bluuebunny/crossref_metadata_2025 huggingface dataset:
A live yeast supplementation to gestating ewes improves bioactive molecules composition in colostrum with no impact on its bacterial composition and beneficially affects immune status of the offspring
Authors: Dunière Lysiane , Renaud Justin B , Steele Michael A , Achard Caroline S , Forano Evelyne , Chaucheyras-Durand Frédérique
Published: October 2021

Colostrum quality is of paramount importance in the management of optimal ruminant growth and infectious disease prevention in early life. Live yeast supplementation effect during the last month of gestation was evaluated on ewes’ colostrum composition. Two groups of ewes (n=14) carrying twin lambs were constituted and twins were separated into groups (mothered or artificially-fed) 12h after birth. Nutrient, oligosaccharides (OS), IgG and lactoferrin concentrations were measured over 72h after lambing, and bacterial community was described in colostrum collected at parturition (T0). Immune passive transfer was evaluated through IgG measurement in lamb serum. In both groups, colostral nutrient, OS concentrations and IgG concentrations in colostrum and lamb serum decreased over time, (p < 0.01) except for lactose, which slightly increased (p < 0.001) and lactoferrin which remained stable. Bacterial population was stable over time with high relative abundances of Aerococcaceae, Corynebacteriaceae, Moraxellaceae and Staphylococcaceae in T0-colostrum. No effect of supplementation was observed in nutrient and lactoferrin concentrations. In supplemented ewes, colostral IgG level was higher at T0 and a higher level of serum IgG was observed in lambs born from supplemented mothers and artificially-fed, while no effect of supplementation was observed in the mothered lambs groups. Using a metabolomic approach, we showed that supplementation affected OS composition with significantly higher levels of colostral Neu-5Gc compounds up to 5h after birth. No effect of supplementation was observed on bacterial composition. Our data suggest that live yeast supplementation offsets the negative impact of early separation and incomplete colostrum feeding in neonate lambs.

Graphical abstract
In vivomRNA delivery to virus-specific T cells by light-induced ligand exchange of MHC class I antigen-presenting nanoparticles
Authors: Su Fang-Yi , Zhao Qingyang , Dahotre Shreyas N. , Gamboa Lena , Bawage Swapnil Subhash , Silva Trenkle Aaron D. , Zamat Ali , Phuengkham Hathaichanok , Ahmed Rafi , Santangelo Philip J. , Kwong Gabriel A.
Published: October 2021

Simultaneous delivery of mRNA to multiple populations of antigen (Ag)-specific CD8+T cells is challenging given the diversity of peptide epitopes and polymorphism of class I major histocompatibility complexes (MHCI). We developed Ag-presenting nanoparticles (APNs) for mRNA delivery using pMHCI molecules that were refolded with photocleavable peptides to allow rapid ligand exchange by UV light and site-specifically conjugated with a lipid tail for post-insertion into preformed mRNA lipid nanoparticles. Across different TCR transgenic mouse models (P14, OT-1, Pmel), UV-exchanged APNs bound and transfected their cognate Ag-specific CD8+T cells equivalent to APNs produced using conventionally refolded pMHCI molecules. In mice infected with PR8 influenza, multiplexed delivery of UV-exchanged APNs against three immunodominant epitopes led to ~50% transfection of a VHH mRNA reporter in cognate Ag-specific CD8+ T cells. Our data shows that UV-mediated peptide exchange can be used to rapidly produce APNs for mRNA delivery to multiple populations of Ag-specific T cellsin vivo.

Teaser

Light-induced rapid production of antigen-presenting nanoparticles for mRNA delivery to multiple virus-specific T cell populations.
Identification of antineoplastic agents for oral squamous cell carcinoma: an integrated bioinformatics approach using differential gene expression and network biology
Authors: Usman Abdussalam , Khan Faisal F.
Published: October 2021

Oral squamous cell carcinoma (OSCC) is the most common malignant epithelial neoplasm and anatomical subtype of head and neck squamous cell carcinoma (HNSCC) with an average 5-year survival rate of less than 50%. To improve the survival rate of OSCC, the discovery of novel anti-cancer drugs is urgently needed. In the present study, we performed metanalysis of 5 gene expression datasets (GSE23558, GSE25099, GSE30784, GSE37991 and TCGA-OSCC) that resulted in 1851 statistically significant DEGs in OSCC. The DEGs were involved in key biological pathways that drive the progression of OSCC. A comprehensive protein-protein interaction (PPI) network was constructed from the DEGs and the top protein clusters (modules) were extracted in Cytoscape. The DEGs from the top modules were searched for antineoplastic agents using L1000CDS2 server. The search resulted in a total of 37 perturbing agents from which 12 well-characterized antineoplastic agents were selected. The selected 12 antineoplastic agents namely Teniposide, Palbociclib, Etoposide, Fedratinib, Tivozanib, Afatinib, Vemurafenib, Mitoxantrone, Idamycin, Canertinib, Dovitinib and Selumetinib. These drugs showed interactions with the over expressed hub genes that regulate cellular proliferation and growth in OSCC progression. These identified antineoplastic agents are candidates for their potential role in treating OSCC.
Theβ-amylase7gene inZea maysencodes a protein with structural and catalytic properties similar to Arabidopsis BAM2
Authors: Ravenburg Claire M. , Riney McKayla B. , Monroe Jonathan D. , Berndsen Christopher E.
Published: October 2021

