Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrated Network Analysis to Identify Key Modules and Potential Hub Genes Involved in Bovine Respiratory Disease: A Systems Biology Approach

Background: Bovine respiratory disease (BRD) is the most common disease in the beef and dairy cattle industry. BRD is a multifactorial disease resulting from the interaction between environmental stressors and infectious agents. However, the molecular mechanisms underlying BRD are not fully understood yet. Therefore, this study aimed to use a systems biology approach to systematically evaluate this disorder to better understand the molecular mechanisms responsible for BRD. Methods: Previously published RNA-seq data from whole blood of 18 healthy and 25 BRD samples were downloaded from the Gene Expression Omnibus (GEO) and then analyzed. Next, two distinct methods of weighted gene coexpression network analysis (WGCNA), i.e., module–trait relationships (MTRs) and module preservation (MP) analysis were used to identify significant highly correlated modules with clinical traits of BRD and non-preserved modules between healthy and BRD samples, respectively. After identifying respective modules by the two mentioned methods of WGCNA, functional enrichment analysis was performed to extract the modules that are biologically related to BRD. Gene coexpression networks based on the hub genes from the candidate modules were then integrated with protein–protein interaction (PPI) networks to identify hub–hub genes and potential transcription factors (TFs). Results: Four significant highly correlated modules with clinical traits of BRD as well as 29 non-preserved modules were identified by MTRs and MP methods, respectively. Among them, two significant highly correlated modules (identified by MTRs) and six nonpreserved modules (identified by MP) were biologically associated with immune response, pulmonary inflammation, and pathogenesis of BRD. After aggregation of gene coexpression networks based on the hub genes with PPI networks, a total of 307 hub–hub genes were identified in the eight candidate modules. Interestingly, most of these hub–hub genes were reported to play an important role in the immune response and BRD pathogenesis. Among the eight candidate modules, the turquoise (identified by MTRs) and purple (identified by MP) modules were highly biologically enriched in BRD. Moreover, STAT1, STAT2, STAT3, IRF7, and IRF9 TFs were suggested to play an important role in the immune system during BRD by regulating the coexpressed genes of these modules. Additionally, a gene set containing several hub–hub genes was identified in the eight candidate modules, such as TLR2, TLR4, IL10, SOCS3, GZMB, ANXA1, ANXA5, PTEN, SGK1, IFI6, ISG15, MX1, MX2, OAS2, IFIH1, DDX58, DHX58, RSAD2, IFI44, IFI44L, EIF2AK2, ISG20, IFIT5, IFITM3, OAS1Y, HERC5, and PRF1, which are potentially critical during infection with agents of bovine respiratory disease complex (BRDC). Conclusion: This study not only helps us to better understand the molecular mechanisms responsible for BRD but also suggested eight candidate modules along with several promising hub–hub genes as diagnosis biomarkers and therapeutic targets for BRD.
Boosting Synergistic Effects of Short Antimicrobial Peptides With Conventional Antibiotics Against Resistant Bacteria

The global spread of antibiotic-resistant infections has meant that there is an urgent need to develop new antimicrobial alternatives. In this study, we developed a strategy to boost and/or synergize the activity of conventional antibiotics by combination with antimicrobial peptides tagged with the bulky non-natural amino acid β-naphthylalanine (Nal) to their N- or C-terminus. A checkerboard method was used to evaluate synergistic effects of the parent peptide and the Nal-tagged peptides. Moreover, boron-dipyrro-methene labeled vancomycin was used to characterize the synergistic mechanism of action between the peptides and vancomycin on the bacterial strains. These Nal-tagged antimicrobial peptides also reduced the antibiotic-induced release of lipopolysaccharide from Gram-negative bacteria by more than 99.95%. Our results demonstrate that Nal-tagged peptides could help in developing antimicrobial peptides that not only have enhanced antibacterial activities but also increase the synergistic effects with conventional antibiotics against antibiotic-resistant bacteria.
Structural and Symbolic Violence Exacerbates the Risks and Consequences of Sexual and Gender-Based Violence for Forced Migrant Women

