bluuebunny/crossref_metadata_2025 huggingface dataset:
Designing Special Nonmetallic Superalkalis Based on a Cage-like Adamanzane Complexant
Authors: Ye Ya-Ling , Pan Kai-Yun , Ni Bi-Lian , Sun Wei-Ming
Published: March 2022

In this study, to examine the possibility of using cage-like complexants to design nonmetallic superalkalis, a series of X@36adz (X = H, B, C, N, O, F, and Si) complexes have been constructed and investigated by embedding nonmetallic atoms into the 36adamanzane (36adz) complexant. Although X atoms possess very high ionization energies, these resulting X@36adz complexes possess low adiabatic ionization energies (AIEs) of 0.78–5.28 eV. In particular, the adiabatic ionization energies (AIEs) of X@36adz (X = H, B, C, N, and Si) are even lower than the ionization energy (3.89 eV) of Cs atoms, and thus, can be classified as novel nonmetallic superalkalis. Moreover, due to the existence of diffuse excess electrons in B@36adz, this complex not only possesses pretty low AIE of 2.16 eV but also exhibits a remarkably large first hyperpolarizability (β0) of 1.35 × 106 au, indicating that it can also be considered as a new kind of nonlinear optical molecule. As a result, this study provides an effective approach to achieve new metal-free species with an excellent reducing capability by utilizing the cage-like organic complexants as building blocks.
Effect of Chinese Patent Medicines on Ocular Fundus Signs and Vision in Calcium Dobesilate-Treated Persons With Non-Proliferative Diabetic Retinopathy: A Systematic Review and Meta-Analysis
Authors: Zhang Yuehong , An Xuedong , Duan Liyun , Jin De , Duan Yingying , Zhou Rongrong , Zhang Yuqing , Kang Xiaomin , Lian Fengmei
Published: March 2022

Background

Diabetic retinopathy (DR), one of the commonest microvascular complications in diabetic patients, is featured by a series of fundus lesions. Conventional Western medicine therapies for DR are always with modest treatment outcome. This paper is to assess the ocular fundus signs, vision and safety of Chinese patent medicines (CPMs) as an add-on treatment for DR.

Method

7 electronic databases were searched to determine eligible trials. Randomized controlled trials (RCTs) of non-proliferative diabetic retinopathy (NPDR) in which the intervention group received CPMs combined with calcium dobesilate (CD), and the control group received only CD were included for analysis. Two reviewers extracted the data independently. Results expressing as mean differences (MD) and relative risks (RR) were analyzed with a fixed-effects or random-effects models.

Results

19 RCTs involved 1568 participants with 1622 eyes met our inclusion criteria. The results suggested that compared with CD alone, CPMs plus CD for NPDR was superior at reducing the microaneurysm volume (MD -3.37; 95% confidence interval [CI], -3.59 to -3.14), microaneurysm counts (MD -2.29; 95%CI -2.97 to -1.61), hemorrhage area (MD -0.79; 95%CI -0.83 to -0.75), and macular thickness (MD -59.72; 95%CI -63.24 to -56.20). Participants in CPMs plus CD group also achieved a better vision. No obvious adverse events occurred.

Conclusion

CPMs as an add-on therapy for NPDR have additional benefits and be generally safe. This meta‐analysis demonstrated that CPMs combined with CD could improve retinal microaneurysm, hemorrhage, macular thickness, visual acuity, fasting blood glucose (FBG), and glycosylated hemoglobin (HbAlc) compared with CD alone. Further studies are needed to provide more conclusive evidence.

Systematic Review Registration

PROSPERO https://www.crd.york.ac.uk/prospero/, identifier CRD42021257999.
The Future of Nature Conservation in Amazonia: Evidence From Transboundary Protected Areas
Authors: Cardona Walter Cano , de Jong Wil , Pokorny Benno
Published: March 2022

Biological diversity has been recognized as a global asset that is key to the well-being and survival of present and future generations. In response to massive destruction of the world’s ecosystems, the international community has agreed on several initiatives, most importantly, the Convention on Biological Diversity (CBD) in 1992, which is the basis of the Strategic Plan for Biodiversity 2011–2020, and the 20 Aichi Biodiversity Targets. A central instrument of these initiative are protected areas. The nine Amazonian countries alone, have designated 390 million hectares of protected forest areas, some of which are under very heavy pressure. As explicitly stated in Aichi Targets 11, 17, and 18, the effective governance and management of these protected areas requires the active participation of indigenous and other local resource user groups and respect for their traditional knowledge and customary practices. This manuscript analyzes to what extent and in which way these targets have been achieved by analyzing three transboundary protected areas in Brazil, Peru, and Bolivia constituted of five national parks. The analysis shows that important progress has been made in terms of the local participation and the generation and sharing of economic benefits, mostly due to the engagement of non-governmental organization (NGOs) funded from overseas development assistance (ODA) sources. However, many of the established mechanisms show major shortcomings, such as power imbalances, lack of legitimacy of decision-makers, unclear responsibilities, unresolved logistical challenges, and the lack of financial support. In addition, the functionality of local governance structures is severely threatened by the vagaries of national policies that often put biodiversity conservation and economic development at loggerheads. In order to ensure the functionality of protected areas in the Amazon region, binding and sufficient commitments by national governments are needed for genuine and effective local governance.
Identification and Characterization of the Growth-Regulating Factors-Interacting Factors in Cotton
Authors: Hu Daowu , Ge Yuting , Jia Yinhua , He Shoupu , Geng Xiaoli , Wang Liru , Pan Zhaoe , Iqbal Zubair , Mahmood Tahir , Li Hongge , Chen Baojun , Wang Xiaoyang , Pang Baoyin , Du Xiongming
Published: March 2022

