bluuebunny/crossref_metadata_2025 huggingface dataset:
Surfactant proteins analysis in perinatal deceased preterm twins among the Romanian population
Authors: Ghitoi Sinziana-Andra , Așchie Mariana , Cozaru Georgeta Camelia , Enciu Manuela , Matei Elena , Nicolau Antonela-Anca , Bălțătescu Gabriela Izabela , Dobrin Nicolae , Cîrjaliu Roxana Elena , Fildan Ariadna Petronela
Published: August 2022

The molecular basis of the evaluation of children suspected of having disorders of surfactant proteins is still under discussion. In this study, we aimed to describe the morphological characteristics and to evaluate the immunohistochemical expression of surfactant proteins (surfactant protein A [SPA], surfactant protein B, and pro-surfactant protein C) in the preterm twins that deceased due to unexplained respiratory distress syndrome (n = 12). Results showed statistically significant positive correlations between surfactant protein B expressions and pulmonary hemorrhage (ρ = 0.678; P < .05), SPA levels, and Apgar score (ρ = 0.605; P < .05) and also expressions of SPA and bronchopneumonia (ρ = 0.695; P < .05). The fetuses and neonates of the same gestational age showed differences among surfactant proteins regarding the immunostaining expression. Our data evidence a marked interindividual variability in the expression of all 3 surfactant proteins among the cases analyzed (n = 12), suggesting the intervention of some individual and epigenetic factors during gestation that might influence surfactant protein production and consequently survival rate.
Prevalence of flatfoot among young Korean males and the correlation among flatfoot angles measured in weight-bearing lateral radiographs
Authors: Ryu Seung Min , Lee Taeg Ki , Lee Sun Ho
Published: August 2022

Flatfoot causes significant fatigue and pain while walking, and even asymptomatic flatfoot may increase the risk of metatarsal stress fracture during long-distance walking. While most studies have used physical examination or plantar footprints to diagnose flatfoot, a weight-bearing radiograph of the foot provides more objective data. However, data on the prevalence of flatfoot in Asian populations gathered in a nationwide cohort of a specific age group is lacking. We examined the prevalence of flatfoot among 19-year-old male Korean army recruits using a weight-bearing lateral radiograph and evaluated the correlation among flatfoot angles. A total of 560,141 19-year-old Korean males were examined at the regional Military Manpower Administration offices between April 2018 and April 2020. Weight-bearing lateral radiographs of the foot were obtained using an X-ray system while the subjects were standing on a table with their feet in a neutral position. Based on these radiographs, military orthopedic surgeons and radiologists measured the talo-first metatarsal angle (TMA) and calcaneal pitch angle (CPA) for flatfoot diagnosis. Mild flatfoot was diagnosed when the TMA ranged from 6 to 15° or the CPA was <17°, and moderate-to-severe flatfoot was diagnosed when the TMA was 15° or greater or the CPA was <10°. Pearson correlation coefficients and scatter plot matrix were used to evaluate the correlation among the flatfoot angles. Finally, we evaluated the relationship between body mass index (BMI) and flatfoot angles and compared the BMI in subjects with or without self-checked foot deformities including flatfoot and pes cavus. Of the 560,141 subjects, 16,102 (2.9%) were diagnosed as flatfoot, and 5265 (0.9%) were diagnosed with moderate-to-severe flatfoot. The coefficients between TMA and CPA ranged from 0.342 to 0.449 (all P values < 0.001), and those between the 2 sides of TMA and CPA were 0.709 and 0.746 (all P values < 0.001), respectively. BMI had a significant correlation with both TMA and CPA in subjects with flatfoot, and those with self-checked foot deformities had a significantly higher BMI than the group without foot deformities. The prevalence of total flatfoot and moderate-to-severe flatfoot in 19-year-old Korean males based on a weight-bearing lateral radiograph was 2.9% and 0.9%, respectively. The correlation coefficients between TMAs and CPAs showed a low degree of positive correlation. Higher BMI was associated with the likelihood of the presence of flatfoot.
CKAP2 overexpression correlates with worse overall survival in patients with lung adenocarcinoma
Authors: Zhang Sen , Li Na , Yang Yonghua , Li Yan , Lin Chenshi , Fu Guoquan , Cai Jun
Published: August 2022

Background:

Adenocarcinoma is a non–small-cell lung cancer that is common cancer in both genders, and has poor clinical outcomes. We aimed to evaluate the role of cytoskeleton-associated protein 2 (CKAP2), its prognostic significance, and the relationship between CKAP2 expression and lung adenocarcinoma driver genes.

Methods:

The expression of CKAP2 was studied by immunohistochemical staining of specimens from 88 patients with lung adenocarcinoma. The correlation between clinicopathological features and CKAP2 expression was analyzed. Kaplan-Meier analysis and Cox proportional hazard models were used to examine the prognostic value of CKAP2 in terms of overall survival (OS). The correlation between epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) rearrangement, and CKAP2 expression was analyzed. All histological samples were detected by fluorescence in situ hybridization for EGFR mutations and ALK rearrangements.

Results:

Eighty-eight patients with positive CKAP2 expression were observed in this study. Patients with high levels of CKAP2 expression were associated with OS (P = .021). Multivariate Cox regression analysis disclosed that positive CKAP2 expression (P = .043) could independently predict unfavorable OS. In addition, CKAP2 expression was not associated with EGFR mutation (P = .219) and ALK rearrangement (P = .389) in lung adenocarcinoma patients.