Starch accumulates in the plastids of green plant tissue during the day to provide carbon for metabolism at night. Starch hydrolysis is catalyzed by members of the β-amylase (BAM) family, which inArabidopsis thaliana(At), includes nine structurally and functionally diverse members. One of these enzymes, AtBAM2, is a plastid-localized enzyme that is unique among characterized β-amylases since it is tetrameric and exhibits sigmoidal kinetics. Sequence alignments show that the BAM domains of AtBAM7, a catalytically inactive, nuclear-localized transcription factor with an N-terminal DNA binding domain, and AtBAM2 are more closely related to each other than they are to any other AtBAM. SinceBAM2is found in more ancient lineages, it was hypothesized thatBAM7evolved fromBAM2. However, analysis of the genomes of 48 flowering plants revealed 12 species that appear to have aBAM7gene but lack aBAM2gene. Upon closer inspection, these BAM7 proteins have a greater percent identity to AtBAM2 than to AtBAM7, and they share all of the AtBAM2 functional residues thatBAM7proteins normally lack. We hypothesize that these genes may encode a BAM2-like protein although they are currently annotated as BAM7-like genes. To test this hypothesis, we designed a cDNA of the short form of corn BAM7 (ZmBAM7-S) for expression inE. coli. Small Angle X-Ray Scattering data indicate that ZmBAM7-S has a tetrameric solution structure more similar to that of AtBAM2 than AtBAM1. In addition, partially purified ZmBAM7-S is catalytically active and exhibits sigmoidal kinetics. Together these data suggest that someBAM7genes may encode a functional BAM2. Exploring and understanding β-amylase gene structure could have impacts on the current annotation of genes.
On the brain networks organization of individuals with high versus average fluid intelligence: a combined DTI and MEG study
Authors: Bruzzone S.E.P. , Lumaca M. , Brattico E. , Vuust P. , Kringelbach M.L , Bonetti L.
Published: October 2021

The neural underpinning of human fluid intelligence (Gf) has gathered a large interest in the scientific community. Nonetheless, previous research did not provide a full understanding of such intriguing topic. Here, we studied the structural (from diffusion tensor imaging, DTI) and functional (from magnetoencephalography (MEG) resting state) connectivity in individuals with high versus average Gf scores. Our findings showed greater values in the brain areas degree distribution and higher proportion of long-range anatomical connections for high versus average Gfs. Further, the two groups presented different community structures, highlighting the structural and functional integration of the cingulate within frontal subnetworks of the brain in high Gfs. These results were consistently observed for structural connectivity and functional connectivity of delta, theta and alpha. Notably, gamma presented an opposite pattern, showing more segregation and lower degree distribution and connectivity in high versus average Gfs. Our study confirmed and expanded previous perspectives and knowledge on the “small-worldness” of the brain. Further, it complemented the widely investigated structural brain network of highly intelligent individuals with analyses on fast-scale functional networks in five frequency bands, highlighting key differences in the integration and segregation of information flow between slow and fast oscillations in groups with different Gf.
Brain Functional Connectome Defines a Transdiagnostic Dimension Shared by Cognitive Dysfunction and Psychopathology in Preadolescents
Authors: Xiao Xiang , Hammond Christopher , Salmeron Betty Jo , Gu Hong , Zhai Tianye , Nguyen Hieu , Lu Hanbing , Ross Thomas J , Yang Yihong
Published: October 2021

Background

Cognitive dysfunction and high-order psychopathologic dimensions are two main classes of transdiagnostic factors related to psychiatric disorders. They may link to common or distinct core brain networks underlying developmental risk of psychiatric disorders.

Method

The current study is a longitudinal investigation with 11,875 youths aged 9-to 10-years-old at study onset, from the Adolescent Brain Cognitive Development study. A machine-learning approach based on canonical correlation analysis was used to identify latent dimensional associations of the resting-state functional connectome with multi-domain behavioral assessments of cognitive functions and psychopathological problems. For the latent rsFC factor showing a robust behavioral association, its ability to predict psychiatric disorders was assessed using two-year follow-up data and its genetic association was evaluated using twin data from the same cohort.

Result

A latent functional connectome pattern was identified that showed a strong and generalizable association with the multi-domain behavioral assessments (5-fold cross validation: ρ = 0.68~0.73, for the training set (N = 5096); ρ = 0.56 ~ 0.58, for the test set (N = 1476)). This functional connectome pattern was highly heritable (h2= 74.42%, 95% CI: 56.76%-85.42%), exhibited a dose-response relationship with cumulative number of psychiatric disorders assessed concurrently and 2-years post-MRI-scan, and predicted the transition of diagnosis across disorders over the 2-year follow-up period.