Growth-regulating factors-interacting factors (GIFs) are a type of transcription co-activators in plants, playing crucial roles in plants’ growth, development, and stress adaptation. Here, a total of 35 GIF genes were identified and clustered into two groups by phylogenetic analysis in four cotton genus. The gene structure and conserved domain analysis proved the conservative characteristics of GIF genes in cotton. The function of GIF genes was evaluated in two cotton accessions, Ji A-1-7 (33xi) and King, which have larger and smaller lateral root numbers, respectively. The results showed that the expression of GhGIF4 in Ji A-1-7 (33xi) was higher than that in King. The enzyme activity and microstructure assay showed a higher POD activity, lower MDA content, and more giant cells of the lateral root emergence part phenotype in Ji A-1-7 (33xi) than in King. A mild waterlogging assay showed the GIF genes were down-regulated in the waterlogged seedling. Further confirmation of the suppression of GhGIF4 in cotton plants further confirmed that GhGIF4 could reduce the lateral root numbers in cotton. This study could provide a basis for future studies of the role of GIF genes in upland cotton.
Identification of Prognosis Biomarkers for High-Grade Serous Ovarian Cancer Based on Stemness
Authors: Wang Zhihang , Yang Lili , Huang Zhenyu , Li Xuan , Xiao Juan , Qu Yinwei , Huang Lan , Wang Yan
Published: March 2022

In this paper, high-grade serous ovarian cancer (HGSOC) is studied, which is the most common histological subtype of ovarian cancer. We use a new analytical procedure to combine the bulk RNA-Seq sample for ovarian cancer, mRNA expression-based stemness index (mRNAsi), and single-cell data for ovarian cancer. Through integrating bulk RNA-Seq sample of cancer samples from TCGA, UCSC Xena and single-cell RNA-Seq (scRNA-Seq) data of HGSOC from GEO, and performing a series of computational analyses on them, we identify stemness markers and survival-related markers, explore stem cell populations in ovarian cancer, and provide potential treatment recommendation. As a result, 171 key genes for capturing stem cell characteristics are screened and one vital cancer stem cell subpopulation is identified. Through further analysis of these key genes and cancer stem cell subpopulation, more critical genes can be obtained as LCP2, FCGR3A, COL1A1, COL1A2, MT-CYB, CCT5, and PAPPA, are closely associated with ovarian cancer. So these genes have the potential to be used as prognostic biomarkers for ovarian cancer.
A Systematic Immuno-Informatic Approach to Design a Multiepitope-Based Vaccine Against Emerging Multiple Drug Resistant Serratia marcescens
Authors: Damas Marcelo Silva Folhas , Mazur Fernando Gabriel , Freire Caio Cesar de Melo , Cunha Anderson Ferreira da , Pranchevicius Maria-Cristina da Silva
Published: March 2022

Serratia marcescens is now an important opportunistic pathogen that can cause serious infections in hospitalized or immunocompromised patients. Here, we used extensive bioinformatic analyses based on reverse vaccinology and subtractive proteomics-based approach to predict potential vaccine candidates against S. marcescens. We analyzed the complete proteome sequence of 49 isolate of Serratia marcescens and identified 5 that were conserved proteins, non-homologous from human and gut flora, extracellular or exported to the outer membrane, and antigenic. The identified proteins were used to select 5 CTL, 12 HTL, and 12 BCL epitopes antigenic, non-allergenic, conserved, hydrophilic, and non-toxic. In addition, HTL epitopes were able to induce interferon-gamma immune response. The selected peptides were used to design 4 multi-epitope vaccines constructs (SMV1, SMV2, SMV3 and SMV4) with immune-modulating adjuvants, PADRE sequence, and linkers. Peptide cleavage analysis showed that antigen vaccines are processed and presented via of MHC class molecule. Several physiochemical and immunological analyses revealed that all multiepitope vaccines were non-allergenic, stable, hydrophilic, and soluble and induced the immunity with high antigenicity. The secondary structure analysis revealed the designed vaccines contain mainly coil structure and alpha helix structures. 3D analyses showed high-quality structure. Molecular docking analyses revealed SMV4 as the best vaccine construct among the four constructed vaccines, demonstrating high affinity with the immune receptor. Molecular dynamics simulation confirmed the low deformability and stability of the vaccine candidate. Discontinuous epitope residues analyses of SMV4 revealed that they are flexible and can interact with antibodies. In silico immune simulation indicated that the designed SMV4 vaccine triggers an effective immune response. In silico codon optimization and cloning in expression vector indicate that SMV4 vaccine can be efficiently expressed in E. coli system. Overall, we showed that SMV4 multi-epitope vaccine successfully elicited antigen-specific humoral and cellular immune responses and may be a potential vaccine candidate against S. marcescens. Further experimental validations could confirm its exact efficacy, the safety and immunogenicity profile. Our findings bring a valuable addition to the development of new strategies to prevent and control the spread of multidrug-resistant Gram-negative bacteria with high clinical relevance.
Experimental Study of GFRP Reinforced Concrete Beams With U-Shaped CFRP Grid-Reinforced ECC Stay-in-Place Formwork
Authors: Wu Chang , Su Yanli , Zhang Pu , Zhu Hong , Gao Danying , Sheikh Shamim Ahmed
Published: March 2022

