bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a Computational Phenotype to Identify Acute Brain Dysfunction in Pediatric Sepsis
Authors: Alcamo Alicia M. , Barren Gregory J. , Becker Andrew E. , Hayes Katie , Fitzgerald Julie C. , Balamuth Fran , Pennington Jeffrey W. , Curley Martha A. Q. , Tasker Robert C. , Topjian Alexis A. , Weiss Scott L.
Published: October 2022

OBJECTIVES:

To validate a computational phenotype that identifies acute brain dysfunction (ABD) based on clinician concern for neurologic or behavioral changes in pediatric sepsis.

DESIGN:

Retrospective observational study.

SETTING:

Single academic children’s hospital.

PATIENTS:

Four thousand two hundred eighty-nine index sepsis episodes.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

An existing computational phenotype of ABD was optimized to include routinely collected variables indicative of clinician concern for acute neurologic or behavioral change (completion of CT or MRI, electroencephalogram, or new antipsychotic administration). First, the computational phenotype was compared with an ABD reference standard established from chart review of 527 random sepsis episodes to determine criterion validity. Next, the computational phenotype was compared with a separate validation cohort of 3,762 index sepsis episodes to determine content and construct validity. Criterion validity for the final phenotype had sensitivity 83% (95% CI, 76–89%), specificity 93% (90–95%), positive predictive value 84% (77–89%), and negative predictive value 93% (90–96%). In the validation cohort, the computational phenotype identified ABD in 35% (95% CI 33–36%). Content validity was demonstrated as those with the ABD computational phenotype were more likely to have characteristics of neurologic dysfunction and severe illness than those without the ABD phenotype, including nonreactive pupils (15% vs 1%; p < 0.001), Glasgow Coma Scale less than 5 (44% vs 12%; p < 0.001), greater than or equal to two nonneurologic organ dysfunctions (50% vs 25%; p < 0.001), and need for intensive care (81% vs 65%; p < 0.001). Construct validity was demonstrated by higher odds for mortality (odds ratio [OR], 6.9; 95% CI, 5.3–9.1) and discharge to rehabilitation (OR, 11.4; 95% CI 7.4–17.5) in patients with, versus without, the ABD computational phenotype.

CONCLUSIONS:

A computational phenotype of ABD indicative of clinician concern for new neurologic or behavioral change offers a valid retrospective measure to identify episodes of sepsis that involved ABD. This computational phenotype provides a feasible and efficient way to study risk factors for and outcomes from ABD using routinely collected clinical data.
Descriptive Analysis of Clinical Encounters by Emergency Medical Services Physicians Using the RE-AIM Framework
Authors: Rosenblum Andrew J. , Wend Christopher M. , Ide Reef A. , Owens Matthew A. , Cutchins V Clifford A. , Levy Matthew J.
Published: October 2022

Context:

Emergency medical services (EMS) medicine continues to expand and mature as a recognized subspeciality within emergency medicine. In the United States, EMS physicians historically supported training, protocol development, and EMS clinician credentialing. In the past, only limited programs existed in which prehospital physicians were engaged in the direct and routine care of prehospital patients; however, a growing number of EMS programs are recognizing the value and impact of direct EMS physician involvement in prehospital patient care.

Program:

A large suburban, volunteer-based EMS agency implemented a volunteer prehospital physician program where providers routinely responded to emergency calls for service.

Implementation:

Beginning in November 2019, a cadre of board-certified physicians completed a field preceptorship and local protocol orientation. Once complete, the physicians were released to function and respond independently to high acuity emergency calls or any call at their discretion. Prehospital physicians were authorized to utilize their full scope of practice and expected to provide field mentorship to traditional prehospital clinicians.

Evaluation:

This study systematically evaluated a prehospital physician program for public health relevance, sustainability, and population health impact using the RE-AIM framework. A retrospective descriptive analysis was performed on the role and responses by a cohort of prehospital physicians using dispatch data and electronic medical records.

Discussion:

Over the 17-month study period, 9 prehospital physicians responded to 482 calls, predominately cardiac arrests, traumatic injuries, and cardiac/chest pain. The physicians performed 99 procedures and administered 113 medications. Ultimately, the program added physician-level care to the prehospital setting in an ongoing and sustainable way. The routine placement of physicians in the prehospital environment can help benefit patients by enhancing access to advanced clinical knowledge and skills, while also benefiting EMS clinicians through opportunities for enhanced patient-side training, education, and medical control.
Public Health Learning Agenda for Systems Change Toolkit: National Pilot Evaluation Results
Authors: Welter Christina , Davis Sarah , Elnicki Jill , Kulik Phoebe K. G. , Lloyd Laura M. , Tenney Martha , Todd Barrett Karla , Rose Barbara , Walter Cassidy
Published: October 2022

Context:

There have been multiple calls in the United States for public health workforce development approaches that expand practitioner skill sets to respond to profound inequities and improve population health more effectively. However, most workforce models address individual competencies that instead focus on collective approaches to systems change.

Program:

In response to this opportunity, the HRSA-funded Regional Public Health Training Centers (PHTCs) and the University of Illinois Chicago Policy, Practice, and Prevention Research Center (P3RC) released Creating a Learning Agenda for Systems Change: A Toolkit for Building an Adaptive Public Health Workforce (the Toolkit) in December 2020. We later supplemented the Toolkit with additional learning activities to launch the Learning Agenda Toolkit Pilot Test (Toolkit Pilot).