While much attention is focused on rape as a weapon of war, evidence shows that forced migrant women and girls face increased risks of Sexual and Gender-Based Violence (SGBV) both during and following forced displacement. In this paper, we argue that gendered forms of structural and symbolic violence enable and compound the harms caused by interpersonal SGBV against forced migrant women and girls. These forms of violence are encountered in multiple contexts, including conflict and post-conflict settings, countries of refuge, and following resettlement. This paper illustrates the consequences of resultant cumulative harms for individuals and communities, and highlights the importance of considering these multiple, intersecting harms for policy and practice.
Tumor-Infiltrating Cytotoxic T Cells and Tumor-Associated Macrophages Correlate With the Outcomes of Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer

Background Tumor-infiltrating immune cells (TIICs) play a key role in immunoregulatory networks and are related to tumor development. Emerging evidence shows that these cells are associated with sensitivity to chemotherapy and radiotherapy. However, the predictive role of TIICs in the outcomes of neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) is unclear. Methods Imaging mass cytometry (IMC) was performed to comprehensively assess the immune status before nCRT in 6 patients with LARC (3 achieved pathological complete response (pCR), 3 did not) with matched clinicopathological parameters. Immunohistochemistry (IHC) for CD8, CD163 and Foxp3 on biopsy samples from 70 patients prior to nCRT and logistic regression analysis were combined to further evaluate its predictive value for treatment responses in an independent validation group. Results A trend of increased CD8+ cytotoxic T lymphocytes (CTLs) and decreased CD163+ tumor-associated macrophages (TAMs) and Foxp3+ regulatory T cells (Tregs) in the pCR group was revealed by IMC. In the validation group, CTLs and TAMs were strong predictors of the clinical response to nCRT. High levels of CTLs were positively associated with the pCR ratio (OR=1.042; 95% CI: 1.015~1.070, p=0.002), whereas TAMs were correlated with a poor response (OR=0.969; 95% CI: 0.941~0.998, p=0.036). A high density of TAMs was also associated with an advanced cN stage. Conclusion CTLs in the tumor microenvironment (TME) may improve the response to nCRT, whereas TAMs have the opposite effect. These results suggest that these cells might be potential markers for the clinical outcomes of nCRT and aid in the clinical decision-making of LARC for improved clinical outcomes.
Increased Signal Delays and Unaltered Synaptic Input Pattern Recognition in Layer III Neocortical Pyramidal Neurons of the rTg4510 Mouse Model of Tauopathy: A Computer Simulation Study With Passive Membrane

Abnormal tau proteins are involved in pathology of many neurodegenerative disorders. Transgenic rTg4510 mice express high levels of human tau protein with P301L mutation linked to chromosome 17 that has been associated with frontotemporal dementia with parkinsonism. By 9 months of age, these mice recapitulate key features of human tauopathies, including presence of hyperphosphorylated tau and neurofibrillary tangles (NFTs) in brain tissue, atrophy and loss of neurons and synapses, and hyperexcitability of neurons, as well as cognitive deficiencies. We investigated effects of such human mutant tau protein on neuronal membrane, subthreshold dendritic signaling, and synaptic input pattern recognition/discrimination in layer III frontal transgenic (TG) pyramidal neurons of 9-month-old rTg4510 mice and compared these characteristics to those of wild-type (WT) pyramidal neurons from age-matched control mice. Passive segmental cable models of WT and TG neurons were set up in the NEURON simulator by using three-dimensionally reconstructed morphology and electrophysiological data of these cells. Our computer simulations predict leakage resistance and capacitance of neuronal membrane to be unaffected by the mutant tau protein. Computer models of TG neurons showed only modest alterations in distance dependence of somatopetal voltage and current transfers along dendrites and in rise times and half-widths of somatic Excitatory Postsynaptic Potential (EPSPs) relative to WT control. In contrast, a consistent and statistically significant slowdown was detected in the speed of simulated subthreshold dendritic signal propagation in all regions of the dendritic surface of mutant neurons. Predictors of synaptic input pattern recognition/discrimination remained unaltered in model TG neurons. This suggests that tau pathology is primarily associated with failures/loss in synaptic connections rather than with altered intraneuronal synaptic integration in neurons of affected networks.
Pyruvate Kinase M2 Mediates Glycolysis Contributes to Psoriasis by Promoting Keratinocyte Proliferation