Conclusion:

High expression of CKAP2 may serve as a marker of poor prognosis in lung adenocarcinoma.
Real-life use of Doravirine in treatment-experienced people living with HIV: A multicenter Italian study
Authors: Mazzitelli Maria , Antoni Melania Degli , Castelli Francesco , Ripamonti Diego , Zuglian Gianluca , Lapadula Giuseppe , Fabbiani Massimiliano , Ferraresi Alice , Putaggio Cristina , Cattelan Anna Maria , Quiros-Roldan Eugenia
Published: August 2022

Use of doravirine (DOR), a new nonnucleoside reverse-transcriptase inhibitors recently approved for HIV treatment, is still unclear in clinical practice and real-life data are scarce.

We retrospectively investigated the rationale for switching people with HIV to DOR-containing/-based regimens in a real-life cohort. Among 132 patients (68.9% males, median age 56 years), the main reasons to start DOR were prevention of toxicities (39.4%) and dyslipidemia (18.2%). DOR was combined with integrase inhibitors in 40.9% cases, and in 25.7% of patients, DOR was prescribed without availability of a genotypic resistance test.

Twenty-four weeks after the switch to DOR-containing/-based regimens, no significant changes in CD4+ T-cell count, CD4/CD8 ratio, detectable HIV-RNA, serum creatinine levels, and body weight were detected. By contrast, a significant reduction in lipids (both cholesterol and triglycerides) was observed in 52 patients for whom a follow-up assessment was available (P = .008 and .01, respectively).

Our data confirmed that switching to DOR-containing/-based regimens may have a favorable impact on lipid profile and a neutral impact on weight gain. However, more data are needed to support its use in patients who do not have a genotypic test available or have an extensive nonnucleoside reverse-transcriptase inhibitors-associated resistance, as well as its use in a dual regimen, especially in combination with second-generation integrase inhibitors.
Intradural extramedullary capillary hemangioma with intramedullary component: A case series
Authors: Zhao Zhen , Zheng Jin , Zhou Yingchun
Published: August 2022

Rationale:

Capillary hemangioma in the spinal cord is an exceedingly rare entity that is liable to be misdiagnosed. To summarize the clinical presentation, radiological characteristics, and pathological features of capillary hemangioma in the spinal cord and to share our experience for the diagnosis and treatment of intradural extramedullary capillary hemangioma.

Patient concerns:

Three patients underwent surgical treatment at our hospital between January 2020 and August 2020. All patients were male[median age at presentation: 57 years (range: 56–60)]. Two patients were experiencing pain and numbness in the lower back, and 1 patient was experiencing numbness and weakness in the left lower limb. The duration of symptoms ranged from 1 to 5 months.

Diagnosis:

All patients were diagnosed with spinal cord capillary hemangioma after treatment. All lesions were in an intradural extramedullary location and involved spinal cord components. Two patients had lesions in thoracic segments (T8, Th9-10), and 1 patient had a lesion in lumbar segment (L1).

Interventions:

All patients underwent microscopic laminectomy and complete resection of the extramedullary and intramedullary components of the spinal cord capillary hemangiomas.

Outcomes:

Postoperatively, all patients experienced transient numbness and pain in the lower limbs, which gradually decreased over time. None of the patients experienced bleeding, severe numbness or pain, or recurrence of symptoms at 3-month follow-up.

Conclusion:

Intradural extramedullary capillary hemangioma has unique morphological characteristics. Gross-total resection of the extramedullary and intramedullary components of spinal cord capillary hemangioma is recommended for patients with symptoms of spinal cord compression. Careful preoperative imaging and intraoperative decision-making may help avoid residual lesions or reoperation.
Correlations of thyroid autoantibodies with allergic diseases: A case-control study of 434 Chinese patients
Authors: Zhang Congcong , Hong Chengwei , Lian Xiaolan , Wen Liping , Xu Kun , Tian Zhuang , Si Wenjie , Li Yongning
Published: August 2022

There is growing interest in the relationship between allergies and autoimmune diseases, although previous studies have yielded inconsistent results.

The thyroglobulin (Tg)/thyroid peroxidase antibody (TPOAb) group consisted of 217 patients with positive thyroglobulin antibody (TgAb) and/or TPOAb test results. Another set of 217 age- and sex-matched individuals with both TgAb- and TPOAb-negative results were selected as control group. History of allergic rhinitis (AR), chronic spontaneous urticaria (CSU), and/or atopic dermatitis (AD) was elicited before autoantibody detection. The association of thyroid autoantibodies with allergic diseases was assessed using univariate and multivariate logistic regression analysis, and the results were reported as odds ratios (ORs).

TgAb positivity (OR, 2.333) was identified as a risk factor for AR, AD, or CSU in Chinese patients, suggesting the involvement of thyroid autoantibodies in the pathogenesis of atopic reactions. Multivariate regression analysis also confirmed that the presence of TgAb (P = .004), rather than TPOAb (P = .468), had a significant impact on the occurrence of allergic disease.