Implementation:

From June to August 2021, 24 diverse teams piloted the Toolkit. Teams completed a multistep process simulating the development of a learning agenda aimed at addressing community health issues and impacting systems change.

Evaluation:

We conducted an evaluation process to assess the usability and impact of the Toolkit Pilot to inform its improvement and future implementation. An evaluation subcommittee analyzed worksheets completed by the Pilot Teams that are aligned to the Learning Agenda steps and conducted and analyzed 12 key informant interviews using concepts from the Toolkit Pilot Logic Model.

Findings and Discussion:

Evaluation results suggest that most Pilot Teams found that the Toolkit Pilot offered a step-by-step process toward a clear vision that produced a concrete product on how to address community challenges through learning and systems change. Pilot Teams noted that the Toolkit Pilot provided exposure to and a unique focus on systems thinking; however, prior knowledge of systems thinking and systems change was important. Building readiness for systems change and having more time, resources, and technical assistance would be needed for future versions of the Learning Agenda Toolkit.
68Ga-FAPI-04 Versus 18F-FDG PET/CT in Detection of Epithelioid Malignant Pleural Mesothelioma
Authors: Dong Aisheng , Zhao Bo , Cheng Chao , Zuo Changjing
Published: October 2022

We describe 68Ga-FAPI (fibroblast activation protein inhibitor)-04 and 18F-FDG PET/CT findings in a case with epithelioid malignant pleural mesothelioma. Compared with 18F-FDG PET/CT, 68Ga-FAPI-04 PET/CT more clearly showed the pleural tumors and lymph node metastases and detected more pleural lesions because the tumors showed higher 68Ga-FAPI-04 activity. This case indicates that 68Ga-FAPI-04 PET/CT may be a promising new tool in evaluation of malignant pleural mesothelioma, which needs further investigation.
Nasal Tube Securement
Authors: McNeely Heidi L. , Quackenbush Debra , Bothwell Samantha , Banks Ashley , Brinton John T.
Published: October 2022

Purpose

The aim of this study was to compare accidental dislodgement rates of nasal gastric tubes secured with standard methods or a nasal tube securement device in pediatric patients.

Design

A randomized controlled trial was conducted.

Methods

Participants (n = 43) were randomized into standard securement or nasal tube securement device using block randomization to control for age and diagnosis. Surveys were collected from staff and caregivers on device ease of use and satisfaction.

Results

There were a similar number of tube dislodgements for patients in the nasal tube securement device group (n = 6) and the standard practice group (n = 7). The median hospital length of stay was higher for the standard practice group (13 days vs. 9 days).

Conclusion

Use of the nasal tube securement device did not significantly decrease the rate of tube dislodgements compared with standard practice.

Clinical Relevance to Rehabilitation Nursing

The study provides information for pediatric rehabilitation nurses in choosing securement options for nasal gastric tubes.
Application of Skin-stretching Device for Closing Scalp Defect
Authors: Zhang Qingtao , Xu Lei , Liu Yang , Tang Xiaoyong , Wang Jia , Deng Yongbing , Chen Peng
Published: October 2022

Background:

The scalp defect was a clinical common constructive challenge. This research verified the efficacy of the skin-stretching device in the treatment of scalp defect and assessed the associated complications.

Methods:

The clinical data of 12 patients with scalp defect treated with skin-stretching device from January 2020 to January 2021 were collected. We used EASApprox skin-stretching device for the treatment of scalp defect. We described a detailed reconstruction procedure for this treatment. We collected the site, distance from wound edge and other characteristics of the wound, and recorded the number of stretching cycles, operation time, closed state, healing time, and observed postoperative complications and wound healing status.

Results:

In this research, the scalp defect was mainly caused by pressure ulcer, and mainly located in the parietooccipital site. The average distance from wound edge was 3.2 cm, the average stretching cycles was 4.2 times during the operation, and the average operation time was 43.5 minutes. Ten patients were directly sutured after stretching, and 2 patients underwent first-stage stretching to reduce the wound. The average time of wound healing was 13.5 days. Postoperative follow-up of 3 months, no patients had wound tear, necrosis, 1 patient suffered from wound exudation and infection due to poor nutrition. Skin function and final scar was acceptable.

Conclusion:

The treatment of skin-stretching device was effective for scalp defect and has the advantages of convenient operation, acceptable functional results, without severe complications. In addition to traditional treatment, this was a promising treatment. However, more clinical and preclinical research of the skin-stretching device were required.
Gender-Affirming Facial Feminization Surgery at a Public, Safety-Net Hospital: A Single-Center Early Experience
Authors: Alcon Andre , Badiee Ryan K. , Barnes Laura L. , Pardo Seth T. , Zevin Barry , Pomerantz Jason H.
Published: October 2022

Background:

Facial feminization surgery (FFS) remains inaccessible to many transgender patients. Zuckerberg San Francisco General Hospital (ZSFG) was among the first public, safety-net hospitals to perform FFS. The purpose of this study is to examine the postoperative outcomes of patients who underwent FFS at ZSFG and describe barriers to providing FFS in a public hospital setting.