Conclusion

These findings provide preliminary evidence for a transdiagnostic connectome-based measure that underlies individual differences in developing psychiatric disorders in early adolescence.
The Respiratory Resistance Sensitivity Task: An Automated Method for Quantifying Respiratory Interoception and Metacognition
Authors: Nikolova Niia , Harrison Olivia , Toohey Sophie , Brændholt Malthe , Legrand Nicolas , Correa Camile , Vejlø Melina , Jensen Martin Snejbjerg , Fardo Francesca , Allen Micah
Published: October 2021

The ability to sense, monitor, and control respiration - e.g., respiratory interoception (henceforth, respiroception) is a core homeostatic ability. Beyond the regulation of gas exchange, enhanced awareness of respiratory sensations is directly related to psychiatric symptoms such as panic and anxiety. Indeed, chronic breathlessness (dyspnea) is associated with a fourfold increase in the risk of developing depression and anxiety, and the regulation of the breath is a key aspect of many mindfulness-based approaches to the treatment of mental illness. Physiologically speaking, the ability to accurately monitor respiratory sensations is important for optimizing cardiorespiratory function during athletic exertion, and can be a key indicator of illness. Given the important role of respiroception in mental and physical health, it is unsurprising that there is increased interest in the quantification of respiratory psychophysiology across different perceptual and metacognitive levels of the psychological hierarchy. Compared to other more popular modalities of interoception, such as in the cardiac domain, there are relatively few methods available for measuring aspects of respiroception. Existing inspiratory loading tasks are difficult to administer and frequently require expensive medical equipment, or offer poor granularity in their quantification of respiratory-related perceptual ability. To facilitate the study of respiroception, we here present a new, fully automated and computer-controlled apparatus and psychophysiological method, which can flexibly and easily measure respiratory-related interoceptive sensitivity, bias and metacognition, in as little as 30 minutes of testing, using easy to make 3D printable parts.
Diet and Domestication Drive Evolution of the Gut Holobiome
Authors: Ramanan Vivek , Mechery Shanti , Sarkar Indra Neil
Published: October 2021

The host microbiome encompasses all microorganisms of a host. Host and microbiome coevolution in the gut result in differing microbial compositions, functionality, and host diet [1]. Host diet modulates what macromolecules are used for gut microbial metabolism, which can determine digestion, health, and behavior [2, 3]. Microbial composition across animals provides data on how microbiomes segregate between species and diets [4]. Here we show that microbiome data from GenBank can model host evolution, providing a “holobiome” insight to the important roles of diet and domestication. The main findings of this study in respect to microbial composition among species were: (1) herbivores are more similar than hosts with other diets; (2) domesticated species are more similar than wild relatives; and (3) humans are distinct from primates. Microbial composition between diets indicates a difference in functionality, where protein and fiber degradation are seen more in carnivores and herbivores respectively. Additionally, herbivores show the most microbial diversity among the diets. Finally, this analysis informs us of gaps in current microbiome data collection, which is biased toward pathogens. Thus, the host-microbiome relationship depicts a complex web of microbial functionality, composition, and diet that impact coevolution.
Sex differences in parental response to offspring begging are associated with pair bond strength across birds
Authors: Caro Shana M. , Wu Karleen , Hofmann Hans A
Published: October 2021

Mothers, fathers, and offspring regularly clash over how much care offspring receive. Offspring beg to solicit for more resources—but how much begging is rewarded can depend on who is listening. While both parents benefit from provisioning offspring, each would benefit from their partner shouldering more of the burden of care, leading to sexual conflict. Additionally, if the costs and benefits of provisioning differ by sex, parent-offspring conflict should vary by sex. How these evolutionary conflicts influence sex differences in parent-offspring communication is unknown. To determine whether the sexes differ in their response to offspring signals, we conducted a meta-analysis on 30 bird species, comparing responsiveness to social and physiological traits affecting conflict. We found that a species’ typical pair bond strength predicts whether males or females respond more to offspring begging. In species with stable and/or monogamous bonds, and thus lower sexual and paternal-offspring conflict, males’ provisioning effort is more strongly correlated with offspring begging than females’. The opposite holds for species with weak pair bonds: females respond more to begging, perhaps compensating for males’ lower responsiveness. These results demonstrate that sex differences in parental care can arise via sex differences in parent-offspring communication, driven by evolutionary conflicts.
A Novel 3D Co-culture Platform for Integrating Tissue Interfaces for Tumor Growth, Migration and Therapeutic Sensitivity: “PP-3D-S”
Authors: Garakani Mansoureh Mohseni , Ahangar Pouyan , Watson Sean , Nisol Bernard , Wertheimer Michael R. , Rosenzweig Derek H. , Ajji Abdellah
Published: October 2021

Metastatic cancers can be highly heterogeneous, show large patient variability and are typically hard to treat due to chemoresistance. Personalized therapies are therefore needed to suppress tumor growth and enhance patient’s quality of life. Identifying appropriate patient-specific therapies remains a challenge though, due mainly to non-physiological in vitro culture systems. Therefore, more complex and physiological in vitro human cancer microenvironment tools could drastically aid in development of new therapies. We developed a plasma-modified, electro-spun 3D scaffold (PP-3D-S) that can mimic the human cancer microenvironment for customized-cancer therapeutic screening. The PP-3D-S were characterized for optimal plasma-modifying treatment and scaffolds morphology including fiber diameter and pore size. PP-3D-S was then seeded with human fibroblasts to mimic a stromal tissue layer; cell adhesion on plasma-modified poly (lactic acid), PLA, electrospun mats vastly exceeded that on untreated controls. The cell-seeded scaffolds were then overlaid with alginate/gelatin-based hydrogel embedded with MDA-MB231 human breast cancer cells, representing a tumor-tissue interface. Among three different plasma treatments, we found that NH3 plasma promoted the most tumor cell migration to the scaffold surfaces after 7 days of culture. For all treated and non-treated mats, we observed a significant difference in tumor cell migration between small-sized and either medium- or large-sized scaffolds. In addition, we found that the PP-3D-S was highly comparable to the standard Matrigel® migration assays in two different sets of doxorubicin screening experiments, where 75% reduction in migration was achieved with 0.5μM doxorubicin for both systems. Taken together, our data indicate that PP-3D-S is an effective, low-cost, and easy-to-use alternate 3D tumor migration model which may be suitable as a physiological drug screening tool for personalized medicine against metastatic cancers.
Heat shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition
Authors: Lu Shan , Hu Jiaojiao , Aladesuyi Bankhole , Goginashvili Alexander , Vazquez-Sanchez Sonia , Diedrich Jolene , Gu Jinge , Blum Jacob , Oung Spencer , Yu Haiyang , Ravits John , Liu Cong , Yates John , Cleveland Don W.
Published: October 2021