Corrosion is a major concern for structures under the harsh environment. In this paper, ECC was applied as an alternative to concrete in tension zones, which was combine with FRP bars to develop a new type of composite beam with excellent durability. The flexural performance of glass fiber-reinforced polymer (GFRP)-reinforced concrete beams with U-shaped CFRP grid-reinforced ECC formwork was investigated. Five beams were designed, including one reference beam with full concrete, one composite beam with a coupon-shaped ECC permanent formwork at the bottom, and three composite beams with the proposed formwork. The effects of the application of the U-shaped ECC formwork, the formwork types, the application of CFRP grids, and the strength of the ECC were investigated. The test results showed that ECCs were an ideal material to improve the flexural behavior of FRP-reinforced concrete beams. The proposed formwork had a positive effect on crack resistance at the serviceability limit and substantially improved the cracking load by 78.57–85.71% and the ultimate load by 5.29–15.71% compared with those of the reference beam. Moreover, the proposed formwork improved the shear stiffness of the composite beam. The addition of CFRP grids improved the tensile strength of the ECC formwork and consequently contributed to the improvement in the load capacity of the composite beams.
Inside the Joint of Inflammatory Arthritis Patients: Handling and Processing of Synovial Tissue Biopsies for High Throughput Analysis
Authors: Floudas Achilleas , Gorman Aine , Neto Nuno , Monaghan Michael G. , Elliott Zoe , Fearon Ursula , Marzaioli Viviana
Published: March 2022

Inflammatory arthritis is a chronic systemic autoimmune disease of unknown etiology, which affects the joints. If untreated, these diseases can have a detrimental effect on the patient's quality of life, leading to disabilities, and therefore, exhibit a significant socioeconomic impact and burden. While studies of immune cell populations in arthritis patient's peripheral blood have been informative regarding potential immune cell dysfunction and possible patient stratification, there are considerable limitations in identifying the early events that lead to synovial inflammation. The joint, as the site of inflammation and the local microenvironment, exhibit unique characteristics that contribute to disease pathogenesis. Understanding the contribution of immune and stromal cell interactions within the inflamed joint has been met with several technical challenges. Additionally, the limited availability of synovial tissue biopsies is a key incentive for the utilization of high-throughput techniques in order to maximize information gain. This review aims to provide an overview of key methods and novel techniques that are used in the handling, processing and analysis of synovial tissue biopsies and the potential synergy between these techniques. Herein, we describe the utilization of high dimensionality flow cytometric analysis, single cell RNA sequencing, ex vivo functional assays and non-intrusive metabolic characterization of synovial cells on a single cell level based on fluorescent lifetime imaging microscopy. Additionally, we recommend important points of consideration regarding the effect of different storage and handling techniques on downstream analysis of synovial tissue samples. The introduction of new powerful techniques in the study of synovial tissue inflammation, brings new challenges but importantly, significant opportunities. Implementation of novel approaches will accelerate our path toward understanding of the mechanisms involved in the pathogenesis of inflammatory arthritis and lead to the identification of new avenues of therapeutic intervention.
Chicken Peripheral Blood Mononuclear Cells Response to Avian Leukosis Virus Subgroup J Infection Assessed by Single-Cell RNA Sequencing
Authors: Qu Xiaoyun , Li Xiaobo , Li Ziwei , Liao Ming , Dai Manman
Published: March 2022

Chicken peripheral blood mononuclear cells (PBMCs) exhibit wide-ranging cell types, but current understanding of their subclasses, immune cell classification, and function is limited and incomplete. Here we performed single-cell RNA sequencing (scRNA-seq) of PBMCs in Avian leukosis virus subgroup J (ALV-J) infected and control chickens at 21 days post infection (DPI) to determine chicken PBMCs subsets and their specific molecular and cellular characteristics. Eight cell populations and their potential marker genes were identified in PBMCs. T cell populations had the strongest response to (ALV-J) infection, based on the detection of the largest number of differentially expressed genes (DEGs), and could be further grouped into four subsets: activated CD4+ T cells, Th1-like cells, Th2-like cells, and cytotoxic CD8+ T cells. Furthermore, pseudotime analysis results suggested that chicken CD4+ T cells could potentially differentiate into Th1-like and Th2-like cells. Moreover, ALV-J infection activated CD4+ T cell was probably inclined to differentiate into Th1-like cells. Compared to the control PBMCs, ALV-J infection also had an obvious impact on PBMCs composition. B cells showed inconspicuous response and their numbers decreased in PBMCs from ALV-J infected chicken. Proportions of cytotoxic Th1-like cells and CD8+ T cells increased in the T cell population of PBMCs from ALV-J infected chicken, which were potentially key mitigating effectors against ALV-J infection. More importantly, our results provide a rich resource of gene expression profiles of chicken PBMCs subsets for a systems-level understanding of their function in homeostatic condition as well as in response to viral infection.
Role of Globotriaosylceramide in Physiology and Pathology
Authors: Celi Ana Beatriz , Goldstein Jorge , Rosato-Siri María Victoria , Pinto Alipio
Published: March 2022

At first glance, the biological function of globoside (Gb) clusters appears to be that of glycosphingolipid (GSL) receptors for bacterial toxins that mediate host-pathogen interaction. Indeed, certain bacterial toxin families have been evolutionarily arranged so that they can enter eukaryotic cells through GSL receptors. A closer look reveals this molecular arrangement allocated on a variety of eukaryotic cell membranes, with its role revolving around physiological regulation and pathological processes. What makes Gb such a ubiquitous functional arrangement? Perhaps its peculiarity is underpinned by the molecular structure itself, the nature of Gb-bound ligands, or the intracellular trafficking unleashed by those ligands. Moreover, Gb biological conspicuousness may not lie on intrinsic properties or on its enzymatic synthesis/degradation pathways. The present review traverses these biological aspects, focusing mainly on globotriaosylceramide (Gb3), a GSL molecule present in cell membranes of distinct cell types, and proposes a wrap-up discussion with a phylogenetic view and the physiological and pathological functional alternatives.
Lateral Habenula Responses During Eye Contact in a Reward Conditioning Task
Authors: Lee Hyunchan , Hikosaka Okihide
Published: March 2022