Psoriasis is characterized by keratinocyte proliferation and immune cell infiltration. M2 isoform of pyruvate kinase (PKM2) was reported to have an important role in cell proliferation, which is a rate-limiting enzyme that regulates the final step of glycolysis. However, how PKM2 regulates cell metabolism and proliferation in psoriatic keratinocytes is still poorly understood. Interestingly, we found that PKM2 was highly expressed in psoriatic epidermis from patients and mouse models. PKM2 overexpression promoted keratinocyte glycolytic metabolism while knockdown inhibited keratinocyte proliferation and glycolysis. Mice lacking PKM2 specifically in keratinocytes, pharmacological inhibition of PKM2 or glycolysis inhibited keratinocyte proliferation and showed obvious remission in an imiquimod-induced psoriatic mouse model. Moreover, the inhibitor of the EGF-receptor blocked EGF-stimulated PKM2 expression and glycolysis in keratinocytes. We identify PKM2 as an upregulated gene in psoriasis. PKM2 is essential in keratinocyte over-proliferation and may represent a therapeutic target for psoriasis.
Natural History of Cutaneous Human Polyomavirus Infection in Healthy Individuals

Several human polyomaviruses (HPyVs) were recently discovered. Merkel cell polyomavirus (MCPyV) induces Merkel cell carcinoma. HPyV6, HPyV7, and TSPyV have been associated with rare skin lesions in immunosuppressed patients. HPyV9, HPyV10, and Saint Louis Polyomavirus (STLPyV) have not been convincingly associated with any disease. The aim of this prospective study was to evaluate the cutaneous prevalence, persistence and viral load of HPyVs in healthy individuals. Eight hundred seventy forehead and hand swabs were collected from 109 volunteers 4–6 weeks apart (collection period-1). Fifty-nine participants were available for follow-up a decade later (collection period-2). HPyV-DNA prevalence and viral loads of MCPyV, HPyV6, HPyV7, TSPyV, HPyV9, HPyV10, and STLPyV were determined by virus-specific real-time PCRs. Risk factors for HPyV prevalence, short- and long-term persistence were explored by logistic regression analyses. Baseline prevalence rates were similar for forehead and hand: MCPyV 67.9/67.0%, HPyV6 31.2/25.7%, HPyV7 13.8/11.0%, HPyV10 11.9/15.6%, STLPyV 7.3/8.3%, TSPyV 0.9/0.9%, and HPyV9 0.9/0.9%. Short-term persistence in period-1 was found in 59.6% (MCPyV), 23.9% (HPyV6), 10.1% (HPyV7), 6.4% (HPyV10), 5.5% (STLPyV), and 0% (TSPyV and HPyV9) on the forehead, with similar values for the hand. Long-term persistence for 9–12 years occurred only for MCPyV (forehead/hand 39.0%/44.1% of volunteers), HPyV6 (16.9%/11.9%), and HPyV7 (3.4%/5.1%). Individuals with short-term persistence had significantly higher viral loads at baseline compared to those with transient DNA-positivity (p < 0.001 for MCPyV, HPyV6, HPyV7, and HPyV10, respectively). This was also true for median viral loads in period-1 of MCPyV, HPyV6, and HPyV7 of volunteers with long-term persistence. Multiplicity (two or more different HPyVs) was a risk factor for prevalence and persistence for most HPyVs. Further risk factors were older age for HPyV6 and male sex for MCPyV on the forehead. Smoking was not a risk factor. In contrast to MCPyV, HPyV6, HPyV7, and rarely STLPyV, polyomaviruses TSPyV, HPyV9, and HPyV10 do not seem to be long-term constituents of the human skin virome of healthy individuals. Furthermore, this study showed that higher viral loads are associated with both short- and long-term persistence of HPyVs on the skin. HPyV multiplicity is a risk factor for prevalence, short-term and/or long-term persistence of MCPyV, HPyV6, HPyV7, and HPyV10.
Attitudes of Postgraduate Students Towards Distance Education During the COVID-19 Pandemic: North Cyprus Example

