimons CP , Xapelli S
Published: April 2023

Chronic stress is a major risk factor of neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects upon cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophin levels, we hypothesized that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, and an overall reduction in neuroinflammation. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasizes the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalize on lifestyle interventions complemented with endocannabinoid pharmacomodulation.
A chromosome-scale and haplotype-resolved genome assembly of tetraploid blackberry (RubusL. subgenusRubusWatson)
Authors: Paudel Dev , Peng Ze , Parajuli Saroj , Parrish S. Brooks , Deng Zhanao
Published: April 2023

Background

Blackberries (RubussubgenusRubus) are a major berry crop consumed globally for being a rich source of anthocyanins and antioxidants, and their unique flavor. However, breeding for fruit improvement in blackberry has been significantly hindered by the scarcity of genomic resources and the genetic complexity of traits. The blackberry genome has been particularly challenging to assemble, largely due to its polyploid nature.

Findings

We present the first chromosome-scale and haplotype-phased genome assembly for the cultivated primocane-fruiting, thornless tetraploid blackberry selection BL1 (RubusL. subgenusRubusWatson). The tetraploid genome assembly was generated using the Oxford Nanopore Technology (ONT) and Hi-C scaffolding, comprising 919 Mb placed on 27 pseudochromosomes with an N50 of 35.73 Mb. The assembly covers >92% of the genome length and contains over 98% of complete BUSCOs. Repetitive sequences constitute 57% of the assembly, with the long terminal repeats (LTR) being the most abundant class. A total of 87,968 protein-coding genes were predicted, of which, 82% were functionally annotated. Gene expression analyses identified candidate genes and transcription factors related to thornlessness in blackberries, including MYB16, lysine histidine transporters, PDR1, Caffeoyl-CoA, glycosylphosphatidylinositol-anchored lipid protein transfer 1, DRN, beta-ketoacyl reductase, and homocysteine S-methyltransferase 3.

Conclusions

The utility of this genome has been demonstrated in this study by identifying candidate genes related to thornlessness in blackberry. Resequencing of tetraploid blackberry cultivars/selections with different horticultural characteristics revealed genes that could impact fruiting habit and disease resistance/susceptibility. This tetraploid reference genome will serve as a valuable resource to accelerate genetic analysis and breeding of this important berry crop, enabling the development of improved varieties with enhanced traits.
Potential biomarkers for fatal outcome prognosis in a cohort of hospitalized COVID-19 patients with pre-existing co-morbidities
Authors: Madera-Sandoval Ruth Lizzeth , Cérbulo-Vázquez Arturo , Arriaga-Pizano Lourdes Andrea , Cabrera-Rivera Graciela Libier , Basilio-Gálvez Edna , Miranda-Cruz Patricia Esther , García de la Rosa María Teresa , Prieto-Chávez Jessica Lashkmin , Rivero-Arredondo Silvia Vanessa , Cruz-Cruz Alonso , Rodríguez-Hernández Daniela , Salazar-Ríos María Eugenia , Salazar-Ríos Enrique , Serrano-Molina Esli David , De Lira-Barraza Roberto Carlos , Villanueva-Compean Abel Humberto , Esquivel-Pineda Alejandra , Ramírez-Montes de Oca Rubén , Unzueta-Marta Omar , Flores-Padilla Guillermo , Anda-Garay Juan Carlos , Sánchez-Hurtado Luis Alejandro , Calleja-Alarcón Salvador , Romero-Gutiérrez Laura , Torres-Rosas Rafel , Bonifaz Laura C. , Pelayo Rosana , Márquez-Márquez Edna , López-Macías Constantino III Roberto , Ferat-Osorio Eduardo
Published: April 2023

Background

The difficulty to predict fatal outcomes in COVID-19 patients, impacts in the general morbidity and mortality due to SARSCoV2 infection, as it wears out the hospital services that care for these patients. Unfortunately, in several of the candidates for prognostic biomarkers proposed, the predictive power is compromised when patients have pre-existing co-morbidities.