For many animals, social interaction may have intrinsic reward value over and above its utility as a means to the desired end. Eye contact is the starting point of interactions in many social animals, including primates, and abnormal patterns of eye contact are present in many mental disorders. Whereas abundant previous studies have shown that negative emotions such as fear strongly affect eye contact behavior, modulation of eye contact by reward has received scant attention. Here we recorded eye movement patterns and neural activity in lateral habenula while monkeys viewed faces in the context of Pavlovian and instrumental conditioning tasks. Faces associated with larger rewards spontaneously elicited longer periods of eye contact from the monkeys, even though this behavior was not required or advantaged in the task. Concurrently, lateral habenula neurons were suppressed by faces signaling high value and excited by faces signaling low value. These results suggest that the reward signaling of lateral habenula may contribute to social behavior and disorders, presumably through its connections with the basal ganglia.
Endovascular Treatment and Angiographic Characteristics of Aneurysms at the Origin of the Anterior Choroidal Artery
Authors: Wang Yiheng , Yu Jinlu
Published: March 2022

Background

The information available about the variations and anatomy of the anterior choroidal artery (AchA) with aneurysm at the origin of the vessel and the outcomes of endovascular treatment (EVT) for AchA aneurysms is incomplete.

Materials and Methods

A retrospective study of 54 consecutive patients who were admitted to our hospital with a diagnosis of AchA aneurysm and treated with EVT was performed. The variations and anatomy of the AchA and the outcomes of EVT for AchA aneurysms were analyzed.

Result

The 54 patients were aged 35–82 years (mean age, 56.1 ± 19.7 years) and included 32 females (59.3%, 32/54). Regarding AchA anatomy, 63.5% of AchAs had a typical S-shaped course. The diameter of the AchA origin averaged 0.8 ± 0.3 mm. Of all the AchA aneurysms, 51.9% were ruptured. The diameter of AchA aneurysms averaged 4.1 ± 2.4 mm. Moreover, 40.7% of 54 cases had multiple aneurysms. EVT was assisted with stenting for 25.9% of 54 AchA aneurysms. An immediate Modified Raymond-Roy Classification grade of I was obtained in 96.3% of AchA aneurysm cases. After EVT, the ischemic complication rate was 13%. In total, 83% of patients had good outcomes, with a Glasgow Outcome Scale score of 4–5. Follow-up angiography showed acceptable treatment results in this study.

Conclusion

The study showed that the AchA had a complex angiographic anatomy in cases with aneurysms at the origin of the vessel and that the anatomical features can be helpful in EVT. EVT for aneurysms at the origin of the AchA had good outcomes.
Sport Practice, Fluid Reasoning, and Soft Skills in 10- to 18-Year-Olds
Authors: Feraco Tommaso , Meneghetti Chiara
Published: March 2022

Engaging in physical activity and sports has been associated with various cognitive abilities and other personal characteristics. The contemporary link between doing sports and personal attributes such as soft skills and an individual’s cognitive abilities have yet to be investigated, however. This study aims to analyze the association between years of practicing a sport, cognitive abilities (in terms of fluid reasoning), and personal attributes (in terms of soft skills). A large sample of 1,115 individuals (10–18 years old) completed the Cattell test (measuring fluid reasoning) and answered a questionnaire measuring six soft skills (adaptability, curiosity, initiative, leadership, perseverance, and social awareness). A multivariate regression analysis show that, after controlling for age and gender, participants’ years of practicing a sport were positively associated with three soft skills (i.e., initiative, leadership, and perseverance) and with fluid reasoning. No differences emerged between team and individual sport practitioners. Our findings suggest an association between practicing sports, which entails more than just physical activity, and both cognitive abilities (fluid reasoning) and other important personal characteristics, such as soft skills.
Feeding and Manual Brushing Influence the Release of Oxytocin, ACTH and Cortisol Differently During Milking in Dairy Cows
Authors: Wredle Ewa , Svennersten-Sjaunja Kerstin , Munksgaard Lene , Herskin Mette S. , Bruckmaier Rupert M. , Uvnäs-Moberg Kerstin
Published: March 2022

Aim

This study aimed to examine the effects of feeding or abdominal brushing on the release of the hormones oxytocin, ACTH and cortisol during milking in dairy cows.

Methods

Twelve cows in early lactation were used (2 × 2 factorial experimental design), testing the effects of two types of sensory stimulation during milking over a 3 day period; feeding concentrate or manual abdominal brushing (1 stroke/s). Blood samples for hormone analyses were collected at time at −15, −1, 0 (onset of cluster), every min for 8 min, at 10, 12, 14, 16, 30, and 60 min. Hormone levels were assayed and AUC was calculated.

Results

Milking was associated with an immediate and significant rise of oxytocin. When milking was combined with feeding, significantly higher levels of oxytocin were observed at 2 and 4 mins (p < 0.05). No effect of brushing on oxytocin levels was observed. Milking alone was associated with a significant rise of ACTH levels. Feeding in connection with milking reduced the immediate rise of ACTH levels (p < 0.05) and AUC (p < 0.02), whereas no effects of brushing were found. Milking caused a progressive rise of cortisol levels. Concomitant feeding did not influence cortisol levels, whereas brushing significantly decreased cortisol levels at 1, 5 and 14 mins after onset of milking (p < 0.05).