The distance education model has become the most common educational model used around the world due to the COVID-19 pandemic that emerged in China at the end of 2019. In North Cyprus (NC), traditional face-to-face education had been resumed through online channels. The rapid shift to online channels has not only caused distress among students who do not have experience with using in online education systems, but also caused many problems to surface in terms of access to education. This study aims to explore the attitudes and views of higher education students in NC regarding the distance education implemented during the COVID-19 pandemic in the 2020–2021 educational year. In this quantitative study, the survey method was used. A random sampling approach was used for determining the study group, which was formed of 470 volunteer higher education students. According to the analysis of the data collected from the students, it was determined that they received an average score of x̅=82.52±19.50 points from the overall Attitudes Regarding the Use of Distance Education Environments During the Pandemic (ASRUDEEDP) scale, x̅=23.03±7.21 from the competence and education sub-dimension, x̅=26.36±5.81 from the practicality sub-dimension, x̅=18.20±4.83 points from the efficiency sub-dimension, and x̅=14.93±4.12 from the satisfaction sub-dimension. It was identified that there were no differences in the scores according to the age group, grade, or Internet use durations (p>0.05) but the scores of male students were observed to be higher than those of female in the sub-dimensions of competence and motivation as well as practicality within the ASRUDEEDP.
Role of Cardiac AMP-Activated Protein Kinase in a Non-pathological Setting: Evidence From Cardiomyocyte-Specific, Inducible AMP-Activated Protein Kinase α1α2-Knockout Mice

AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis under conditions of energy stress. Though heart is one of the most energy requiring organs and depends on a perfect match of energy supply with high and fluctuating energy demand to maintain its contractile performance, the role of AMPK in this organ is still not entirely clear, in particular in a non-pathological setting. In this work, we characterized cardiomyocyte-specific, inducible AMPKα1 and α2 knockout mice (KO), where KO was induced at the age of 8 weeks, and assessed their phenotype under physiological conditions. In the heart of KO mice, both AMPKα isoforms were strongly reduced and thus deleted in a large part of cardiomyocytes already 2 weeks after tamoxifen administration, persisting during the entire study period. AMPK KO had no effect on heart function at baseline, but alterations were observed under increased workload induced by dobutamine stress, consistent with lower endurance exercise capacity observed in AMPK KO mice. AMPKα deletion also induced a decrease in basal metabolic rate (oxygen uptake, energy expenditure) together with a trend to lower locomotor activity of AMPK KO mice 12 months after tamoxifen administration. Loss of AMPK resulted in multiple alterations of cardiac mitochondria: reduced respiration with complex I substrates as measured in isolated mitochondria, reduced activity of complexes I and IV, and a shift in mitochondrial cristae morphology from lamellar to mixed lamellar-tubular. A strong tendency to diminished ATP and glycogen level was observed in older animals, 1 year after tamoxifen administration. Our study suggests important roles of cardiac AMPK at increased cardiac workload, potentially limiting exercise performance. This is at least partially due to impaired mitochondrial function and bioenergetics which degrades with age.
Investigations on Regulation of MicroRNAs in Rice Reveal [Ca2+]cyt Signal Transduction Regulated MicroRNAs