Methods

A cohort of one hundred and forty-seven patients hospitalized for severe COVID19 was included in a descriptive, observational, single-center, and prospective study. Patients were recruited during the first COVID-19 pandemic wave (April-Nov, 2020). Data were collected from the clinical history while immunophenotyping by multiparameter flow cytometry analysis allowed us to assess the expression of surface markers on peripheral leukocytes. Patients were grouped according to the outcome in survivor or decease. The prognostic value of leukocytes, cytokines or HLA-DR, CD39, and CD73 was calculated.

Results

Hypertension and chronic renal failure but not obesity and diabetes were conditions more frequent among the decease group. Mixed hypercitokinemia, including inflammatory (IL-6) and anti-inflammatory (IL-10) cytokines, was more evident in deceased patients. In the decease group, lymphopenia with a higher NLR value was present. HLA-DR expression and the percentage of CD39+ cells were higher than non COVID-19 patients, but remain similar despite outcome. ROC analysis and cut-off value of NLR (69.6%, 9.4), pNLR (71.1%, 13.6), IL-6 (79.7%, 135.2 pg/mL).

Conclusion

The expression of HLA-DR, CD39, and CD73, as many serum cytokines (other than IL-6) and chemokines levels do not show prognostic potential compared to NLR and pNLR values.
Cocoa flavanols improve peakVO2and exercise capacity in a randomized double blinded clinical trial in healthy elderly
Authors: Gröne Michael , Duse Dragos , Kramser Nicolas , Ophoff Niklas , Schweers Hendrik , Voß Fabian , Quast Christine , Sansone Roberto , Heiss Christian , Jung Christian , Kelm Malte , Erkens Ralf
Published: April 2023

Background

Loss of functional capacity is one of the hallmarks in cardiovascular aging. Cocoa flavanols (CF) exert favorable effects on endothelial function, blood pressure, and inflammation. These cardiovascular health markers worsen with increasing age and limit functional exercise capacity.

Aim

To investigate the effect of CF on cardiorespiratory-fitness in healthy elderly.

Methods

In a randomized, double-masked, placebo-controlled, parallel-group dietary intervention trial, 68 healthy elderly (55-79 years, 28 female) received either 500 mg of CF or a nutrient-matched control capsule twice a day for 30 days. Primary endpoint was defined as peak oxygen consumption (VO2) in a cardiopulmonary exercise test (CPET). Secondary endpoints were oxygen pulse (VO2/heart rate (HR)), resting blood pressure (BP), and resting vascular function.

Results

After 30 days of CF intake peakVO2increased by 190 ml/min (95% CI 1-371 ml/min) and peakVO2/kg by 2.5 ml/(min*kg) (95% CI 0.30-4.2 ml/(min*kg)). O2-pulse increased by 1.7 ml (95% CI 0.29-3.2 ml) and max exercise capacity by 9.6 W (95% CI 2.1-17.7 W). CF decreased resting systolic and diastolic BP by 5.4 mmHg (95% CI -10.7 - -0.1 mmHg) and 2.9 mmHg (95% CI (-) 5.5-(-) 0.4 mmHg), respectively. Flow-mediated vasodilation (FMD) increased by an absolute 1.3% (95% CI 0.76-1.79 %) in the CF group. Indexes of pulmonary function were not affected. No changes for primary and secondary endpoints were detected in control.

Conclusion

CF substantially improve markers of cardiorespiratory fitness in healthy elderly humans highlighting their potential to preserve cardiovascular health with increasing age.
New insights into the genetic etiology of 57 essential and non-essential trace elements in humans
Authors: Moksnes Marta R. , Hansen Ailin F. , Wolford Brooke N. , Thomas Laurent F. , Rasheed Humaira , Simić Anica , Bhatta Laxmi , Brantsæter Anne Lise , Surakka Ida , Zhou Wei , Magnus Per , Njølstad Pål R. , Andreassen Ole A. , Syversen Tore , Zheng Jie , Fritsche Lars G. , Evans David M. , Warrington Nicole M. , Nøst Therese H. , Åsvold Bjørn Olav , Flaten Trond Peder , Willer Cristen J. , Hveem Kristian , Brumpton Ben M.
Published: April 2023

Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study (GWAS) of 57 essential and non-essential trace elements. We performed GWA meta-analyses of 14 trace elements in up to 6580 Scandinavian whole-blood samples, and GWASs of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identified 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide meta-analyses. In HUNT, several genome-wide significant loci were also indicated for other trace elements. Using two-sample Mendelian randomization, we found several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our new understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.
Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study)
Authors: Saunders David , Arnold Thomas B. , Lavender Jason M. , Bi Daoqin , Alcover Karl , Hellwig Lydia D. , Leazer Sahar T , Mohammed Roshila , Markos Bethelhem , Perera Kanchana , Shaw Dutchabong , Kobi Priscilla , Evans Martin , Mains Autumn , Tanofsky-Kraff Marian , Goguet Emilie , Mitre Edward , Pratt Kathleen P , Dalgard Clifton L , Haigney Mark C
Published: April 2023

Background:

Significant clinical similarities have been observed between the recently Described ‘Long-Haul’ COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog”, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms.

Methods/Design:

A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights.

Discussion:

Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.

Trial registration:

ClinicalTrials.gov, ID:NCT05481177Registered on 29 July 2022.
Genome structure and population genomics of the canine heartwormDirofilaria immitis
Authors: Gandasegui Javier , Power Rosemonde I. , Curry Emily , Lau Daisy Ching-Wai , O’Neill Connor M. , Wolstenholme Adrian , Prichard Roger , Šlapeta Jan , Doyle Stephen R.
Published: April 2023

The heartworm,Dirofilaria immitis, is a filarial parasitic nematode responsible for significant morbidity and mortality in wild and domesticated canids. Resistance to macrocyclic lactone drug prevention represents a significant threat to parasite control and has prompted investigations to understand the genetic determinants of resistance. This study aimed to improve the genomic resources ofD. immitisto enable a more precise understanding of how genetic variation is distributed within and between parasite populations worldwide, which will inform the likelihood and rate by which parasites, and in turn, resistant alleles, might spread. We have guided the scaffolding of a recently published genome assembly forD. immitis(ICBAS_JMDir_1.0) using the chromosomal-scale reference genomes ofBrugia malayiandOnchocerca volvulus, resulting in an 89.5 Mb assembly composed of four autosomal- and one X-linked chromosomal-scale scaffolds representing 99.7% of the genome. Publicly available and new whole-genome sequencing data from 32D. immitissamples from Australia, Italy and the USA were assessed using principal component analysis, nucleotide diversity (Pi) and absolute genetic divergence (Dxy) to characterise the global genetic structure and measure within- and between population diversity. These population genetic analyses revealed broad-scale genetic structure among globally diverse samples and differences in genetic diversity between populations; however, fine-scale subpopulation analysis was limited and biased by differences between sample types. Finally, we mapped SNPs previously associated with macrocyclic lactone resistance in the new genome assembly, revealing physical linkage of high-priority variants on chromosome 3, and determined their frequency in the studied populations. This new chromosomal assembly forD. immitisnow allows for a more precise investigation of selection on genome-wide genetic variation and will enhance our understanding of parasite transmission and the spread of genetic variants responsible for resistance to treatment.
Local Monomer Levels and Established Filaments Potentiate Non-Muscle Myosin 2 Assembly
Authors: Quintanilla Melissa A. , Patel Hiral , Wu Huini , Sochacki Kem A. , Akamatsu Matthew , Rotty Jeremy D. , Korobova Farida , Bear James E. , Taraska Justin W. , Oakes Patrick W. , Beach Jordan R.
Published: April 2023

The ability to dynamically assemble contractile networks is required throughout cell physiology, yet the biophysical mechanisms regulating non-muscle myosin 2 filament assembly in living cells are lacking. Here we use a suite of dynamic, quantitative imaging approaches to identify deterministic factors that drive myosin filament appearance and amplification. We find that actin dynamics regulate myosin assembly, but that the actin architecture plays a minimal direct role. Instead, remodeling of actin networks modulates the local myosin monomer levels and facilitates assembly through myosin:myosin driven interactions. Using optogenetically controlled myosin, we demonstrate that locally concentrating myosin is sufficient to both form filaments and jump-start filament amplification and partitioning. By counting myosin monomers within filaments, we demonstrate a myosin-facilitated assembly process that establishes sub-resolution filament stacks prior to partitioning into clusters that feed higher-order networks.