Conclusion

Feeding increases oxytocin release in response to milking and decreases ACTH levels. Abdominal brushing did not influence these variables, but decreased cortisol levels. These data demonstrate that activation of afferent vagal nerve fibres and of cutaneous sensory nerves originating from the abdominal skin in front of the udder influence milking related hormone release differently.
Long-Term Effects of Moderate Concussive Brain Injury During Adolescence on Synaptic and Tonic GABA Currents in Dentate Granule Cells and Semilunar Granule Cells
Authors: Gupta Akshay , Dovek Laura , Proddutur Archana , Elgammal Fatima S. , Santhakumar Vijayalakshmi
Published: March 2022

Progressive physiological changes in the hippocampal dentate gyrus circuits following traumatic brain injury (TBI) contribute to temporal evolution of neurological sequelae. Although early posttraumatic changes in dentate synaptic and extrasynaptic GABA currents have been reported, and whether they evolve over time and remain distinct between the two projection neuron classes, granule cells and semilunar granule cells, have not been evaluated. We examined long-term changes in tonic GABA currents and spontaneous inhibitory postsynaptic currents (sIPSCs) and in dentate projection neurons 3 months after moderate concussive fluid percussion injury (FPI) in adolescent rats. Granule cell tonic GABA current amplitude remained elevated up to 1 month after FPI, but decreased to levels comparable with age-matched controls by 3 months postinjury. Granule cell sIPSC frequency, which we previously reported to be increased 1 week after FPI, remained higher than in age-matched controls at 1 month and was significantly reduced 3 months after FPI. In semilunar granule cells, tonic GABA current amplitude and sIPSC frequency were not different from controls 3 months after FPI, which contrast with decreases observed 1 week after injury. The switch in granule cell inhibitory inputs from early increase to subsequent decrease could contribute to the delayed emergence of cognitive deficits and seizure susceptibility after brain injury.
Bone Mineral Density and Current Bone Health Screening Practices in Friedreich’s Ataxia
Authors: Dunn Julia , Tamaroff Jaclyn , DeDio Anna , Nguyen Sara , Wade Kristin , Cilenti Nicolette , Weber David R. , Lynch David R. , McCormack Shana E.
Published: March 2022

Introduction

Friedreich’s Ataxia (FRDA) is a progressive neurological disorder caused by mutations in both alleles of the frataxin (FXN) gene. Impaired bone health is a complication of other disorders affecting mobility, but there is little information regarding bone health in FRDA.

Methods

Dual energy X-ray absorptiometry (DXA) scan-based assessments of areal bone mineral density (aBMD) in individuals with FRDA were abstracted from four studies at the Children’s Hospital of Philadelphia (CHOP). Disease outcomes, including the modified FRDA Rating Scale (mFARS), were abstracted from the FRDA Clinical Outcomes Measures Study (FACOMS), a longitudinal natural history study. A survey regarding bone health and fractures was sent to individuals in FACOMS-CHOP.

Results

Adults with FRDA (n = 24) have lower mean whole body (WB) (–0.45 vs. 0.33, p = 0.008) and femoral neck (FN) (–0.71 vs. 0.004, p = 0.02) aBMD Z-scores than healthy controls (n = 24). Children with FRDA (n = 10) have a lower WB-less-head (–2.2 vs. 0.19, p < 0.0001) and FN (–1.1 vs. 0.04, p = 0.01) aBMD than a reference population (n = 30). In adults, lower FN aBMD correlated with functional disease severity, as reflected by mFARS (R = –0.56, p = 0.04). Of 137 survey respondents (median age 27 y, 50% female), 70 (51%) reported using wheelchairs as their primary ambulatory device: of these, 20 (29%) reported a history of potentially pathologic fracture and 11 (16%) had undergone DXA scans.

Conclusions

Low aBMD is prevalent in FRDA, but few of even the highest risk individuals are undergoing screening. Our findings highlight potential missed opportunities for the screening and treatment of low aBMD in FRDA.
Low-Rank Plus Sparse Decomposition of fMRI Data With Application to Alzheimer's Disease
Authors: Tu Wei , Fu Fangfang , Kong Linglong , Jiang Bei , Cobzas Dana , Huang Chao
Published: March 2022

Studying functional brain connectivity plays an important role in understanding how human brain functions and neuropsychological diseases such as autism, attention-deficit hyperactivity disorder, and Alzheimer's disease (AD). Functional magnetic resonance imaging (fMRI) is one of the most popularly used tool to construct functional brain connectivity. However, the presence of noises and outliers in fMRI blood oxygen level dependent (BOLD) signals might lead to unreliable and unstable results in the construction of connectivity matrix. In this paper, we propose a pipeline that enables us to estimate robust and stable connectivity matrix, which increases the detectability of group differences. In particular, a low-rank plus sparse (L + S) matrix decomposition technique is adopted to decompose the original signals, where the low-rank matrix L recovers the essential common features from regions of interest, and the sparse matrix S catches the sparse individual variability and potential outliers. On the basis of decomposed signals, we construct connectivity matrix using the proposed novel concentration inequality-based sparse estimator. In order to facilitate the comparisons, we also consider correlation, partial correlation, and graphical Lasso-based methods. Hypothesis testing is then conducted to detect group differences. The proposed pipeline is applied to rs-fMRI data in Alzheimer's disease neuroimaging initiative to detect AD-related biomarkers, and we show that the proposed pipeline provides accurate yet more stable results than using the original BOLD signals.
Predicting the Influence of Axon Myelination on Sound Localization Precision Using a Spiking Neural Network Model of Auditory Brainstem
Authors: Li Ben-Zheng , Pun Sio Hang , Vai Mang I. , Lei Tim C. , Klug Achim
Published: March 2022