Physicians should carefully monitor atopic symptoms in individuals with elevated TgAb or TPOAb levels to reduce the risk of allergic diseases, such as AR, AD, and CSU.
A TRPV1 common missense variant affected the prognosis of ischemic cardiomyopathy
Authors: Li Shiyang , Xiao Lei , Sun Yang , Hu Senlin , Hu Dong
Published: August 2022

The purpose was to identify the Transient receptor potential (TRP) superfamily gene variants associate with the prognosis of ischemic cardiomyopathy (ICM). A whole-exome sequencing study involving 252 ICM and 252 healthy controls participants enrolled from March 2003 to November 2017. Optimal sequence kernel association test and Cox regression dominant was conducted to identify the cause genes of TRP with ICM and association of common SNPs with prognosis of ICM. Rs224534 was verified in the replication population. Besides, the expression of TRPV1 was detectable in human failed heart ventricular tissues. The TRPs was not associated with the risk of ICM (P > .05). Rs224534 was significantly associated with the prognosis of ICM (Hazard ratio, 2.27, 95%CI: 1.31–3.94; P = 3.7 × 10–3), in the replication cohort, (hazard ratio 1.47, 95%CI: 1.04–2.07; P = 2.9 × 10–2), and in combined cohort hazard ratio 1.62 (95%CI: 1.21–2.18; P = 1.1 × 10–3). The common SNP of TRPV1 (rs224534) is associated with the prognosis of ICM, and homozygote rs224534-AA showed an unfavorable prognosis of ICM in the dominant model tested. Genotyping the variant may benefit to further progress judgment of ICM.
Serum levels of apolipoprotein A-I and E are associated with postoperative delirium: A post hoc analysis
Authors: Mietani Kazuhito , Hasegawa-Moriyama Maiko , Inoue Reo , Ogata Toru , Shimojo Nobutake , Kurano Makoto , Yatomi Yutaka , Uchida Kanji , Sumitani Masahiko
Published: August 2022

Postoperative delirium is a common complication for elderly patients. Detection of phosphorylated neurofilament heavy subunit in the serum reflects axonal damage with postoperative delirium. Although it has been implicated that serum apolipoprotein levels might be associated with senile cognitive disorder, its role in the development of delirium has not been fully investigated. This study examined the association of apolipoproteins with delirium after surgery.

This was a post hoc analysis of 117 patients who participated in a prospective observational study of delirium in patients undergoing cancer surgery. Patients were clinically assessed for delirium within the first 5 days of surgery. Serum levels of apolipoprotein A-I, B, and E were measured on postoperative day 3.

Forty-one patients (35%) were clinically diagnosed with postoperative delirium. Serum levels of apolipoprotein A-I and B were increased in patients with delirium whereas those of apolipoprotein E were decreased. These changes in apolipoprotein A-I and E levels were associated with the presence of phosphorylated neurofilament heavy subunit in the serum, and were significantly associated with delirium (A-I: adjusted odds ratio [aOR], 6.238; 95% confidence interval [CI], 2.766–20.68; P < .0001; E: aOR, 0.253; 95% CI, 0.066–0.810; P = .0193). A combination of apolipoprotein A-I and E offers significant discrimination between delirium and nondelirium with high accuracy (area under the curve, 0.8899).

Serum apolipoprotein A-I and E levels were associated with delirium and the presence of phosphorylated neurofilament heavy subunit in serum. Therefore, apolipoproteins might be useful biomarkers of postoperative delirium.
Leisure-time physical activity and risk of depression: A dose-response meta-analysis of prospective cohort studies
Authors: Guo ZhiGuang , Li Rui , Lu Songtao
Published: August 2022

Background:

There has never been a dose-response meta-analysis of the relationship between physical activity and the risk of depression. Hence, we aimed to explore the dose-response relationship between leisure-time physical activity (LTPA) and the risk of depression through a meta-analysis to provide a basis for the prevention of depression.

Methods:

PubMed and Web of Science databases were searched using a computer to collect prospective cohort studies on the relationship between LTPA and depression between January 1997 and July 2021. A dose-response meta-analysis was performed using the Stata 14 software to calculate the combined effect size relative risk (RR and 95% confidence interval CI).

Results:

Twelve cohort studies included 310,359 subjects who met the inclusion criteria. The categorical dose-response analysis results showed that the risk of incident depression was 27%, 17%, and 8% lower for the light, moderate, and highest dose LTPA participants, respectively (RR: 0.73, 95% CI: 0.64–0.82; RR: 0.83, 95% CI: 0.78–0.87; RR: 0.92, 95% CI: 0.86–0.99), compared with the lowest LTPA category. Continuous dose-response analysis showed a nonlinear relationship between LTPA and the risk of incident depression (P = .04). The risk of incident depression was reduced by 3% (RR: 0.97, 95% CI: 0.95–0.98) for every 5 MET-h/week increase in LTPA < 25 MET-h/week; when LTPA was higher than 25 MET-h/week, a 4% increase in the risk of depression for every 5 MET-h/week increase was observed (RR: 1.04, 95% CI: 1.02–1.05).

Conclusions:

There was a nonlinear relationship between LTPA and the risk of incident depression. Moderate and low doses of LTPA were protective factors in preventing the risk of incident depression, while high doses of LTPA may increase the risk of incident depression.
Trastuzumab-induced cardiotoxicity in early breast cancer over a 10-year period in Uruguay
Authors: Castillo Cecilia , Camejo Natalia , Etcheverria Cristian , Ferradaz Jessica , Ferreira Agustin , Fontan Analia , Gabin Ana Sofia , Herrera Guadalupe , Artagaveytia Nora , Parma Gabriel , Delgado Lucía
Published: August 2022

This srudy aimed to estimate the prevalence of trastuzumab-induced cardiotoxicity in Uruguayan women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive breast cancer over a 10-year period, who were treated under the financial coverage of the National Resources Fund (Fondo Nacional de Recursos).