Methods:

A retrospective review identified patients who underwent FFS at ZSFG. Demographic data, comorbidity profiles, postoperative outcomes, and hospital utilization data were collected from the medical records. FACE-Q modules (scored 0–100) were used to survey patient satisfaction at least 1 year postoperatively.

Results:

Seventeen patients underwent comprehensive FFS surgery at ZSFG. The median age was 41 years [interquartile range (IQR): 38–55], median body mass index was 26.4 (IQR: 24.1–31.3). Patients underwent a median of 9 procedures, the most common of which included frontal cranioplasty (n=13, 77%), open brow lift (n=13, 77%), rhinoplasty (n=12, 71%), and mandible contouring (n=12, 71%). There were no complications, readmissions, or reoperations within 30 days. Patients reported high satisfaction with the surgical outcome (median: 87, IQR: 87–100), excellent postoperative psychological functioning (median: 100, IQR: 88–100), and low levels of appearance-related distress (median: 3, IQR: 0–35). An estimated 243 operating room hours and 51 inpatient bed days were required to cover all FFS procedures.

Conclusions:

Performing FFS in a public, safety-net hospital was associated with zero postoperative complications, few revision procedures, and excellent patient satisfaction. Limited operating room hours and inpatient availability represented barriers to providing FFS in this setting.
Regulatory T Cells: Liquid and Living Precision Medicine for the Future of VCA
Authors: Kauke-Navarro Martin , Knoedler Samuel , Panayi Adriana C. , Knoedler Leonard , Noel Olivier F. , Pomahac Bohdan
Published: October 2022

Transplant rejection remains a challenge especially in the field of vascularized composite allotransplantation (VCA). To blunt the alloreactive immune response‚ stable levels of maintenance immunosupression are required. However‚ the need for lifelong immunosuppression poses the risk of severe side effects, such as increased risk of infection, metabolic complications, and malignancies. To balance therapeutic efficacy and medication side effects, immunotolerance promoting immune cells (especially regulatory T cells [Treg]) have become of great scientific interest. This approach leverages immune system mechanisms that usually ensure immunotolerance toward self-antigens and prevent autoimmunopathies. Treg can be bioengineered to express a chimeric antigen receptor or a T-cell receptor. Such bioengineered Treg can target specific antigens and thereby reduce unwanted off-target effects. Treg have demonstrated beneficial clinical effects in solid organ transplantation and promising in vivo data in VCAs. In this review, we summarize the functional, phenotypic, and immunometabolic characteristics of Treg and outline recent advancements and current developments regarding Treg in the field of VCA and solid organ transplantation.
Toward inhibition of human cytomegalovirus replication with compounds targeting cellular proteins
Authors: Strang Blair L.
Published: October 2022

Antiviral therapy for human cytomegalovirus (HCMV) currently relies upon direct-acting antiviral drugs. However, it is now well known that these drugs have shortcomings, which limit their use. Here I review the identification and investigation of compounds targeting cellular proteins that have anti-HCMV activity and could supersede those anti-HCMV drugs currently in use. This includes discussion of drug repurposing, for example the use of artemisinin compounds, and discussion of new directions to identify compounds that target cellular factors in HCMV-infected cells, for example screening of kinase inhibitors. In addition, I highlight developing areas such as the use of machine learning and emphasize how interaction with fields outside virology will be critical for development of anti-HCMV compounds.
Generalized habitual tendencies in alcohol dependent rats
Authors: Giannone Francesco , Hach Arian , Chrószcz Magda , Friske Marion M. , Meinhardt Marcus , Spanagel Rainer , Sommer Wolfgang H. , Hansson Anita C.
Published: October 2022

Habitual responses and ultimately compulsive behavior are thought to be at the core of addiction including alcohol use disorder (AUD). Little is known whether the habitization concerns exclusively the response towards alcohol or generalizes to other daily activities. Here, we address this question in a well-established animal model of AUD – the postdependent rat model – by testing habitual responses towards a sweet palatable reward in two striatal learning paradigms: spatial navigation and reward conditioning. For the spatial navigation task, alcohol-dependent and control rats were tested on a sequential decision-making test after short and prolonged T-Maze training; for the reward conditioning task, rats were trained under a random interval schedule for a short and prolonged period and tested in a satiety devaluation test at each time point. Another cohort of alcohol-naive rats was trained and tested on both paradigms under DREADD (designer receptors exclusively activated by designer drugs)-mediated inactivation of the dorsomedial striatum (DMS) which controls goal-directed behavior. Our results show that alcohol-dependent rats displayed increased habitual behavior to obtain saccharin reward on both paradigms, with overall more habitual choices after prolonged training on the spatial navigation task, and increased habitual responses already after short training on the reward conditioning task. Finally, DREADD-mediated inactivation of the DMS increased habitual behavior in non-dependent rats on both paradigms. Our results provide evidence that a history of alcohol dependence produces a bias towards habitual responding that generalizes to a natural reward in rats. Similarly, a habitual bias was induced in non-dependent rats after inactivation of the DMS, thus confirming the critical role of this region in maintaining goal-directed behavior and suggesting its diminished control in AUD.
The investigation on metabolites, genes and open chromatins involved in colored leaves ofEucommia ulmoides‘Ziye’
Authors: Long Li , Qianqian Shi , Wenjing Yao
Published: October 2022