While the RNA binding protein TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) with TDP-43-containing liquid outer shells and liquid centers of HSP70 family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including ALS. Here we show that transient oxidative stress, proteasome inhibition, or inhibition of HSP70’s ATP-dependent chaperone activity provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independent of RNA binding or stress granules. Isotope labeling mass spectrometry is used to identify that phase separated cytoplasmic TDP-43 is primarily bound by the small heat shock protein HSPB1. Binding is direct, mediated through TDP-43’s RNA binding and low complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced, TDP-43 droplets. Decrease of HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion is identified within ALS-patient spinal motor neurons containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.
Reproducible, high-dimensional imaging in archival human tissue by Multiplexed Ion Beam Imaging by Time-of-Flight (MIBI-TOF)
Authors: Liu Candace C. , Bosse Marc , Kong Alex , Kagel Adam , Kinders Robert , Hewitt Stephen M. , Bendall Sean C. , Angelo Michael
Published: October 2021

Multiplexed ion beam imaging by time-of-flight (MIBI-TOF) is a form of mass spectrometry imaging that uses metal labeled antibodies and secondary ion mass spectrometry to image dozens of proteins simultaneously in the same tissue section. Working with the National Cancer Institute’s (NCI) Cancer Immune Monitoring and Analysis Centers (CIMAC), we undertook a validation study, assessing concordance across a dozen serial sections of a tissue microarray of 21 samples that were independently processed and imaged by MIBI-TOF or single-plex immunohistochemistry (IHC) over 12 days. Pixel-level features were highly concordant across all 16 targets assessed in both staining intensity (R2 = 0.94 ± 0.04) and frequency (R2 = 0.95 ± 0.04). Comparison to digitized, single-plex IHC on adjacent serial sections revealed similar concordance (R2 = 0.85 ± 0.08) as well. Lastly, automated segmentation and clustering of eight cell populations found that cell frequencies between replicates yielded an average correlation of R2 = 0.92 ± 0.06. Taken together, we demonstrate that MIBI-TOF, with well-vetted reagents and automated analysis, can generate consistent and quantitative annotations of clinically relevant cell states in archival human tissue, and more broadly, present a scalable framework for benchmarking multiplexed IHC approaches.
Decoding of cortex-wide brain activity from local recordings of neural potentials
Authors: Liu Xin , Ren Chi , Huang Zhisheng , Wilson Madison , Kim Jeong-Hoon , Lu Yichen , Ramezani Mehrdad , Komiyama Takaki , Kuzum Duygu
Published: October 2021

Objective

Electrical recordings of neural activity from brain surface have been widely employed in basic neuroscience research and clinical practice for investigations of neural circuit functions, brain-computer interfaces, and treatments for neurological disorders. Traditionally, these surface potentials have been believed to mainly reflect local neural activity. It is not known how informative the locally recorded surface potentials are for the neural activities across multiple cortical regions.

Approach

To investigate that, we perform simultaneous local electrical recording and wide-field calcium imaging in awake head-fixed mice. Using a recurrent neural network model, we try to decode the calcium fluorescence activity of multiple cortical regions from local electrical recordings.

Main results

The mean activity of different cortical regions could be decoded from locally recorded surface potentials. Also, each frequency band of surface potentials differentially encodes activities from multiple cortical regions so that including all the frequency bands in the decoding model gives the highest decoding performance. Despite the close spacing between recording channels, surface potentials from different channels provide complementary information about the large-scale cortical activity and the decoding performance continues to improve as more channels are included. Finally, we demonstrate the successful decoding of whole dorsal cortex activity at pixel-level using locally recorded surface potentials.