This was an observational, descriptive study based on the analysis of an anonymized database of Uruguayan women diagnosed with HER2-positive breast cancer who received adjuvant trastuzumab treatment from to 2006 to 2016, provided by the Fondo Nacional de Recursos. Statistical analysis was performed using SPSS Statistics version 25, and variables were assessed using measures of central tendency, dispersion, contingency tables, and proportions. The chi-square test was used to analyze the association between the different variables.

The study included 1401 patients diagnosed with stage I to III HER2-positive breast cancer. The mean age at diagnosis was 52 years. The prevalence of cardiotoxicity was 20.3%. Most patients who discontinued treatment owing to cardiotoxicity eventually resumed treatment (92.6%). Moreover, the prevalence of cardiotoxicity was similar among patients who received regimens with and without anthracyclines. No association was observed between prior cardiovascular events or trastuzumab administration (concurrent vs sequential) and the development of cardiotoxicity.

In the present study, the prevalence of cardiotoxicity was similar to that reported nationally and internationally. Most patients did not develop cardiotoxicity, while the ones who developed it remained asymptomatic and cardiotoxicity was reversible.
Clinical characteristics and survival analysis of patients with limb epithelioid sarcoma
Authors: Lu Huanxin , Xu Qiang , Chen Xiaowei , Wang Zhan , He Fangming
Published: August 2022

Limb epithelioid sarcoma (LES) is a rare and aggressive soft tissue sarcoma, which is scarcely reported. Therefore, the current study was performed to analyze the clinicopathologic features and risk factors of survival among patients with LES.

By using the Surveillance, Epidemiology, and End Results database, data were obtained regarding patients who were diagnosed with LES for the period between 2010 and 2016. We first analyzed overall survival (OS) and cancer-specific survival (CSS) by applying univariate Cox regression analysis. Then we performed multivariate analysis to confirm independent predictors of survival.

In total, we identified 475 patients with LES for survival analysis, of which 291 were males (61.3%) and 184 females (38.7%). The mean and median age at diagnosis were 38 and 36 years, respectively. The 5-year OS and CSS rates among Patients with LES were 65.4% and 69.5%, respectively. Gender, age, tumor stage, tumor size, and treatment type were significant predictors of OS on both univariate and multivariate analyses (P < .05). As for CSS, multivariable analysis revealed that age <60 years, localized stage, and tumor size <5 cm were significantly associated with increased survival (P < .05).

Predictors of improved survival for LES patients include gender, age, tumor stage, tumor size, and treatment type. Surgery only was recommended for treating LES patients. Future studies are warranted to determine effective treatment types for LES patients.
Suicide Via Multiple Shotgun Wounds
Authors: Giffen Mark A. , Blankenship Heath , Harrison William
Published: August 2022

Suicide via multiple gunshot wounds is an uncommonly encountered phenomenon, which is important to recognize in the forensic community. Suicide by multiple shotgun wounds is a fleeting rare entity with few previously reported cases in the literature. In a review of autopsies performed at our institution during a 20-year period from 2000 to 2020, only 4 prior cases of suicide by multiple gunshot wounds were identified with no previously recorded cases of suicide by multiple shotgun wounds. Here we describe the case of a 20-year-old man with a history of depression who was discovered deceased in his secured residence with shotgun wounds of the head, neck, and chest. Because of the presence of 3 shotgun wounds, coupled with concerning initial investigative findings, an autopsy was performed. We illustrate how careful examination of the wounds and thorough investigation can allow for reconstruction of a plausible self-inflicted wound scenario.
A Rare Cause of Shock in a Child Diagnosed by Point-of-Care Ultrasound
Authors: Statler James R. , Cohen Stephanie G.
Published: August 2022

A 3-year-old boy presented to the emergency department with vomiting and abdominal pain. Point-of-care ultrasound identified a sinus of Valsalva aneurysm. We describe a case where point-of-care ultrasound was used to evaluate a child who presented with nonspecific abdominal pain leading to the diagnosis of this rare cardiac condition and life-saving surgical treatment.
Clarifying “chronic primary musculoskeletal pain”? The waters remain murky
Authors: Cohen Milton L.
Published: August 2022

Commentary on: Fitzcharles M-A, Cohen SP, Clauw DJ, Littlejohn G, Usui C, Häuser W. Chronic primary musculoskeletal pain: a new concept of non-structural regional pain. PAIN Reports 2022;7:e1024.