Spatial hearing allows animals to rapidly detect and localize auditory events in the surrounding environment. The auditory brainstem plays a central role in processing and extracting binaural spatial cues through microsecond-precise binaural integration, especially for detecting interaural time differences (ITDs) of low-frequency sounds at the medial superior olive (MSO). A series of mechanisms exist in the underlying neural circuits for preserving accurate action potential timing across multiple fibers, synapses and nuclei along this pathway. One of these is the myelination of afferent fibers that ensures reliable and temporally precise action potential propagation in the axon. There are several reports of fine-tuned myelination patterns in the MSO circuit, but how specifically myelination influences the precision of sound localization remains incompletely understood. Here we present a spiking neural network (SNN) model of the Mongolian gerbil auditory brainstem with myelinated axons to investigate whether different axon myelination thicknesses alter the sound localization process. Our model demonstrates that axon myelin thickness along the contralateral pathways can substantially modulate ITD detection. Furthermore, optimal ITD sensitivity is reached when the MSO receives contralateral inhibition via thicker myelinated axons compared to contralateral excitation, a result that is consistent with previously reported experimental observations. Our results suggest specific roles of axon myelination for extracting temporal dynamics in ITD decoding, especially in the pathway of the contralateral inhibition.
Phenotypic Spectrum and Prognosis of Epilepsy Patients With GABRG2 Variants
Authors: Yang Ying , Niu Xueyang , Cheng Miaomiao , Zeng Qi , Deng Jie , Tian Xiaojuan , Wang Yi , Yu Jing , Shi Wenli , Wu Wenjuan , Ma Jiehui , Li Yufen , Yang Xiaoling , Zhang Xiaoli , Jia Tianming , Yang Zhixian , Liao Jianxiang , Sun Yan , Zheng Hong , Sun Suzhen , Sun Dan , Jiang Yuwu , Zhang Yuehua
Published: March 2022

Objective

This study aimed to obtain a comprehensive understanding of the genetic and phenotypic aspects of GABRG2-related epilepsy and its prognosis and to explore the potential prospects for personalized medicine.

Methods

Through a multicenter collaboration in China, we analyzed the genotype-phenotype correlation and antiseizure medication (ASM) of patients with GABRG2-related epilepsy. The three-dimensional protein structure of the GABRG2 variant was modeled to predict the effect of GABRG2 missense variants using PyMOL 2.3 software.

Results

In 35 patients with GABRG2 variants, 22 variants were de novo, and 18 variants were novel. The seizure onset age was ranged from 2 days after birth to 34 months (median age: 9 months). The seizure onset age was less than 1 year old in 22 patients (22/35, 62.9%). Seizure types included focal seizures (68.6%), generalized tonic-clonic seizures (60%), myoclonic seizures (14.3%), and absence seizures (11.4%). Other clinical features included fever-sensitive seizures (91.4%), cluster seizures (57.1%), and developmental delay (45.7%). Neuroimaging was abnormal in 2 patients, including dysplasia of the frontotemporal cortex and delayed myelination of white matter. Twelve patients were diagnosed with febrile seizures plus, eleven with epilepsy and developmental delay, two with Dravet syndrome, two with developmental and epileptic encephalopathy, two with focal epilepsy, two with febrile seizures, and four with unclassified epilepsy. The proportions of patients with missense variants in the extracellular region and the transmembrane region exhibiting developmental delay were 40% and 63.2%, respectively. The last follow-up age ranged from 11 months to 17 years. Seizures were controlled in 71.4% of patients, and 92% of their seizures were controlled by valproate and/or levetiracetam.

Conclusion

The clinical features of GABRG2-related epilepsy included seizure onset, usually in infancy, and seizures were fever-sensitive. More than half of the patients had cluster seizures. Phenotypes of GABRG2-related epilepsy were ranged from mild febrile seizures to severe epileptic encephalopathies. Most patients with GABRG2 variants who experienced seizures had a good prognosis. Valproate and levetiracetam were effective treatments for most patients.
Clarify Sit-to-Stand Muscle Synergy and Tension Changes in Subacute Stroke Rehabilitation by Musculoskeletal Modeling
Authors: Wang Ruoxi , An Qi , Yang Ningjia , Kogami Hiroki , Yoshida Kazunori , Yamakawa Hiroshi , Hamada Hiroyuki , Shimoda Shingo , Yamasaki Hiroshi R. , Yokoyama Moeka , Alnajjar Fady , Hattori Noriaki , Takahashi Kouji , Fujii Takanori , Otomune Hironori , Miyai Ichiro , Yamashita Atsushi , Asama Hajime
Published: March 2022