Significance

These results show that the locally recorded surface potentials indeed contain rich information of the large-scale neural activities, which could be further demixed to recover the neural activity across individual cortical regions. In the future, our cross-modality inference approach could be adapted to virtually reconstruct cortex-wide brain activity, greatly expanding the spatial reach of surface electrical recordings without increasing invasiveness. Furthermore, it could be used to facilitate imaging neural activity across the whole cortex in freely moving animals, without requirement of head-fixed microscopy configurations.
Ultraviolet radiation modulates DNA methylation in melanocytes
Authors: Preston-Alp Sarah , Jelinek Jaroslav , Issa Jean-Pierre , Zaidi M. Raza
Published: October 2021

Ultraviolet radiation (UVR) is the principal causal factor for melanoma; albeit the underlying mechanisms remain unclear. While the mutagenic properties of UVR are irrefutable, the role of UVR-induced mutations in the initiation of melanoma is controversial which highlights the gap in our knowledge of the initial critical molecular mechanisms of UVR-induced melanomagenesis. To investigate the potential non-mutational mechanisms of UVR-induced melanomagenesis, we studied the role of UVR in modulating DNA methylation changes in melanocytes via next-generation sequencing-based methodologies. Here we show that UVR directly causes stable changes in the DNA methylome and transcriptome, one month after exposure. Genomic features associated with transcription were protected from 5mC alterations whereas CpG sites found in intergenic regions were more likely to be affected. Additionally, the long-term effects of UVR seem to perturb signaling pathways important for melanocyte biology. Interestingly, UVR-sensitive CpG sites were found to be prognostic of overall patient survival and highlighted a subset of CpG sites that may be relevant in melanomagenesis.

Significance

We report a novel finding that ultraviolet radiation (UVR) induces DNA methylation changes along with stable alterations in gene expression in cultured melanocytes. Our results provide experimental evidence of UVR-induced epigenetic rewiring, which may be implicated in the susceptibility to melanomagenesis, independently of its mutational effects. These findings offer novel insight into the role of UVR in the initiation and pathogenesis of melanoma via a currently underappreciated mechanism.
Evaluation of Deep Neural Network ProSPr for Accurate Protein Distance Predictions on CASP14 Targets
Authors: Stern Jacob , Hedelius Bryce , Fisher Olivia , Billings Wendy M. , Corte Dennis Della
Published: October 2021

The field of protein structure prediction has recently been revolutionized through the introduction of deep learning. The current state-of-the-art tool AlphaFold2 can predict highly accurate structures, however, it has a prohibitively long inference time for applications that require the folding of hundreds of sequences. The prediction of protein structure annotations, such as amino acid distances, can be achieved at a higher speed with existing tools, such as the ProSPr network. Here, we report on important updates to the ProSPr network, its performance on the recent Critical Assessment of Structure Prediction (CASP14) competition, and an evaluation of its accuracy dependency on multiple sequence alignment depth. We also provide a detailed description of the architecture and the training process, accompanied by reusable code. This work is anticipated to provide a solid foundation for the further development of protein distance prediction tools.
Application of Machine Learning in Prediction of COVID-19 Diagnosis for Indonesian Healthcare Workers
Authors: Sonthalia Shreyash , Muharoom Muhammad Aji , Sumulyo Sinta Amalia Kusumastuti , Kamilah Fariza Zahra , Aldila Fatma , Rabbani Bijak , Tirtawisata Andhika , Herlinda Olivia , Khaimani Jatin , Sani Levana , Irwanto Astrid , Hapsari Rebriarina , Luntungan Nurul , Saminarsih Diah , Taher Akmal
Published: October 2021

The COVID-19 pandemic poses a heightened risk to health workers, especially in low- and middle-income countries such as Indonesia. Due to the limitations of implementing mass RT-PCR testing for health workers, high-performing and cost-effective methodologies must be developed to help identify COVID-19 positive health workers and protect the spearhead of the battle against the pandemic. This study aimed to investigate the application of machine learning classifiers to predict the risk of COVID-19 positivity (by RT-PCR) using data obtained from a survey specific to health workers. Machine learning tools can enhance COVID-19 screening capacity in high-risk populations such as health workers in environments where cost is a barrier to the accessibility of adequate testing and screening supplies. We built two sets of COVID-19 Likelihood Meter (CLM) models: one trained on data from a broad population of health workers in Jakarta and Semarang (full model) and tested on the same, and one trained on health workers from Jakarta only (Jakarta model) and tested on both the same and an independent population of Semarang health workers. The area under the receiver-operating-characteristic curve (AUC), average precision (AP), and the Brier score (BS) were used to assess model performance. Shapely additive explanations (SHAP) were used to analyse future importance. The final dataset for the study included 5,393 healthcare workers. For the full model, the random forest was selected as the algorithm choice. It achieved cross-validation of mean AUC of 0.832 ± 0.015, AP of 0.513 ± 0.039, and BS of 0.124 ± 0.005, and was high performing during testing with AUC and AP of 0.849 and 0.51, respectively. The random forest classifier also displayed the best and most robust performance for the Jakarta model, with AUC of 0.856 ± 0.015, AP of 0.434 ± 0.039, and BS of 0.08 ± 0.0003. The performance when testing on the Semarang healthcare workers was AUC of 0.745 and AP of 0.694. Meanwhile, the performance for Jakarta 2022 test set was an AUC of 0.761 and AP of 0.535. Our models yielded high predictive performance and can be used as an alternative COVID-19 methodology for healthcare workers in Indonesia, therefore helping in predicting an increased trend of transmission during the transition into endemic.
Systematic review and meta-analyses on the prevalence of dementia in Latin America and Caribbean countries: Exploring sex, rurality, age, and education as possible determinants
Authors: Ribeiro Fabiana , Teixeira-Santos Ana C. , Caramelli Paulo , Leist Anja K.
Published: October 2021

Background

Studies have shown that the prevalence of dementia in Latin America and the Caribbean (LAC) may be higher than in high-income countries. Thus, we sought to systematically analyse the prevalence of dementia and explore possible drivers that lead to this disparity in LAC countries.