See also: Treede R-D. Chronic musculoskeletal pain: traps and pitfalls in classification and management of a major global disease burden. PAIN Reports 2022;7:e1023.
Chronic primary musculoskeletal pain: a new concept of nonstructural regional pain
Authors: Fitzcharles Mary-Ann , Cohen Steven P. , Clauw Daniel J. , Littlejohn Geoffrey , Usui Chie , Häuser Winfried
Published: August 2022

The concept that a regional musculoskeletal pain may occur in the absence of identifiable tissue abnormality may be puzzling. Previously these regional complaints were generally categorized as myofascial pain syndromes, or prior to the formalization of the nociplastic pain concept, as musculoskeletal pain with a neuropathic component, and treatments were anatomically focussed. Chronic primary musculoskeletal pain is now identified under the chronic primary pain stem category with the mechanistic descriptor of nociplastic pain. It is possible that many patients previously diagnosed with myofascial pain do in fact suffer from chronic primary musculoskeletal pain, requiring a paradigm shift in management towards more centrally directed treatment strategies. Many questions remain, including validation of the proposed examination techniques, prevalence, ideal treatment, and uptake and acceptance by the healthcare community. This new classification should be welcomed as an explanation for regional pain conditions that previously responded poorly to physically focussed treatments.
Unravelling the Complex Anatomy of the Tear Trough and Lower Eyelid Folds
Authors: Ting Michelle , Ezra Daniel G.
Published: August 2022

The lower eyelid tear trough deformity is a common cosmetic concern which is the result of multiple anatomic changes in the lower eyelid, usually resulting from age. A sound understanding of the underlying anatomy is vital to inform surgeons about the ideal treatment options for rejuvenation of this region and to minimize the risk of complications. Cadaveric studies provide unique insight into underlying anatomic changes. Here we review the relevant published cadaveric studies relating to the tear trough deformity and its treatment.
Facilitation as a component of evidence implementation: a multinational perspective
Authors: Lizarondo Lucylynn , McArthur Alexa , Moola Sandeep , Albornos-Muñoz Laura , Badeaux Jennifer , Bennett Marsha , Püschel Vilanice Alves de Araújo , González-Monasterio Emilia Irene , Mwita Clifford , Perrenoud Beatrice , Porche Demetrius , Rodrigues Rogério , Stannard Daphne
Published: August 2022

Background:

Facilitation is a key component of JBI's approach to evidence implementation along with context analysis and evaluation of process and outcomes. Although the role of facilitation is recognized as a critical component of evidence implementation, what constitutes effective facilitation is poorly understood.

Aim:

This article presents a descriptive exploration of facilitation as it occurs in evidence implementation initiatives conducted in various healthcare and geographical contexts. All projects used the JBI approach to evidence implementation.

Methods:

To provide a multinational perspective on how facilitation was operationalized to promote positive changes in clinical practice and health outcomes, five case studies of evidence implementation projects are presented.

Results:

The cases highlighted that facilitation is a multifaceted process that can be met through a variety of roles that address aspects of education and capacity building, partnerships, action planning, problem solving and evaluation. Facilitation in all cases appeared to be collaborative, with multiple ‘players’ within and outside of the health organization being involved in the process. Although there are similarities in activities, facilitation involved some level of local contextualization where there were unique or additional activities performed to accommodate the local needs and requirements of the health organization involved in each case. Numerous contextual factors influenced the success of the implementation initiative.

Conclusion:

The cases emphasized the complex nature of facilitation as a strategy for evidence implementation, indicating that contextual attributes and features define the range of knowledge, skills, and activities that should take place in order for facilitation to be effective. Although there appears to be some core components, tailoring and adaptation of the facilitation process (or roles) is required.
Hexagonal Voronoi pattern detected in the microstructural design of the echinoid skeleton
Authors: Perricone Valentina , Grun Tobias B. , Rendina Francesco , Marmo Francesco , Candia Carnevali Maria Daniela , Kowalewski Michal , Facchini Angelo , De Stefano Mario , Santella Luigia , Langella Carla , Micheletti Alessandra
Published: August 2022

Repeated polygonal patterns are pervasive in natural forms and structures. These patterns provide inherent structural stability while optimizing strength-per-weight and minimizing construction costs. In echinoids (sea urchins), a visible regularity can be found in the endoskeleton, consisting of a lightweight and resistant micro-trabecular meshwork (stereom). This foam-like structure follows an intrinsic geometrical pattern that has never been investigated. This study aims to analyse and describe it by focusing on the boss of tubercles—spine attachment sites subject to strong mechanical stresses—in the common sea urchinParacentrotus lividus. The boss microstructure was identified as a Voronoi construction characterized by 82% concordance to the computed Voronoi models, a prevalence of hexagonal polygons, and a regularly organized seed distribution. This pattern is interpreted as an evolutionary solution for the construction of the echinoid skeleton using a lightweight microstructural design that optimizes the trabecular arrangement, maximizes the structural strength and minimizes the metabolic costs of secreting calcitic stereom. Hence, this identification is particularly valuable to improve the understanding of the mechanical function of the stereom as well as to effectively model and reconstruct similar structures in view of future applications in biomimetic technologies and designs.
Application of machine learning in predicting blood flow and red cell distribution in capillary vessel networks
Authors: Ebrahimi Saman , Bagchi Prosenjit
Published: August 2022