Post-stroke patients exhibit distinct muscle activation electromyography (EMG) features in sit-to-stand (STS) due to motor deficiency. Muscle activation amplitude, related to muscle tension and muscle synergy activation levels, is one of the defining EMG features that reflects post-stroke motor functioning and motor impairment. Although some qualitative findings are available, it is not clear if and how muscle activation amplitude-related biomechanical attributes may quantitatively reflect during subacute stroke rehabilitation. To better enable a longitudinal investigation into a patient's muscle activation changes during rehabilitation or an inter-subject comparison, EMG normalization is usually applied. However, current normalization methods using maximum voluntary contraction (MVC) or within-task peak/mean EMG may not be feasible when MVC cannot be obtained from stroke survivors due to motor paralysis and the subject of comparison is EMG amplitude. Here, focusing on the paretic side, we first propose a novel, joint torque-based normalization method that incorporates musculoskeletal modeling, forward dynamics simulation, and mathematical optimization. Next, upon method validation, we apply it to quantify changes in muscle tension and muscle synergy activation levels in STS motor control units for patients in subacute stroke rehabilitation. The novel method was validated against MVC-normalized EMG data from eight healthy participants, and it retained muscle activation amplitude differences for inter- and intra-subject comparisons. The proposed joint torque-based method was also compared with the common static optimization based on squared muscle activation and showed higher simulation accuracy overall. Serial STS measurements were conducted with four post-stroke patients during their subacute rehabilitation stay (137 ± 22 days) in the hospital. Quantitative results of patients suggest that maximum muscle tension and activation level of muscle synergy temporal patterns may reflect the effectiveness of subacute stroke rehabilitation. A quality comparison between muscle synergies computed with the conventional within-task peak/mean EMG normalization and our proposed method showed that the conventional was prone to activation amplitude overestimation and underestimation. The contributed method and findings help recapitulate and understand the post-stroke motor recovery process, which may facilitate developing more effective rehabilitation strategies for future stroke survivors.
Efficacy and Safety of Complementary Therapy With Jing Si Herbal Tea in Patients With Mild-To-Moderate COVID-19: A Prospective Cohort Study
Authors: Hsieh Po-Chun , Chao You-Chen , Tsai Kuo-Wang , Li Chung-Hsien , Tzeng I-Shiang , Wu Yao-Kuang , Shih Cheng Yen
Published: March 2022

Background

Since late 2019, there has been a global COVID-19 pandemic. To preserve medical capacity and decrease adverse health effects, preventing the progression of COVID-19 to severe status is essential. Jing-Si Herbal Tea (JSHT), a novel traditional Chinese medicine formula was developed to treat COVID-19. This study examined the clinical efficacy and safety of JSHT in patients with mild-to-moderate COVID-19.

Methods

In this prospective cohort study, we enrolled 260 patients with mild-to-moderate COVID-19. The enrolled patients were divided into the JSHT (n = 117) and control (n = 143) groups. Both groups received standard management. The JSHT group was treated with JSHT as a complementary therapy.

Results

Compared with standard management alone, JSHT combined with standard management more effectively improved the reverse transcription–polymerase chain reaction cycle threshold value, C-reactive protein level, and Brixia score in the adult patients with mild-to-moderate COVID-19, especially in the male and older patients (those aged ≥60 years). The results revealed that the patients treated with JSHT combined with standard management had 51, 70, and 100% lower risks of intubation, Medisave Care Unit admission, and mortality compared with those receiving standard management only.

Conclusions

JSHT combined with standard management more effectively reduced the SARS-CoV-2 viral load and systemic inflammation and alleviated lung infiltrates in the patients with mild-to-moderate COVID-19, especially in the male and older patients (those aged ≥60 years). JSHT combined with standard management may prevent critical status and mortality in patients with mild-to-moderate COVID-19. JSHT is a promising complementary therapy for patients with mild-to-moderate COVID-19.
Breast Cancer Mortality Trends and Predictions to 2030 and Its Attributable Risk Factors in East and South Asian Countries
Authors: Mubarik Sumaira , Sharma Rajesh , Hussain Syeda Rija , Iqbal Mujahid , Nawsherwan  , Liu Xiaoxue , Yu Chuanhua
Published: March 2022

Background

Amidst the rising breast cancer burden in Asia, we aim to predict the future mortality risk due to breast cancer and identify the risk-attributable deaths for breast cancer among East and South Asian countries.

Methods

We used country-level data to predict the trends in the next decade relating to female breast cancer mortality by employing data from 1990 to 2019 from the Global Burden of Disease 2019 study. We used the stochastic mortality modeling and prediction techniques to forecast the age-specific and risk-attributable breast cancer mortality trends at the regional and national levels of East and South Asia.

Results

The number of deaths caused by the breast cancer is predicted to increase in East and South Asian countries in the next decade (2020–2030). Age-standardized death rate (ASDR) of breast cancer is predicted to increase by 7.0% from 9.20/100,000 (95% CI: 6.04–12.12) in 1990 to 9.88/100,000 (95% CI: 7.12–11.4) in 2030 in East Asia, and about 35% increase from 13.4/100,000 (95% CI: 9.21–16.02) in 1990 to 18.1/100,000 (95% CI: 13.23–21.10) in 2030 in South Asia. At the national level, the highest percent change in ASDR between 1990 and 2030 was reported in Pakistan (a 62% increase) and Nepal (a 47% increase). The highest percent change in breast cancer mortality between 2020 and 2030 for females of age group 80–84 years was observed in Pakistan [21.6, (95% CI, 20.6–94.7)], followed by Afghanistan [13.3 (4.0–80.8)], and Nepal [36.6 (11.1–125.7)] as compared to the other countries. In the females of aged 50–80 years, the predicted death rates were associated with high body mass index, high-fasting plasma glucose, and diet high in red meat, across the majority of countries under study. Furthermore, reductions in percent change in mortality rates occurred in several countries with increases in sociodemographic index (SDI), notably across high SDI countries.