Method

We searched Pubmed, Web of Knowledge, Scopus, Lilacs, and SciELO for studies on dementia in LAC countries in English, Spanish, and Portuguese languages. Random-effects model was applied.

Results

Twenty-nine studies from 12 LAC countries were included. Pooled prevalence of all-cause dementia was 11%. Further analyses with studies providing raw prevalence by sex, area, and educational level showed a higher prevalence for women (9%) than for men (5%). Also, dementia prevalence was higher for rural than urban residents (12% vs 8%, respectively). Participants without formal education presented more than double the prevalence of dementia (22%) compared to those with at least one year of formal education (10%). Studies with more recent data collection showed higher dementia prevalence.

Conclusion

Our findings suggest a high global dementia prevalence in LAC countries and an unequal burden of dementia for women, lower-educated, and rural residents. Secular raises in dementia prevalence call for increased public health efforts for preventative action.

Highlights

Rigorous and most comprehensive review of dementia prevalence in Latin America and the Caribbean (LAC) to date.

Pooled dementia prevalence estimates are higher in LAC countries compared to high-income countries.

Higher prevalence of dementia among women and lower-educated adults.

Higher prevalence among older adults living in rural compared to urban areas.

Qualitative analyses suggest a modest increase in dementia prevalence in LAC countries over time.
Updated Model for the USA Summer 2021 CoVID-19 Resurgence
Authors: Eng Genghmun
Published: October 2021

Over the course of the CoVID-19 pandemic, we utilized widely-available real-time data to create models for predicting its spread, and to estimate the time evolution for each of the USA CoVID-19 waves. Our recent medrxiv.org preprint (10.1101_2021.08.16.21262150) examined the USA Summer 2021 resurgence, from ∼6/7/2021 up through ∼8/15/2021 (Stage 1). Our preprint covering this period showed that CoVID-19 could infect virtually all susceptible non-vaccinated persons, who were practicing minimal Social Distancing and NO Mask-Wearing.

The most recent USA Summer 2021 resurgence data, from ∼8/13/2021 up through 10/7/2021 (Stage 2), shows a significant “flattening of the curve”. Since no new government mandates were involved, our interpretation is that some vaccine-hesitant people have now elected to become vaccinated. The Social Distancing parameter in our model showed a ∼6.67X increase between Stage 1 and Stage 2, indicating that this parameter also can serve as an indicator of vaccination rates. The other parameter in our model, which is associated with Mask-Wearing, increased from zero to a finite but relatively small value. Using the 10/7/2021 USA CoVID-19 overall mortality rate of ∼1.60942 % gives these updated predictions for the total number of USA CoVID-19 cases and deaths:

NTOTAL(3/21/2022) ≈ 52, 188, 000 ; NDeaths(3/21/2022) ≈ 839, 900, NTOTAL(3/21/2024) ≈ [52, 787, 000 ; NDeaths(3/21/2024) ≈ 849, 600, assuming no new 2021 Winter Resurgence occurs (with 3 Figures).
Ubiquitin E3 ligases Atrogin-1 and MuRF1 protein contents are differentially regulated in the rapamycin-sensitive mTOR-S6K1 signaling pathway in C2C12 myotubes
Authors: Nishimura Yusuke , Musa Ibrahim , Dawson Peter , Holm Lars , Lai Yu-Chiang
Published: October 2021

Muscle-specific ubiquitin E3 ligases, Atrogin-1 and MuRF1, are highly expressed in multiple conditions of skeletal muscle atrophy. The PI3K/Akt/FoxO signaling pathway is well known to regulate Atrogin-1 and MuRF1 gene expressions. Evidence supporting this is largely based on stimuli by insulin and IGF-1, that activate anabolic signaling, including Akt and Akt-dependent transcription factors. However, Akt activation also activates the mammalian target of rapamycin complex 1 (mTORC1) which induces skeletal muscle hypertrophy. However, whether mTORC1-dependent signaling has a role in regulating Atrogin-1 and/or MuRF1 gene and protein expression is currently unclear. In this study, we confirmed that activation of insulin-mediated Akt signaling suppresses both Atrogin-1 and MuRF1 protein content and that inhibition of Akt increases both Atrogin-1 and MuRF1 protein content in C2C12 myotubes. Interestingly, inhibition of mTORC1 using a specific mTORC1 inhibitor, rapamycin, increased Atrogin-1, but not MuRF1, protein content. Furthermore, activation of AMP-activated protein kinase (AMPK), a negative regulator of the mTORC1 signaling pathway, also showed distinct time-dependent changes between Atrogin-1 and MuRF1 protein content, suggesting differential regulatory mechanisms between Atrogin-1 and MuRF1 protein content. To further explore the downstream of mTORC1 signaling, we employed a specific S6K1 inhibitor, PF-4708671, and found that Atrogin-1 protein content was dose-dependently increased with PF-4708671 treatment, whereas MuRF1 protein content was not significantly altered. Overall, our results indicate that Atrogin-1 and MuRF1 protein contents are regulated by different mechanisms, the downstream of Akt, and that Atrogin-1 protein content can be regulated by rapamycin-sensitive mTOR-S6K1 dependent signaling pathway.
A New Mouse Model of Diffuse Midline Glioma to Test Targeted Immunotherapies
Authors: Seblani M , Zannikou M , Duffy J.T. , Levine R.N. , Liu Q , Horbinski C.M. , Becher O.J. , Balyasnikova I.V.
Published: October 2021

BACKGROUND

Diffuse midline gliomas remain incurable, with consistently poor outcomes in children despite radiotherapy. Immunotherapeutic approaches hold promise, with the integration of the host’s immune system fundamental to their design. Here, we describe a new, genetically engineered immunocompetent model that incorporates interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen, which is suitable for further evaluation of the antitumor activity of IL13Rα2-targeted immunotherapeutics in preclinical studies.