Capillary blood vessels in the body partake in the exchange of gas and nutrients with tissues. They are interconnected via multiple vascular junctions forming the microvascular network. Distributions of blood flow and red cells (RBCs) in such networks are spatially uneven and vary in time. Since they dictate the pathophysiology of tissues, their knowledge is important. Theoretical models used to obtain flow and RBC distribution in large networks have limitations as they treat each vessel as a one-dimensional segment and do not explicitly consider cell–cell and cell–vessel interactions. High-fidelity computational models that accurately model each individual RBC are computationally too expensive to predict haemodynamics in large vascular networks and over a long time. Here we investigate the applicability of machine learning (ML) techniques to predict blood flow and RBC distributions in physiologically realistic vascular networks. We acquire data from high-fidelity simulations of deformable RBC suspension flowing in the networks. With the flow and haematocrit specified at an inlet of vasculature, the ML models predict the time-averaged flow rate and RBC distributions in the entire network, time-dependent flow rate and haematocrit in each vessel and vascular bifurcation in isolation over a long time, and finally, simultaneous spatially and temporally evolving quantities through the vessel hierarchy in the networks.
Multi-omics analysis for potential inflammation-related genes involved in tumour immune evasion via extended application of epigenetic data
Authors: Huang Chenshen , Wang Ning , Zhang Na , Chen Zhizhong , Ni Zhizhan , Liu Xiaohong , Xiong Hao , Xie Huahao , Lin Boxu , Ge Bujun , Huang Qi , Du Bing
Published: August 2022

Accumulating evidence suggests that inflammation-related genes may play key roles in tumour immune evasion. Programmed cell death ligand 1 (PD-L1) is an important immune checkpoint involved in mediating anti-tumour immunity. We performed multi-omics analysis to explore key inflammation-related genes affecting the transcriptional regulation of PD-L1 expression. The open chromatin region of the PD-L1 promoter was mapped using the assay for transposase-accessible chromatin using sequencing (ATAC-seq) profiles. Correlation analysis of epigenetic data (ATAC-seq) and transcriptome data (RNA-seq) were performed to identify inflammation-related transcription factors (TFs) whose expression levels were correlated with the chromatin accessibility of the PD-L1 promoter. Chromatin immunoprecipitation sequencing (ChIP-seq) profiles were used to confirm the physical binding of the TF STAT2 and the predicted binding regions. We also confirmed the results of the bioinformatics analysis with cell experiments. We identified chr9 : 5449463–5449962 and chr9 : 5450250–5450749 as reproducible open chromatin regions in the PD-L1 promoter. Moreover, we observed a correlation between STAT2 expression and the accessibility of the aforementioned regions. Furthermore, we confirmed its physical binding through ChIP-seq profiles and demonstrated the regulation of PD-L1 by STAT2 overexpression
in vitro
. Multiple databases were also used for the validation of the results. Our study identified STAT2 as a direct upstream TF regulating PD-L1 expression. The interaction of STAT2 and PD-L1 might be associated with tumour immune evasion in cancers, suggesting the potential value for tumour treatment.
A genetic model for
in vivo
proximity labelling of the mammalian secretome
Authors: Yang Rui , Meyer Amanda S. , Droujinine Ilia A. , Udeshi Namrata D. , Hu Yanhui , Guo Jinjin , McMahon Jill A. , Carey Dominique K. , Xu Charles , Fang Qiao , Sha Jihui , Qin Shishang , Rocco David , Wohlschlegel James , Ting Alice Y. , Carr Steven A. , Perrimon Norbert , McMahon Andrew P.
Published: August 2022

Organ functions are highly specialized and interdependent. Secreted factors regulate organ development and mediate homeostasis through serum trafficking and inter-organ communication. Enzyme-catalysed proximity labelling enables the identification of proteins within a specific cellular compartment. Here, we report a
BirA*G3
mouse strain that enables CRE-dependent promiscuous biotinylation of proteins trafficking through the endoplasmic reticulum. When broadly activated throughout the mouse, widespread labelling of proteins was observed within the secretory pathway. Streptavidin affinity purification and peptide mapping by quantitative mass spectrometry (MS) proteomics revealed organ-specific secretory profiles and serum trafficking. As expected, secretory proteomes were highly enriched for signal peptide-containing proteins, highlighting both conventional and non-conventional secretory processes, and ectodomain shedding. Lower-abundance proteins with hormone-like properties were recovered and validated using orthogonal approaches. Hepatocyte-specific activation of BirA*G3 highlighted liver-specific biotinylated secretome profiles. The BirA*G3 mouse model demonstrates enhanced labelling efficiency and tissue specificity over viral transduction approaches and will facilitate a deeper understanding of secretory protein interplay in development, and in healthy and diseased adult states.
Heterologous vaccination as a strategy to minimize inequity in COVID-19 vaccine access: A modeling study in Thailand
Authors: Anupong Suparinthon , Chantanasaro Tanakorn , Wilasang Chaiwat , Jitsuk Natcha C. , Sararat Chayanin , Sornbundit Kan , Pattanasiri Busara , Chadsuthi Sudarat , Modchang Charin
Published: August 2022

Background

Vaccinations are the best hope to control the COVID-19 pandemic and save lives. Due to the high demand and failure to share vaccines equitably, there were not enough vaccine supplies to cover the majority of people in low- and middle-income countries during the early stage of vaccination. To cope with this problem, Thailand, an upper-middle-income country, decided to employ a heterologous vaccination strategy as the primary COVID-19 vaccination regimen in the country. The CoronaVac (CV) vaccine was administered as the first dose, followed by the ChAdOx1 nCoV-19 (AZ) vaccine as the second dose. However, there is no study to assess the effectiveness of the heterologous vaccination employed in Thailand compared to the standard homologous vaccination.

Methods

We delineated the course and timeline of COVID-19 vaccination in Thailand. An age-structured compartmental model for COVID-19 transmission and vaccination was constructed and employed to assess the effectiveness of the heterologous vaccination strategy. The impact of the vaccine prioritization strategies on COVID-19 mortality and infections was also investigated.