Eucommia ulmoidesOliver ‘Ziye’ has unique purple-red leaves, which contain a variety of flavonoids, so it has high ornamental and medicinal value. However, the categories of flavonoids and molecular mechanism of specific accumulation of flavonoids in ‘Ziye’ leaves is still unclear. Here, differences in metabolic level, gene expression level, chromatin accessibility and cis-regulatory elements were compared between ‘Ziye’ and ‘Huazhong 1’ with green leaf color by metabolome profiling, RNA-seq, and ATAC-seq. A total of 205 flavonoids were identified from these two varieties using ultraperformance liquid chromatography–mass spectrometry (UPLC-MS). The accumulation of most delphinidin, cyaniding, quercetin, myricetin, and isorhamnetin derivatives peaked in old leaves of ‘Ziye’. Single-molecule long-read sequencing indicated that genes in the phenylpropanoid biosynthesis and flavonoid biosynthetic pathway, as well as many transcription factors including MYB, ERF, and WRKY were highly expressed in ‘Ziye’ leaves. ATAC-seq revealed the presence of cell preferentially enriched peaks, which annotated to 6114 genes. Analysis of the genomic regions preferentially accessible in each cell type identified hundreds of overrepresented TF-binding motifs, highlighting sets of TFs such as MYB, ERF, and WRKY that are probably important for color formation of ‘Ziye’ cell. Interestingly, the TFs within each of these cell type-enriched sets also showed evidence of extensively co-regulating each other. Our work demonstrated how chromatin accessibility and TF expression level influenced the expression of flavonoid biosynthesis associated genes, resulted in flavonoids accumulation in ‘Ziye’ leaf. Our results could lay a foundation for further studies of gene expression and functional genomics inE. ulmoides.
Benchmarking Automated Cell Type Annotation Tools for Single-cell ATAC-seq Data
Authors: Wang Yuge , Sun Xingzhi , Zhao Hongyu
Published: October 2022

As single-cell chromatin accessibility profiling methods advance, scATAC-seq has become ever more important in the study of candidate regulatory genomic regions and their roles underlying developmental, evolutionary and disease processes. At the same time, cell type annotation is critical in understanding the cellular composition of complex tissues and identifying potential novel cell types. However, most existing methods that can perform automated cell type annotation are designed to transfer labels from an annotated scRNA-seq data set to another scRNA-seq data set, and it is not clear whether these methods are adaptable to annotate scATAC-seq data. Several methods have been recently proposed for label transfer from scRNA-seq data to scATAC-seq data, but there is a lack of benchmarking study on the performance of these methods. Here, we evaluated the performance of five scATAC-seq annotation methods on both their classification accuracy and scalability using publicly available single-cell datasets from mouse and human tissues including brain, lung, kidney, PBMC and BMMC. Using the BMMC data as basis, we further investigated the performance of these methods across different data sizes, mislabeling rates, sequencing depths and the number of cell types unique to scATAC-seq. Bridge integration, which is the only method that requires additional multimodal data and does not need gene activity calculation, was overall the best method and robust to changes in data size, mislabeling rate and sequencing depth. Conos was the most time and memory efficient method but performed the worst in terms of prediction accuracy. scJoint tended to assign cells to similar cell types and performed relatively poorly for complex datasets with deep annotations but performed better for datasets only with major label annotations. The performance of scGCN and Seurat v3 was moderate, but scGCN was the most time-consuming method and had the most similar performance to random classifiers for cell types unique to scATAC-seq.
Comprehensive Physical Exam versus Lung Ultrasound for Dyspneic Patients in the Emergency Department
Authors: Secko Michael , Cheng Yuwen , Raj Sonika , Goradia Eshani , Reardon Lindsay , Thode Henry C. , Singer Adam J.
Published: October 2022

Objective

Overreliance on technology has led to dwindling physical exam (PE) skills. We compared the diagnostic accuracy of a structured lung physical examination (L-PE) to structured lung ultrasound (LUS) in ED patients with undifferentiated dyspnea. We also examined the change in differential diagnosis and degree of certainty based on order and type of exam

Methods

This was a prospective, randomized, crossover study of a convenience sample of adult ED patients with undifferentiated dyspnea. Comprehensive L-PE and LUS were performed in random order followed by the other exam. An adjudication committee determined the final diagnosis based on all available data and served as the criterion standard. Primary outcome was diagnostic accuracy. A sample of 86 patients had 80% power to detect a 25% difference in diagnostic accuracy.

Results

A total of 102 patients were enrolled. Similar accuracies were found between L-PE and LUS for both COPD [75% (95% CI 65-83) vs. 76% (95% CI 67-84)] and asthma [87% (95% CI 79-93) vs. 87% (95 CI 79-93)]. LUS [81% (95 CI 72-88)] was slightly more accurate compared to L-PE [72% (95 CI 62-80)] for diagnosis of pneumonia but not statistically significant. For patients presenting with pulmonary edema, LUS was slightly [76% (95 CI 66-84)] more accurate than L-PE [73% (95 CI 63-81)], but not statistically significant. Finally, for detecting pleural effusions, L-PE [96% (95 CI 90-99)] was more accurate than LUS [82% (95 CI 73-89)].