METHODS

The RCAS-Tv-a delivery system was used to induce gliomagenesis through overexpression of PDGFB and p53 deletion with and without human IL13Rα2 in Nestin-Tva; p53fl/fl mice. Hindbrain or cerebral cortex nestin progenitors of neonatal pups were infected with Cre recombinase and PDGFB+IL13Rα2 or Cre recombinase and PDGFB to model diffuse midline glioma and supratentorial high-grade glioma, respectively. Immunoblotting and flow cytometry was used to confirm target expression. Kaplan-Meier survival curves were established to compare tumor latency in both models. Tumor tissue was analyzed through immunohistochemistry and H&E staining. Cell lines generated from tumor-bearing mice were used for in vitro studies and orthotopic injections.

RESULTS

The protein expression of PDGFB and IL13Rα2 was confirmed by flow cytometry and western blot. In both groups, de novo tumors developed without significant difference in median survival between PDGFB and p53 loss (n=25, 40 days) and PDGFB, IL13Rα2, and p53 loss (n=33, 38 days, p=0.62). Tumors demonstrated characteristics of high-grade glioma such as infiltration, palisading necrosis, microvascular proliferation, high Ki-67 index, heterogeneous IL13Rα2 expression, and CD11b+ macrophages, along with a low proportion of CD3+ T cells. Orthotopic tumors developed from cell lines retained histopathological characteristics of de novo tumors. Mice orthotopically implanted with cells in the hindbrain or right cortex showed a median survival of 42 days and 41 (p=0.56) days, respectively.

CONCLUSION

Generation of de novo tumors using the RCAS-Tv-a delivery system was successful, with tumors possessing histopathologic features common to pediatric diffuse gliomas. The development of these models opens the opportunity for preclinical assessment of IL13Rα2-directed immunotherapies with the potential for clinical translation.
SEX DIFFERENCES IN BLOOD PRESSURE RESPONSE TO CONTINUOUS ANG II INFUSION: ARE ONLY SEX HORMONES TO BLAME?
Authors: Dadam Florencia , Godino Andrea , Vivas Laura , Caeiro Ximena E.
Published: October 2021

To investigate the involvement of the sex chromosome complement (SCC), organizational and activational hormonal effects in changes in mean arterial pressure during acute Ang II infusion, we used gonadectomized (GDX) mice of the “four core genotypes” model, which dissociates the effect of gonadal sex and SCC, allowing comparisons of sexually dimorphic traits between XX and XY females as well as XX and XY males. Additionally, β-estradiol and testosterone propionate (2ug/g) were daily injected for 4 days to evaluate activational hormonal effects.

Statistical analysis of the changes in mean arterial pressure revealed an interaction of SCC, organizational and activational hormonal effects during Ang II infusion {F(7,39=2,60 p<0.01)}. Our results indicate that, in absence of activational hormonal effects, interaction between the SCC and organizational hormonal action differentially modulates changes in arterial pressure. In GDX mice without hormone replacement, Ang II infusion resulted in an increase in mean arterial pressure in XX-male, XX-female and XY-female mice, while no changes were observed in XY-male mice. Furthermore, β-estradiol replacement (GDX+E2 group) resulted in a decrease in blood pressure in XX-males, XX-females and XY-females (indicating an activational β-estradiol effect), while no changes were observed in the XY-male group. Moreover, testosterone propionate replacement (GDX+TP group) showed a greater increase in blood pressure in XY-male mice than in XX-males and XX-females, demonstrating an activational hormonal effect of testosterone in XY-male mice.

Our data isolates and highlights the contribution and interaction of SCC, activational and organizational hormonal effects in sex differences in Ang II blood pressure regulation.
findPC: An R package to automatically select number of principal components in single-cell analysis
Authors: Zhuang Haotian , Ji Zhicheng
Published: October 2021

Principal component analysis (PCA) is widely used in analyzing single-cell genomic data. Selecting the optimal number of PCs is a crucial step for downstream analyses. The elbow method is most commonly used for this task, but it requires one to visually inspect the elbow plot and manually choose the elbow point. To address this limitation, we developed six methods to automatically select the optimal number of PCs based on the elbow method. We evaluated the performance of these methods on real single-cell RNA-seq data from multiple human and mouse tissues. The perpendicular line method with 20 PCs has the best overall performance, and its results are highly consistent with the numbers of PCs identified manually. We implemented the six methods in an R package, findPC, that objectively selects the number of PCs and can be easily incorporated into any automatic analysis pipeline.