Results

We found that the CV+AZ heterologous vaccination strategy outperforms the separate CV and AZ homologous vaccinations in reducing cumulative cases and deaths when combined with other non-pharmaceutical interventions. Furthermore, the results suggested that prioritizing vaccines for the elderly could be optimal in reducing COVID-19 mortality for a wide range of vaccination rates and disease transmission dynamics.

Conclusions

Our modeling results suggested that to minimize the impacts of inequity in early COVID-19 vaccine access in low- and middle-income countries, those countries may use early accessible but maybe lower-efficacy vaccines as the first dose of heterologous vaccination in combination with higher-efficacy vaccines as the second dose when they are available.
Genome-wide characterization of the common bean kinome: catalog and insights into expression patterns and genetic organization
Authors: Aono Alexandre Hild , Pimenta Ricardo José Gonzaga , Dambroz Caroline Marcela da Silva , Costa Francisco Cleilson Lopes , Kuroshu Reginaldo Massanobu , de Souza Anete Pereira , Pereira Welison Andrade
Published: August 2022

The protein kinase (PK) superfamily is one of the largest superfamilies in plants and is the core regulator of cellular signaling. Even considering this substantial importance, the kinome of common bean (Phaseolus vulgaris) has not been profiled yet. Here, we identified and characterised the complete set of kinases of common bean, performing an in-depth investigation with phylogenetic analyses and measurements of gene distribution, structural organization, protein properties, and expression patterns over a large set of RNA-Sequencing data. Being composed of 1,203 PKs distributed across all P. vulgaris chromosomes, this set represents 3.25% of all predicted proteins for the species. These PKs could be classified into 20 groups and 119 subfamilies, with a more pronounced abundance of subfamilies belonging to the receptor-like kinase (RLK)-Pelle group. In addition to provide a vast and rich reservoir of data, our study supplied insights into the compositional similarities between PK subfamilies, their evolutionary divergences, highly variable functional profile, structural diversity, and expression patterns, modeled with coexpression networks for investigating putative interactions associated with stress response.
Molecular underpinnings of programming by early-life stress and the protective effects of early dietary ω6/ω3 ratio, basally and in response to LPS: hippocampal mRNA-miRNAs integrated approach
Authors: Reemst Kitty , Lopizzo Nicola , Abbink Maralinde R. , Engelenburg Hendrik J. , Cattaneo Annamaria , Korosi Aniko
Published: August 2022

Early-life stress (ELS) exposure increases the risk for mental disorders, including cognitive impairments later in life. We have previously demonstrated that a dietary low ω6/ω3 polyunsaturated fatty acid (PUFA) ratio protects against ELS-induced cognitive impairments. Several studies have implicated the neuroimmune system in the ELS and diet mediated effects, but currently the molecular pathways via which ELS and early diet exert their long-term impact are not yet fully understood. Here we study the effects of ELS and dietary PUFA ratio on hippocampal mRNA and miRNA expression in adulthood, both under basal and inflammatory conditions.

Male mice were exposed to chronic ELS by the limiting bedding and nesting material paradigm from postnatal day(P)2 to P9, and provided with a diet containing a high (15:1.1) or low (1.1:1) ω6 linoleic acid to ω3 alpha-linolenic acid ratio from P2 to P42. At P120, memory was assessed using the object location task. Subsequently, a single lipopolysaccharide (LPS) injection was given and 24 hours later hippocampal genome-wide mRNA and microRNA (miRNA) expression was measured using microarray.

An integrated miRNA – mRNA analysis revealed that ELS and early diet induced miRNA driven mRNA expression changes into adulthood. Under basal conditions both ELS and the diet affected molecular pathways related to hippocampal plasticity, with a low ω6/ω3 ratio diet specific activation of molecular pathways associated with improved hippocampal plasticity and learning and memory in mice previously exposed to ELS (e.g., CREB signaling and endocannabinoid neuronal synapse pathway). LPS induced miRNA and mRNA expression was strongly influenced by both ELS and early diet. In mice fed the high ω6/ω3 diet, LPS increased miRNA expression leading to activation of inflammatory pathways. In contrast, in mice fed the low ω6/ω3 diet, LPS reduced miRNA expression and altered target mRNA expression ultimately leading to limited activation of inflammatory signaling pathways and inhibition of pathways associated with hippocampal plasticity which was especially apparent in mice previously exposed to ELS.

This data provides molecular insights into how the low ω6/ω3 diet during development could exert its long-lasting beneficial effects on hippocampal plasticity and learning and memory especially in a vulnerable population exposed to stress early in life, providing the basis for the development of intervention strategies.
Hepatocyte Differentiation From Mouse Liver Ductal Organoids By Transducing Four Liver-Specific Transcription Factors
Authors: Tomofuji Katsuhiro , Kondo Jumpei , Onuma Kunishige , Oyama Koki , Miyoshi Eiji , Fukumitsu Ken , Ishii Takamichi , Hatano Etsuro , Inoue Masahiro
Published: August 2022

Background & Aims

Hepatocyte sources that are expandable in vitro are required for liver regenerative medicine and to elucidate the mechanisms underlying the physiological functions of the liver. Liver ductal organoids (LDOs) comprise liver tissue stem cells with a bipotential capacity to differentiate into hepatocyte and cholangiocyte lineages, and can thus serve as a hepatocyte source. However, using current differentiation methods LDOs differentiate into immature hepatocytes while retaining strong cholangiocyte characteristics. We thus investigated an alternative differentiation method for LDOs to achieve hepatocyte maturation.