Conclusions

The diagnostic accuracies of comprehensive lung physical examination and focused lung ultrasound were generally similar in ED patients with dyspnea and should be used concurrently to maximize diagnostic accuracy.
Molecular and genetic mechanisms conferring dissolution of dioecy inDiospyros oleiferaCheng
Authors: Sun Peng , Nishiyama Soichiro , Li Huawei , Mai Yini , Han Weijuan , Suo Yujing , Liang Chengzhi , Du Huilong , Diao Songfeng , Wang Yiru , Yuan Jiaying , Zhang Yue , Tao Ryutaro , Li Fangdong , Fu Jianmin
Published: October 2022

Dioecy, a sexual system of single-sex (gynoecious/androecious) individuals, is rare in flowering plants. This rarity may be a result of the frequent transition from dioecy into systems with co-sex individuals. Here, we report potential molecular and genetic mechanisms that underlie the dissolution of dioecy to monoecy and andro(gyno)monoecy, based on multiscale genome-wide investigations of 150 accessions ofDiospyros oleifera. All co-sexD. oleiferaplants, including monoecious and andro(gyno)monoecious individuals, possessed the male determinant geneOGI, implying that genetic factors control gynoecia development in genetically maleD. oleifera. In both single- and co-sex plants, female function was expressed in the presence of a genome-wide decrease in methylation levels, along with sexually distinct regulatory networks of smRNAs and their targets. Furthermore, a genome-wide association study (GWAS) identified a genomic region and aDUF247gene cluster strongly associated with the monoecious phenotype, as well as several regions that may contribute to andromonoecy. Collectively, our findings imply stable breakdown of the dioecious system inD. oleifera, presumably a result of the genomic features of the sex-linked region.
MAMBA: a model-driven, constraint-based multiomic integration method
Authors: Ugidos Manuel , Nuño-Cabanes Carme , Tarazona Sonia , Ferrer Alberto , Nielsen Lars Keld , Rodríguez-Navarro Susana , Marín de Mas Igor , Conesa Ana
Published: October 2022

The inclusion of omic data into constraint-based modeling (CBM) has improved metabolic network characterization of biological models. However, the integration of semi-quantitative metabolomic data into CBM remains challenging. Here, we present MAMBA (Metabolic Adjustment via Multiomic Blocks Aggregation), a CBM approach that enables the use of semi-quantitative metabolomic data together with a gene-centric omic data type (e.g. transcriptomics, ChIP-seq or chromatin accessibility data, among others), and the combination of different time points and conditions. MAMBA outperformed other methods in terms of metabolic network characterization and metabolite prediction accuracy. As a case study, we applied MAMBA to a yeast multiomic dataset with time series design where two different yeast strains where exposed to heat stress. MAMBA captured known biology of heat stress in yeast and identified novel affected metabolic pathways. MAMBA was implemented as an integer linear programming (ILP) problem to guarantee efficient computation, and coded for MATLAB (freely available at github.com/ConesaLab/MAMBA).
1H-MRS characterization of metabolic changes induced by photoperiod in the sheep brain: a promising eye into in-vivo adult neurogenesis?
Authors: Just Nathalie , Chevillard Pierre Marie , Batailler Martine , Dubois Jean-Philippe , Vaudin Pascal , Pillon Delphine , Migaud Martine
Published: October 2022

The hypothalamus is a central structure of the mammalian brain, which controls physiological, endocrine and metabolic brain homeostasis. Despite this essential role, little is known about the normal and altered neurochemical changes occurring within the hypothalamic structures. Here, the metabolism of the hypothalamus of ewes was investigated at 3T using proton magnetic resonance spectroscopy (1H-MRS). We used the sensitivity of these animals to photoperiod i.e. the ratio of day to night length, to investigate the hypothalamic metabolic changes and their relationship to hypothalamic adult neurogenesis. A longitudinal study involving 4 ewes per timepoint was conducted at 4 time points (P01, P02, P03 and P04) during long days (LD) and 4 time points during short days (SD). Significant metabolic changes were found between LD and SD at all time points in particular for glutamate (Glu), glutamine, myo-inositol and total N-acetyl-Aspartate (NAA). During SD, glutamate and glutamine concentrations were significantly smaller at P01 compared to all other time points while significant neurochemical changes occurred during the entire LD period. Neurochemical changes relative to P01 remained stable during LD and SD except for Glu and Gln which increased between P01 and P02 during SD. Relative metabolic changes were significantly higher on average for NAA and Glu and significantly smaller on average for total choline during SD compared to LD, respectively, paralleling the average changes in the numbers of neural stem cells and glial and oligodendrocyte progenitors found by immunohistochemistry. Despite important differences between MRS and immunohistochemistry in terms of spatial resolution, both techniques suggest complementary findings that should contribute to a better characterization of the hypothalamus during photoperiodism and adult neurogenesis. We conclude that1H-MRS could be a promising non-invasive translational technique to investigate the existence of adult neurogenesis in-vivo in gyrencephalic brains.
Outer membrane β-barrel structure prediction through the lens of AlphaFold2
Authors: Topitsch Annika , Schwede Torsten , Pereira Joana
Published: October 2022