Conclusion

Breast cancer mortality risk varies substantially across East and South Asian countries with higher mortality risk in low/middle SDI countries. Early detection using screening, awareness among females and health workers, and cost-effective and timely treatment of patients with breast cancer is vital in stemming the tide of breast cancer in the next decade.
Prognostic Pathways Guide Drug Indications in Pan-Cancers
Authors: Meng Fanlin , Zhang Kenan , Yang Changlin , Zhang Ke , Xu Quan , Ren Ruifang , Zhou Yiming , Sun Yimin , Peng Yan , Li Yanze , Guo Hongyan , Ren Yonghong , Zhao Zheng
Published: March 2022

Pathway-level analysis is a powerful approach enabling the interpretation of post-genomic data at a higher level than that of individual molecules. Molecular-targeted therapy focusing on cascade signaling pathways has become a new paradigm in anticancer therapy, instead of a single protein. However, the approaches to narrowing down the long list of biological pathways are limited. Here, we proposed a strategy for in silico Drug Prescription on biological pathways across pan-Cancers (CDP), by connecting drugs to candidate pathways. Applying on a list of 120 traditional Chinese medicines (TCM), we especially identified the “TCM–pathways–cancers” triplet and constructed it into a heterogeneous network across pan-cancers. Applying them into TCMs, the computational prescribing methods deepened the understanding of the efficacy of TCM at the molecular level. Further applying them into Western medicines, CDP could promote drug reposition avoiding time-consuming developments of new drugs.
High-Throughput Metabolomics Platform for the Rapid Data-Driven Development of Novel Additive Solutions for Blood Storage
Authors: Nemkov Travis , Yoshida Tatsuro , Nikulina Maria , D’Alessandro Angelo
Published: March 2022

Red blood cell transfusion is a life-saving intervention, and storage is a logistic necessity to make ~110 million units available for transfusion every year worldwide. However, storage in the blood bank is associated with a progressive metabolic decline, which correlates with the accumulation of morphological lesions, increased intra- and extra-vascular hemolysis upon transfusion, and altered oxygen binding/off-loading kinetics. Prior to storage, red blood cells are suspended in nutrient formulations known as additive solutions to prolong cellular viability. Despite a thorough expansion of knowledge regarding red blood cell biology over the past few decades, only a single new additive solution has been approved by the Food and Drug Administration this century, owing in part to the limited capacity for development of novel formulations. As a proof of principle, we leveraged a novel high-throughput metabolomics technology as a platform for rapid data-driven development and screening of novel additive solutions for blood storage under both normoxic and hypoxic conditions. To this end, we obtained leukocyte-filtered red blood cells (RBCs) and stored them under normoxic or hypoxic conditions in 96 well plates (containing polyvinylchloride plasticized with diethylhexylphthalate to concentrations comparable to full size storage units) in the presence of an additive solution supplemented with six different compounds. To inform this data-driven strategy, we relied on previously identified metabolic markers of the RBC storage lesion that associates with measures of hemolysis and post-transfusion recovery, which are the FDA gold standards to predict stored blood quality, as well as and metabolic predictors of oxygen binding/off-loading parameters. Direct quantitation of these predictors of RBC storage quality were used here—along with detailed pathway analysis of central energy and redox metabolism—as a decision-making tool to screen novel additive formulations in a multiplexed fashion. Candidate supplements are shown here that boost-specific pathways. These metabolic effects are only in part dependent on the SO2 storage conditions. Through this platform, we anticipate testing thousands of novel additives and combinations thereof in the upcoming months.
Stability in the South, Turbulence Toward the North: Evolutionary History of Aurinia saxatilis (Brassicaceae) Revealed by Phylogenomic and Climatic Modelling Data
Authors: Rešetnik Ivana , Záveská Eliška , Grgurev Marin , Bogdanović Sandro , Bartolić Paolo , Frajman Božo
Published: March 2022

The Balkan Peninsula played an important role in the evolution of many Mediterranean plants and served as a major source for post-Pleistocene colonisation of central and northern Europe. Its complex geo-climatic history and environmental heterogeneity significantly influenced spatiotemporal diversification and resulted in intricate phylogeographic patterns. To explore the evolutionary dynamics and phylogeographic patterns within the widespread eastern Mediterranean and central European species Aurinia saxatilis, we used a combination of phylogenomic (restriction-site associated DNA sequencing, RADseq) and phylogenetic (sequences of the plastid marker ndhF) data as well as species distribution models generated for the present and the Last Glacial Maximum (LGM). The inferred phylogenies retrieved three main geographically distinct lineages. The southern lineage is restricted to the eastern Mediterranean, where it is distributed throughout the Aegean area, the southern Balkan Peninsula, and the southern Apennine Peninsula, and corresponds to the species main distribution area during the LGM. The eastern lineage extends from the eastern Balkan Peninsula over the Carpathians to central Europe, while the central lineage occupies the central Balkan Peninsula. Molecular dating places the divergence among all the three lineages to the early to middle Pleistocene, indicating their long-term independent evolutionary trajectories. Our data revealed an early divergence and stable in situ persistence of the southernmost, eastern Mediterranean lineage, whereas the mainland, south-east European lineages experienced more complex and turbulent evolutionary dynamics triggered by Pleistocene climatic oscillations. Our data also support the existence of multiple glacial refugia in southeast Europe and highlight the central Balkan Peninsula not only as a cradle of lineage diversifications but also as a source of lineage dispersal. Finally, the extant genetic variation within A. saxatilis is congruent with the taxonomic separation of peripatric A. saxatilis subsp. saxatilis and A. saxatilis subsp. orientalis, whereas the taxonomic status of A. saxatilis subsp. megalocarpa remains doubtful.