Together these findings establish the biophysical mechanisms regulating the assembly of non-muscle contractile structures that are ubiquitous throughout cell biology.
IPMK modulates FFA-induced insulin resistance in primary mouse hepatocytes
Authors: Jung Ik-Rak , Ahima Rexford S. , Kim Sangwon F.
Published: April 2023

Insulin resistance is a critical mediator of the development of non-alcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of non-alcoholic fatty liver disease (NAFLD). Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of Akt phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-Acetyl Cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.
Foxc1andFoxc2function in osteochondral progenitors for the progression through chondrocyte hypertrophy and mineralization of the primary ossification center
Authors: Almubarak Asra , Zhang Qiuwan , Zhang Cheng-Hai , Lassar Andrew B. , Kume Tsutomu , Berry Fred B
Published: April 2023

The forkhead box transcription factor genesFoxc1andFoxc2are expressed in the condensing mesenchyme of the developing skeleton prior to the onset of chondrocyte differentiation. To determine the roles of these transcription factors in limb development we deleted bothFoxc1andFoxc2in lateral plate mesoderm using the Prx1-cre mouse line. Resulting compound homozygous mice died shortly after birth with exencephaly, and malformations to this sternum and limb skeleton. Notably distal limb structures were preferentially affected, with the autopods displaying reduced or absent mineralization. The radius and tibia bowed and the ulna and fibula were reduced to an unmineralized rudimentary structure. Molecular analysis revealed reduced expression of Ihh leading to reduced proliferation and delayed chondrocyte hypertrophy at E14.5. At later ages, Prx1-cre;Foxc1Δ/Δ;Foxc2Δ/Δembryos exhibited restored Ihh expression and an expanded COLX-positive hypertrophic chondrocyte region, indicating a delayed exit and impaired remodeling of the hypertrophic chondrocytes. Osteoblast differentiation and mineralization were disrupted at the osteochondral junction and in the primary ossification center (POC). Levels of OSTEOPONTIN were elevated in the POC of compound homozygous mutants, while expression of Phex was reduced, indicating that impaired OPN processing by PHEX may underlie the mineralization defect we observe. Together our findings suggest that Foxc1 and Foxc2 act at different stages of endochondral ossification. Initially these genes act during the onset of chondrogenesis leading to the formation of hypertrophic chondrocytes. At later stages Foxc1 and Foxc2 are required for remodeling of HC and for Phex expression required for mineralization of the POC.
NextPolish2:a repeat-aware polishing tool for genomes assembled using HiFi long reads
Authors: Hu Jiang , Wang Zhuo , Liang Fan , Liu Shanlin , Ye Kai , Wang De-Peng
Published: April 2023

The high-fidelity (HiFi) long-read sequencing technology developed by PacBio has greatly improved the base-level accuracy of genome assemblies, but these assemblies still contain some base-level errors, particularly within the error-prone regions of HiFi long reads. However, existing genome polishing tools usually introduce overcorrections and haplotype switch errors when correcting errors in genomes assembled from HiFi long reads. Here we describe an upgraded genome polishing tool - NextPolish2, which can fix base errors remaining in those “highly accurate” genomes assembled from HiFi long reads without introducing excess overcorrections and haplotype switch errors. We believe NextPolish2 has a great significance to further improve the accuracy of Telomere-to-Telomere (T2T) genomes. NextPolish2 is freely available athttps://github.com/Nextomics/NextPolish2.
A centrifugation-based method for high-throughput biomaterial separation using magnetic microbeads
Authors: Sugishita Hiroki , Hojo Kazunori , Hayashi Tetsutaro , Nikaido Itoshi , Gotoh Yukiko
Published: April 2023