Methods

We extracted 12 candidate transcription factors to induce hepatocyte differentiation by comparing their gene expression in LDOs and liver tissues. After evaluating the effects of these transcription factors on LDOs, we analyzed the comprehensive gene expression profile, protein expression, and hepatic function in the transduced organoids.

Results

We identified a combination of four transcription factors, Hnf4a, Foxa1, Prox1, and Hlf, which upregulated hepatic lineage markers and downregulated cholangiocyte markers. Differentiation-induced LDOs showed more hepatocyte-specific characteristics than those with the conventional method, enhancing the transition from cholangiocyte to hepatocyte lineage and hepatic functions, such as liver-specific protein synthesis, lipid droplet deposition, and ammonia detoxification.

Conclusion

Transduction of the four transcription factors (Hnf4a, Foxa1, Prox1, Hlf) is a promising strategy to promote the differentiation of LDOs to obtain mature hepatocyte-like cells with better functionality.
A unified analysis of atlas single cell data
Authors: Chen Hao , Nguyen Nam D. , Ruffalo Matthew , Bar-Joseph Ziv
Published: August 2022

Recent efforts to generate atlas-scale single cell data provide opportunities for joint analysis across tissues and across modalities. Most of the existing methods for single cell atlas analysis use cells as the reference unit to combine datasets. However, such methods suffer from the inability to effectively integrate cross-modality data, hindering downstream gene-based analysis, and loss of genuine biological variations. Here we present a new data integration method, GIANT, which is for the first time designed for the atlas-scale analysis from the gene perspective. GIANT first converts datasets from different modalities into gene graphs, and then recursively embeds genes in the graphs into a latent space without additional alignment. Applying GIANT to the HuBMAP datasets creates a unified gene embedding space across multiple human tissues and data modalities, where gene representations reflect the functions of genes in their cells. Further evaluations demonstrate the usefulness of GIANT in discovering diverse gene functions, and underlying gene regulations in cells of different tissues.
LRIT3 expression in cone photoreceptors restores post-synaptic bipolar cell signalplex assembly and function in Lrit3-/- mice
Authors: Gregg Ronald G. , Hasan Nazarul , Borghuis Bart G.
Published: August 2022

Complete congenital stationary night blindness (cCSNB) is a heterogeneous disorder characterized by poor dim light vision, myopia, and nystagmus, that is caused by mutations in genes critical for signal transmission between photoreceptors and depolarizing bipolar cells (DBCs). One such gene, LRIT3, is required for assembly of the post-synaptic signaling complex (signalplex) at the dendritic tips of DBCs, although the number of signalplex components impacted is greater in cone DBCs than in rod bipolar cells. This difference raises the possibility that LRIT3 is expressed both pre- and post-synaptically at cone terminals. Here we show that rAAV-mediated expression of LRIT3 in cones results in robust rescue of cone DBC signalplex components and restores downstream visual function, as measured by the light adapted ERG b-wave and electrophysiological recordings of BCs and RGCs. These data show that LRIT3 successfully restores function to cone DBCs in a trans-synaptic manner, potentially paving the way for therapeutic intervention in LRIT3-associated cCSNB.
Integrative genetic and genomic networks identify microRNA associated with COPD and ILD
Authors: Pavel Ana B. , Garrison Carly , Luo Lingqi , Liu Gang , Taub Daniel , Xiao Ji , Juan-Guardela Brenda , Tedrow John , Alekseyev Yuriy O. , Yang Ivana V. , Geraci Mark W. , Sciurba Frank , Schwartz David A. , Kaminski Naftali , Beane Jennifer , Spira Avrum , Lenburg Marc E. , Campbell Joshua D.
Published: August 2022

Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) are clinically and molecularly heterogeneous diseases. We utilized clustering and integrative network analyses to elucidate roles for microRNAs (miRNAs) and miRNA isoforms (isomiRs) in COPD and ILD pathogenesis. Short RNA sequencing was performed on 351 lung tissue samples of COPD (n=145), ILD (n=144) and controls (n=64). Five distinct subclusters of samples were identified including 1 COPD-predominant cluster and 2 ILD-predominant clusters which associated with different clinical measurements of disease severity. Utilizing 262 samples with gene expression and SNP microarrays, we built disease-specific genetic and expression networks to predict key miRNA regulators of gene expression. Members of miR-449/34 family, known to promote airway differentiation by repressing the Notch pathway, were among the top connected miRNAs in both COPD and ILD networks. Genes associated with miR-449/34 members in the disease networks were enriched among genes that increase in expression with airway differentiation at an air-liquid interface. A highly expressed isomiR containing a novel seed sequence was identified at the miR-34c-5p locus. 47% of the anticorrelated predicted targets for this isomiR were distinct from the canonical seed sequence for miR-34c-5p. Overexpression of the canonical miR-34c-5p and the miR-34c-5p isomiR with an alternative seed sequence down-regulated NOTCH1 and NOTCH4. However, only overexpression of the isomiR down-regulated genes involved in Ras signaling such as CRKL and GRB2. Overall, these findings elucidate molecular heterogeneity inherent across COPD and ILD patients and further suggest roles for miR-34c in regulating disease-associated gene-expression.