Most proteins found in the outer membrane of Gram-negative bacteria share a common domain: the transmembrane β-barrel. These outer membrane β-barrels (OMBBs) occur in multiple sizes, and different families with a wide range of functions evolved independently by amplification from a pool of homologous ancestral ββ-hairpins. This is part of the reason why predicting their three-dimensional (3D) structure, especially by homology modeling, is a major challenge. Recently, DeepMind’s AlphaFold v2 (AF2) became the first structure prediction method to reach close-to-experimental atomic accuracy in CASP even for difficult targets. However, membrane proteins, especially OMBBs, were not abundant during its training, raising the question of how accurate the predictions are for these families. In this study, we assessed the performance of AF2 in the prediction of OMBBs of various topologies using an in-house-developed tool for the analysis of OMBB 3D structures,barrOs. In agreement with previous studies on other membrane protein classes, our results indicate that AF2 predicts OMBB structures at high accuracy independently of the use of templates, even for novel topologies absent from the training set. These results provide confidence on the models generated by AF2 and open the door to the structural elucidation of novel OMBB topologies identified in high-throughput OMBB annotation studies.
High-resolution Nanopore methylome-maps reveal random hyper-methylation at CpG-poor regions as driver of chemoresistance in leukemias
Authors: Magi Alberto , Mattei Gianluca , Mingrino Alessandra , Caprioli Chiara , Ronchini Chiara , Frigè GianMaria , Semeraro Roberto , Bolognini Davide , Rambaldi Alessandro , Candoni Anna , Colombo Emanuela , Mazzarella Luca , Pelicci Pier Giuseppe
Published: October 2022

Aberrant DNA methylation at CpG dinucleotides is a hallmark of cancer and is associated with the emergence of resistance to anti cancer treatment, though molecular mechanisms and biological significance remain elusive. Genome scale methylation maps by currently used methods are based on chemical modification of DNA and are best suited for analyses of methylation at CpG rich regions (CpG islands). We report the first high coverage whole genome map in cancer using the long read nanopore technology, which allows simultaneous DNA-sequence and -methylation analyses on native DNA. We analyzed clonal epigenomic/genomic evolution in Acute Myeloid Leukemias (AMLs) at diagnosis and relapse, after chemotherapy. Long read sequencing coupled to a novel computational method allowed definition of differential methylation at unprecedented resolution, and showed that the relapse methylome is characterized by hypermethylation at both CpG islands and sparse CpGs regions. Most differentially methylated genes, however, were not differentially expressed nor enriched for chemoresistance genes. A small fraction of under-expressed and hyper-methylated genes at sparse CpGs, in the gene body, was significantly enriched in transcription factors (TFs). Remarkably, these few TFs supported large gene-regulatory networks including 50% of all differentially expressed genes in the relapsed AMLs and highly-enriched in chemoresistance genes. Notably, hypermethylated regions at sparse CpGs were poorly conserved in the relapsed AMLs, under-represented at their genomic positions and showed higher methylation entropy, as compared to CpG islands. Relapsed AMLs carried few patient specific structural variants and DNA mutations, apparently not involved in drug resistance. Thus, drug resistance in AMLs can be mainly ascribed to the selection of random epigenetic alterations at sparse CpGs of a few transcription factors, which then induce reprogramming of the relapsing phenotype, independently of clonal genomic evolution.
How a tarantula can help treat infections:Avicularia juruensis’s theraphotoxins that also act as antimicrobials
Authors: do Nascimento Soraia Maria , Roa Andrea Díaz , Mendonça Ronaldo Zucatelli , da Silva Junior Pedro Ismael
Published: October 2022

Short abstract

Considering that there are still many species little-studied, this work aimed to analyze the venom of the spiderAvicularia juruensissearching for antimicrobial peptides. Using reverse-phase high-performance liquid chromatography, microbial growth inhibition assay, transcriptomics, and proteomics approaches we identified three antimicrobial peptides: Avilin, Juruin_2, and Juruenine. All of them showed similarities with neurotoxins that act on ion channels and, probably, they have the ICK motif. The study of animal venoms is of great importance to carry out the characterization of unknown components and that may have a biotechnological application, in special venoms from spiders that are from less studied families.

Spiders are the most successful group of venomous animals, comprising more than 50,350 species distributed in all terrestrial habitats. One strategy that facility their broad distribution is the production of elaborate venoms, which are composed of inorganic salts, organic molecules with low molecular mass, free amino acids, small polypeptides, linear peptides, nucleotides, disulfide-rich peptides, enzymes, and high molecular mass proteins. Considering that there are still many species little-studied, this work aimed to analyze the venom of the mygalomorph spiderAvicularia juruensissearching for new antimicrobial peptides. Using reverse-phase high-performance liquid chromatography, microbial growth inhibition assay, transcriptomics, and proteomics approaches we identified three antimicrobial peptides that were named Avilin, Juruin_2, and Juruenine. All of them showed similarities with neurotoxins that act on ion channels and, probably, they have the ICK motif in their structure. The ICK fold seems to be conserved in several venomous animal lineages and presents elevated functional diversity, as well as gives stability to the toxins. The study of animal venoms is of great importance to carry out the characterization of unknown components and that may have a biotechnological application (like the antimicrobial peptides), in special venoms from spiders that are from less studied families.
7q11.23 CNV alters protein synthesis and REST-mediated neuronal intrinsic excitability
Authors: Mihailovich Marija , Germain Pierre-Luc , Shyti Reinald , Pozzi Davide , Noberini Roberta , Liu Yansheng , Aprile Davide , Tenderini Erika , Troglio Flavia , Trattaro Sebastiano , Fabris Sonia , Ciptasari Ummi , Rigoli Marco Tullio , Caporale Nicolò , D’Agostino Giuseppe , Vitriolo Alessandro , Capocefalo Daniele , Skaros Adrianos , Franchini Agnese , Ricciardi Sara , Biunno Ida , Neri Antonino , Kasri Nael Nadif , Bonaldi Tiziana , Aebersold Rudolf , Matteoli Michela , Testa Giuseppe
Published: October 2022

Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and excitability. Genes related to neuronal transmission chiefly followed 7q11.23 dosage and appeared transcriptionally controlled, while translation and ribosomal protein genes followed the opposite trend and were post-transcriptionally buffered. Mechanistically, we uncovered REST regulon as a key mediator of observed phenotypes and rescued transcriptional and excitability alterations through REST inhibition. We identified downregulation of global protein synthesis, mGLUR5 and ERK-mTOR pathways activity in steady-state in both WBS and 7Dup, whereas BDNF stimulation rescued them specifically in 7Dup. Overall, we show that 7q11.23 CNVs alter protein synthesis and neuronal firing-established molecular and cellular phenotypes of neurodevelopmental disorders.

Graphical abstract
Dopamine depletion leads to pathological synchronization of distinct basal ganglia loops in the beta band
Authors: Ortone Andrea , Vergani Alberto Arturo , Mannella Riccardo , Mazzoni Alberto
Published: October 2022

Motor symptoms of Parkinson’s Disease (PD) are associated with dopamine deficits and pathological oscillation of basal ganglia (BG) neurons in theβrange ([12-30] Hz). However, how the dopamine depletion affects the oscillation dynamics of BG nuclei is still unclear. With a spiking neurons model, we here captured the features of BG nuclei interactions leading to oscillations in dopamine-depleted condition. We found that both the loop between subthalamic nucleus and Globus Pallidus pars externa (GPe) and the loop between striatal fast spiking and medium spiny neurons and GPe displayed resonances in theβrange, and synchronized to a commonβfrequency through interaction. Crucially, the synchronization depends on dopamine depletion: the two loops were largely independent for high levels of dopamine, but progressively synchronized as dopamine was depleted due to the increased strength of the striatal loop. Our results highlight the role of the interplay between the GPe-STN and the GPe-striatum loop in generating sustainedβoscillations in PD subjects, and explain how this interplay depends on the level of dopamine. This paves the way to the design of therapies specifically addressing the onset of pathologicalβoscillations.

Author summary

Parkinson’s Disease is associated to the death of neurons generating a particular neurotransmitter: the dopamine. Motor symptoms of PD, on the other hand, are known to be due to dysfunctions in a particular subcortical area of the brain, the BG network. In particular, the BG network develops pathological oscillations in a specific frequency range (β: [12-30] Hz). What is unclear is how dopamine depletion leads to these oscillations. In this work we developed a BG network model and we found the actual reason for these abnormal oscillations is the synchronization of two loops within the network that are individually oscillating in theβrange. For healthy level of dopamine the two loops are decoupled and the oscillation power is low. When dopamine is depleted (as in PD) the two loops synchronize and originate the pathological oscillations associated with motor symptoms.
Autophagy in parvalbumin interneurons is required for inhibitory transmission and memory via regulation of synaptic proteostasis
Authors: Chalatsi Theodora , Fernandez Laura M.J. , Scholler Jules , Batti Laura , Kolaxi Angeliki , Restivo Leonardo , Lüthi Anita , Mameli Manuel , Nikoletopoulou Vassiliki
Published: October 2022

With the emerging role of the autophagic machinery in healthy brain development and aging, there is a pressing need to better characterize its functions in different neuronal populations, providing cellular insight into autophagy-related brain diseases. Here, we generated and characterized mice with conditional ablation ofatg5in GABAergic neurons expressing parvalbumin (PV-atg5KO), mostly comprising fast-spiking interneurons, as well as Purkinje cells in the cerebellum. Using light-sheet microscopy to image PV neurons throughout the brain, we reveal that autophagy is required for the sustenance of Purkinje cells but not of PV-interneurons. Yet, proteomic analysis showed that autophagy deficiency in cortical and hippocampal PV-interneurons alters the proteostasis of key synaptic proteins, as well as the surface expression of glutamate receptor subunits. Consistently, hippocampal autophagy-deficient PV-interneurons exhibit reduced inhibitory neurotransmission andPV-atg5KOmice display excitation-inhibition imbalance in the hippocampus and memory deficits. Our findings demonstrate a neuronal type-specific vulnerability to autophagy deficiency, while also identifying PV-interneurons as cellular substrates where autophagy is required for memory.
Chi-miR-3880 mediates the regulatory role of interferon gamma in goat mammary gland
Authors: Zhang Yue , Liu Jidan , Niu Guanglin , Wu Qiong , Cao Fangjun , Cao Binyun
Published: October 2022