Availability and Implementation

findPC R package is freely available at https://github.com/haotian-zhuang/findPC

Contact

zhicheng.ji@duke.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Diversity and evolution of nitric oxide reduction
Authors: Murali Ranjani , Pace Laura A. , Sanford Robert A. , Ward Lewis M. , Lynes Mackenzie , Hatzenpichler Roland , Lingappa Usha F. , Fischer Woodward W. , Gennis Robert B. , Hemp James
Published: October 2021

Nitrogen is an essential element for life, with the availability of fixed nitrogen limiting productivity in many ecosystems. The return of oxidized nitrogen species to the atmospheric N2 pool is predominately catalyzed by microbial denitrification (NO3- → NO2- → NO → N2O → N2)1. Incomplete denitrification can produce N2O as a terminal product, leading to an increase in atmospheric N2O, a potent greenhouse and ozone-depleting gas2. The production of N2O is catalyzed by nitric oxide reductase (NOR) members of the heme-copper oxidoreductase (HCO) superfamily3. Here we use phylogenomics to identify a number of previously uncharacterized HCO families and propose that many of them (eNOR, sNOR, gNOR, and nNOR) perform nitric oxide reduction. These families have novel active-site structures and several have conserved proton channels, suggesting that they might be able to couple nitric oxide reduction to energy conservation. We isolated and biochemically characterized a member of the eNOR family from Rhodothermus marinus, verifying that it performs nitric oxide reduction both in vitro and in vivo. These newly identified NORs exhibit broad phylogenetic and environmental distributions, expanding the diversity of microbes that can perform denitrification. Phylogenetic analyses of the HCO superfamily demonstrate that nitric oxide reductases evolved multiple times independently from oxygen reductases, suggesting that complete denitrification evolved after aerobic respiration.
Network-based analysis on pharmacological mechanisms underlying the anti-diabetic property of Coix lacryma-jobi
Authors: Taquiqui Arvin , Ferrer Angelu Mae , David Janella Rayne , Deocaris Custer C. , Alinsug Malona V.
Published: October 2021

Diabetes mellitus (DM) is the most common endocrine disorder and among the top 10 leading diseases causing death worldwide. Coicis semen [CS] (Coix lacryma-jobi), also known as adlay have been reported to display anti-diabetic properties. Unfortunately, studies on the pharmacological mechanisms involving adlay for the treatment of diabetes are nil. Thus, this study was conducted to evaluate the interactions and mechanisms of the bioactive compound targets of adlay in the treatment of diabetes using network analysis. Adlay bioactive compounds and potential target genes were obtained from SymMap. Diabetes related target genes were collected from CTD. Protein-Protein Interaction Network was analyzed using the STRING database. GO and KEGG pathway enrichment analyses were performed using DAVID to further explore the mechanisms of adlay in treating diabetes. PPI and compound-target-pathway were visualized using Cytoscape. A total of 25 bioactive compounds, 201 corresponding targets, and 35839 diabetes mellitus associated targets were obtained while 200 were considered potential therapeutic targets. The 9 bioactive compounds studied were berberine, oleic acid, beta-sitosterol, sitosterol, linoleic acid, berberrubine, jatrorrhizine, thalifendine, and stigmasterol. The identified 5 core targets were ESR1, JUN, MAPK14, and RXRA. Adlai targets enriched in GO terms were mostly involved with positive regulation of transcription, response to drugs, and negative regulation of apoptosis. This study provides novel research insights into the clinical properties of adlay in diabetes melitus treatment.
Genetic and environmental influences on the evolution of virulence in the HIV-associated opportunistic human fungal pathogen Cryptococcus neoformans
Authors: Yu Yiwu , Wang Yuanyuan , Li Linghua , Chen Xiaoqing , Huang Xinhua , Liang Huaping , Jiang Tong , Liao Guojian , Chen Min , Zhu Liping , Li Muyuan , Zhou Tao , Tang Qinyu , Zhao Jingjun , Chen Changbin
Published: October 2021

The fungus Cryptococcus neoformans is considered the leading cause of death in immunocompromised patients. Despite numerous investigations concerning its molecular epidemiology, there are only a few studies addressing the impacts of varying factors on genotype-phenotype correlations. It remains largely unknown whether genetic and environmental variabilities among isolates from different sources may have dramatic consequences on virulence. In this study, we analyzed 105 Chinese C. neoformans isolates, including 54 from HIV-infected patients, 44 from HIV-uninfected individuals and 7 from a natural environment, to investigate factors influencing the outcome of C. neoformans infection. MLST analysis clearly identified sequence type (ST) 5 as the prevalent sequence type in all clinical isolates and interestingly, genotypic diversities were observed in isolates from both HIV-uninfected individual and natural environment but not those from HIV-infected patients. Moreover, we found that compared to those from HIV-infected patients, the isolates from HIV-uninfected individuals exhibited enhanced virulence-associated traits including significantly elevated capsule production and melanin formation, increases in survival in human cerebrospinal fluid (CSF), less effective uptake by host phagocytes, and higher mortality in a mouse model of cryptococcosis. Consistently, pathogenic phenotypes were associated with CD4 counts of patients, implying environmental impact on within-host C. neoformans virulence. Importantly, a large-scale whole-genome sequencing analysis revealed that genomic variations within genes related to specific functions may act as a vital driving force of host intrinsic virulence evolution. Taken together, our results support a strong genotype-phenotype correlation suggesting that the pathogenic evolution of C. neoformans could be heavily affected by both genetic and environmental factors.