Magnetic microbeads are small iron oxide nanoparticles coated with a bioaffinity material that selectively binds to specific biomolecules of interest, enabling their capture and isolation from complex biological samples. Magnetic microbeads are widely used for purification of specific biomolecules in various experiments in molecular biology. However, current methods of manual pipetting to separate supernatants from magnetic microbeads are often inefficient- time-consuming, labor intensive and inaccurate. Furthermore, the use of pipetting robots and liquid handlers specifically designed for multi-well plates can be a cost-prohibitive approach due to the high cost of equipment and disposable supplies. Here, we developed a centrifugation-based method for high-throughput separation of supernatant from magnetic microbeads. To facilitate the centrifugal separation process, we used the 384 transfer plate™ (Watson, Japan) and a magnetic stand equipped with a 384-well magnetic stand, allowing easy handling of several hundred samples and rapid separation of supernatant from magnetic microbeads. The centrifugal force was used to drive the separation of target molecules from the magnetic microbeads, and sample were successfully separated with relatively high recovery rates. Thus, this technology provides a simple, rapid, and cost- and labor-effective biomolecule separation method with potential applications in various fields, including molecular biology, clinical diagnostics, and biotechnology, and is a valuable addition to the existing toolbox of biomolecule separation methods.
An unconventional gatekeeper mutation sensitizes inositol hexakisphosphate kinases to an allosteric inhibitor
Authors: Aguirre Tim , Dornan Gillian L. , Hostachy Sarah , Neuenschwander Martin , Seyffarth Carola , Haucke Volker , Schütz Anja , von Kries Jens P. , Fiedler Dorothea
Published: April 2023

Inositol hexakisphosphate kinases (IP6Ks) are emerging as relevant pharmacological targets because a multitude of disease-related phenotypes has been associated with their function. While the development of potent IP6K inhibitors is gaining momentum, a pharmacological tool to distinguish the mammalian isozymes is still lacking. Here, we implemented an analog-sensitive approach for IP6Ks and performed a high-throughput screen to identify suitable lead compounds. The most promising hit, FMP-201300, exhibited high potency and selectivity towards the unique valine gatekeeper mutants of IP6K1 and IP6K2, compared to the respective wild-type kinases. Biochemical validation experiments revealed an allosteric mechanism of action that was corroborated by HDX-MS measurements. The latter analysis suggested that displacement of theαC helix, caused by the gatekeeper mutation, facilitates the binding of FMP-201300 to an allosteric pocket adjacent to the ATP binding site. FMP-201300 therefore serves as a valuable springboard for the further development of compounds that can selectively target the three mammalian IP6Ks; either as analog-sensitive kinase inhibitors or as an allosteric lead compound for the wild-type kinases.
Shortwave infrared (SWIR) fluorescence imaging of peripheral organs in awake and freely moving mice
Authors: Arús Bernardo A. , Cosco Emily D. , Yiu Joycelyn , Balba Ilaria , Bischof Thomas S. , Sletten Ellen M. , Bruns Oliver T.
Published: April 2023

Extracting biological information from awake and unrestrained mice is imperative to in vivo basic and pre-clinical research. Accordingly, imaging methods which preclude invasiveness, anesthesia, and/or physical restraint enable more physiologically relevant biological data extraction by eliminating these extrinsic confounders. In this article we discuss the recent development of shortwave infrared (SWIR) fluorescent imaging to visualize peripheral organs in freely-behaving mice, as well as propose potential applications of this imaging modality in the neurosciences.
Ketone Bodies in Right Ventricular Failure: A Unique Therapeutic Opportunity
Authors: Blake Madelyn , Puchalska Patrycja , Kazmirczak Felipe , Thenappan Thenappan , Crawford Peter A. , Prins Kurt W.
Published: April 2023