A healthy mammary gland is a necessity for milk production of dairy goats. The role of chi-miR-3880 in goat lactation is illustrated in our previous study. Among the differentially expressed genes regulated by chi-miR-3880, one seventh are interferon stimulated genes, includingMX1,MX2,IFIT3,IFI44L, andDDX58. As the inflammatory cytokine interferon gamma (IFNγ) has been identified as a potential marker of caseous lymphadenitis in lactating sheep, the interaction between IFNγ and immune-related microRNAs is explored. In this study, it was found that chi-miR-3880 could be one of the microRNAs downregulated by IFNγ in goat mammary epithelial cells (GMECs). The regulation among IFNγ, chi-miR-3880, andDDX58, as well as their roles in mammary gland were investigated. The study illustrated that IFNγ/chi-miR-3880/DDX58axis modulates GMEC proliferation and lipid formation through PI3K/AKT/mTOR pathway, and regulates apoptosis through Caspase-3 and Bcl-2/Bax. The role of the axis in involution was reflected by the expression of p53 and NF-κB. In conclusion, IFNγ/chi-miR-3880/DDX58axis plays an important part in lactation.
Direct measurement of Stokes–Einstein diffusion of Cowpea mosaic virus with 19 µs-resolved XPCS
Authors: Switalski Kacper , Fan Jingyu , Li Luxi , Chu Miaoqi , Sarnello Erik , Jemian Pete , Li Tao , Wang Qian , Zhang Qingteng
Published: October 2022

Brownian motion of Cowpea mosaic virus (CPMV) in water was measured using small-angle X-ray photon correlation spectroscopy (SA-XPCS) at 19.2 µs time resolution. It was found that the decorrelation time τ(Q) = 1/DQ
2 up to Q = 0.091 nm−1. The hydrodynamic radius R
H determined from XPCS using Stokes–Einstein diffusion D = kT/(6πηR
H) is 43% larger than the geometric radius R
0 determined from SAXS in the 0.007 M K3PO4 buffer solution, whereas it is 80% larger for CPMV in 0.5 M NaCl and 104% larger in 0.5 M (NH4)2SO4, a possible effect of aggregation as well as slight variation of the structures of the capsid resulting from the salt–protein interactions.
Union influence on change-oriented organizational citizenship behavior: evidence from China
Authors: Hu Enhua , Han Mingyan , Zhang Mengyue , Huang Lin , Shan Hongmei
Published: October 2022

Purpose

Despite the considerable research into China's industrial relation system, little attention has been focused on what do Chinese unions at the enterprise level do and how their daily work influences employees' work-related outcomes. Drawing on the theory of planned behavior, this paper aims to examine the impact of Chinese enterprise union practices on employees' change-oriented organizational citizenship behavior through the mediating roles of psychological safety, perceived insider status, and role breadth self-efficacy.

Design/methodology/approach

Data were collected from 450 employees at 45 unionized enterprises in China through a three-wave survey. Multilevel analyses were conducted to test the hypothesized effects.

Findings

Chinese enterprise union practices positively predicted change-oriented organizational citizenship behavior. Critically, psychological safety and role breadth self-efficacy mediated the positive relationship between Chinese enterprise union practices and change-oriented organizational citizenship behavior.

Originality/value

This study provides new evidence on the effectiveness of Chinese enterprise union practices from a perspective of employees' work-related outcomes. It also enriches the existing literature on antecedents of change-oriented organizational citizenship behavior and provides a “planned” perspective to understand the mechanism that underlies the relationship between Chinese enterprise union practices and change-oriented organizational citizenship behavior.
Integration of Six Sigma and simulations in real production factory to improve performance – a case study analysis
Authors: Ahmed Ali , Olsen John , Page John
Published: October 2022

Purpose

The overarching objective of this research is to integrate the Lean Six Sigma (LSS) framework with computer simulation to improve the production efficiency of a light-emitting diode (LED) manufacturing factory.

Design/methodology/approach

Recently, the idea of taking advantage of the benefits of Six Sigma and simulation models together has led both industry and the academy towards further investigation and implementation of these methodologies. From this perspective, the present research will illustrate the effectiveness of using LSS methodology in a real factory environment by using the combination of three simulation methods which are system dynamics (SD), discrete-event simulation (DES) and agent-based (AB) modelling.

Findings

The hybrid simulation method applied in this research was found to accurately mimic and model the existing real factory environment. The define, measure, analyse, control and improve (DMAIC)-based improvements showed that the applied method is able to improve machine utilization rates while balancing the workload. Moreover, queue lengths for several stations were shortened, and the average processing time was decreased by around 50%. Also, a weekly production increase of 25% was achieved while lowering the cost per unit by around 8%.

Research limitations/implications

While the case study used was for a LED manufacturing system, the proposed framework could be implemented for any other existing production system. The research also meticulously presents the steps carried out for the development of the multi-method simulation model to allow readers to replicate the model and tailor it for their own case studies and projects. The hybrid model enables managers to navigate the trade-off decisions they often face when choosing advanced production output ahead of continuous improvement practices. The adoption of methodologies outlined in this paper would attain improvements in terms of queue lengths, utilization, reduced costs and improved quality and efficiency of a real, small factory. The findings suggest improvements and create awareness among practitioners for the utilization of quality tools that will provide direct benefits to their companies. Although the multi-method simulation is effective, a limitation of the current study is the lack of micro details within each station. Furthermore, the results are all based on one specific case study which is not enough to suggest and generalized findings.

Originality/value

This research combines the use of the three main hybrid simulation paradigms (SD, DES and AB) in a unified framework DMAIC methodology. Choosing the right models in DMAIC is important, challenging and urgently necessary. Also, this paper shows empirical evidence on its effectiveness.