Introductory Paragraph

Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and multiple approaches that increase ketone concentrations exert advantageous cardiac effects in rodents and humans. However, the relationships between ketone bodies and right ventricular failure (RVF) are relatively unexplored. Moreover, the cardioprotective properties of ketones in preclinical RVF are unknown. Here, we show a compensatory ketosis is absent in pulmonary arterial hypertension (PAH) patients with RVF. In the monocrotaline (MCT) rat model of PAH-mediated RVF, a dietary-induced ketosis improves RV function, suppresses NLRP3 inflammasome activation, and combats RV fibrosis. The summation of these data suggest ketogenic therapies may be particularly efficacious in RVF, and therefore future studies evaluating ketogenic interventions in human RVF are warranted.
TFOFinder: Python program for identifying purine-only double-stranded stretches in the predicted secondary structure(s) of RNA targets
Authors: Neugroschl Atara , Catrina Irina E.
Published: April 2023

Nucleic acid probes are valuable tools in biology and chemistry and are indispensable for PCR amplification of DNA, RNA quantification and visualization, and downregulation of gene expression. Recently, triplex forming oligonucleotides (TFO) have received increased attention due to their improved selectivity and sensitivity in recognizing purine-rich double-stranded RNA regions at physiological pH by incorporating backbone and base modifications. For example, triplex forming peptide nucleic acid (PNA) oligomers have been used for imaging structured RNA in cells and inhibiting influenza A replication. Although a handful of programs are available to identify triplex target sites (TTS) in DNA, none are available that find such regions in structured RNAs. Here, we describeTFOFinder, a Python program that facilitates the identification of intramolecular purine-only RNA duplexes that are amenable to forming parallel triple helices (pyrimidine/purine/pyrimidine). We performed genome- and transcriptome-wide analyses of TTS inDrosophila melanogasterand found that only 0.3% (123) of total unique transcripts (35,642) show the potential of forming 12-purine long triplex forming sites that contain at least one guanine. Using minimization algorithms, we predicted the secondary structure(s) of these transcripts, and usingTFOFinder, we found that 97 (79%) of the identified 123 transcripts are predicted to fold to form at least one TTS for parallel triple helix formation. The number of transcripts with potential purine TTS increases when the strict search conditions are relaxed by decreasing the length of the probes or by allowing up to two pyrimidine inversions or 1-nucleotide bulge in the target site. These results are encouraging for the use of modified triplex forming probes for live imaging of endogenous structured RNA targets, such as pre-miRNAs, and inhibition of target-specific translation and viral replication.
The dual role of a highly structured RNA (the S fragment) in the replication of foot-and-mouth disease virus
Authors: Ward Joseph C. , Lasecka-Dykes Lidia , Dobson Samuel J. , Gold Sarah , Kingston Natalie J. , Herod Morgan R. , King Donald P. , Tuthill Tobias J. , Rowlands David J. , Stonehouse Nicola J.
Published: April 2023

Secondary and tertiary RNA structures play key roles in genome replication of single stranded positive sense RNA viruses. Complex, functional structures are particularly abundant in the untranslated regions of picornaviruses, where they are involved in initiation of translation, priming of new strand synthesis and genome circularisation. The 5′ UTR of foot-and-mouth disease virus (FMDV) is predicted to include ac.360 nucleotide-long stem-loop, termed the short (S) fragment. This structure is highly conserved and essential for viral replication, but the precise function(s) are unclear. Here, we used selective 2′ hydroxyl acetylation analysed by primer extension (SHAPE) to experimentally-determine aspects of the structure, alongside comparative genomic analyses to confirm structure conservation from a wide range of field isolates. To examine its role in virus replication, we introduced a series of deletions to the distal and proximal regions of the stem loop. These truncations affected genome replication in a size-dependent and, in some cases, host cell-dependent manner. Furthermore, during passage of viruses incorporating the largest tolerated deletion from the proximal region of the S fragment stem loop, an additional mutation was selected in the viral RNA-dependent RNA polymerase, 3Dpol.These data suggest that the S fragment and 3Dpolinteract in the formation of the FMDV replication complex.