MicroRNAs (miRNAs) are critical components of the multidimensional regulatory networks in eukaryotic systems. Given their diverse spectrum of function, it is apparent that the transcription, processing, and activity of the miRNAs themselves, is very dynamically regulated. One of the most important and universally implicated signaling molecules is [Ca2+]cyt. It is known to regulate a plethora of developmental and metabolic processes in both plants and animals; however, its impact on the regulation of miRNA expression is relatively less explored. The current study employed a combination of internal and external calcium channel inhibitors to establishing that [Ca2+]cyt signatures actively regulate miRNA expression in rice. Involvement of [Ca2+]cyt in the regulation of miRNA expression was further confirmed by treatment with calcimycin, the calcium ionophore. Modulation of the cytosolic calcium levels was also found to regulate the drought-responsive expression as well as ABA-mediated response of miRNA genes in rice seedlings. The study further establishes the role of calmodulins and Calmodulin-binding Transcription Activators (CAMTAs) as important components of the signal transduction schema that regulates miRNA expression. Yeast one-hybrid assay established that OsCAMTA4 & 6 are involved in the transcriptional regulation of miR156a and miR167h. Thus, the study was able to establish that [Ca2+]cyt is actively involved in regulating the expression of miRNA genes both under control and stress conditions.
Abundance and Diversity of Ophiostomatoid Fungi Associated With the Great Spruce Bark Beetle (Dendroctonus micans) in the Northeastern Qinghai-Tibet Plateau

The role of several virulent tree pathogens in host death has been overlooked because of the aggressiveness of their associated bark beetles. The great spruce bark beetle (Dendroctonus micans) is a widely distributed beetle that infests coniferous plants in Eurasia; however, its associated fungi have been poorly studied. Therefore, in this study, we elucidated the diversity of ophiostomatoid fungi associated with D. micans in the northeastern Qinghai-Tibet Plateau through field investigation, laboratory isolation, and culture analyses. A total of 220 strains of ophiostomatoid fungi were isolated from adults and tunnel galleries of D. micans infesting Picea crassifolia. We identified that the isolated strains belonged to eight ophiostomatoid species, including five new species (Ophiostoma huangnanense sp. nov., Ophiostoma maixiuense sp. nov., Ophiostoma sanum sp. nov., Leptographium sanjiangyuanense sp. nov., and Leptographium zekuense sp. nov.), one undefined species (Ophiostoma sp. 1), and two known species (Ophiostoma bicolor and Endoconidiophora laricicola), using phylogenetic analysis of multigene DNA sequences and morphological characteristics. This is the first time that E. laricicola, a pioneer invader and virulent pathogen, has been reported in China. We found that E. laricicola was the dominant species, accounting for 40.91% of the total number of ophiostomatoid communities. This study enriched the knowledge of the fungal associates of D. micans and elucidated that it carried the virulent pathogen E. laricicola at a surprisingly high frequency. Our findings show increased species association between D. micans and ophiostomatoid fungi and provide a basis for understanding the occurrence of forest diseases and pests.
Frequency-Dependent Effects on Coordination and Prefrontal Hemodynamics During Finger Force Production Tasks

Behavioral stability partially depends on the variability of net outcomes by means of the co-varied adjustment of individual elements such as multi-finger forces. The properties of cyclic actions affect stability and variability of the performance as well as the activation of the prefrontal cortex that is an origin of subcortical structure for the coordinative actions. Little research has been done on the issue of the relationship between stability and neuronal response. The purpose of the study was to investigate the changes in the neural response, particularly at the prefrontal cortex, to the frequencies of isometric cyclic finger force production. The main experimental task was to produce finger forces while matching the produced force to sine-wave templates as accurately as possible. Also, the hemodynamics responses of the prefrontal cortex, including oxy-hemoglobin concentration (ΔHbO) and the functional connectivity, were measured using functional near-infrared spectroscopy. The frequency conditions comprised 0.1, 1, and 2 Hz. The uncontrolled manifold (UCM) approach was applied to compute synergy indices in time-series. The relative phase (RP), the coefficient of variation (CV) of the peak and trough force values were computed as the indices of performance accuracy. The statistical parametric mapping (SPM) was implemented to compare the synergy indices of three frequency conditions in time-series. A less accurate performance in the high-frequency condition was caused not by the RP, but mainly by the inconsistent peak force values (CV; p < 0.01, ηp2 = 0.90). The SPM analysis revealed that the synergy indices were larger in the low-frequency than in high-frequency conditions. Further, the ΔHbO remained unchanged under all frequency conditions, while the functional connectivity decreased with an increase in the frequency of cyclic force production. The current results suggested that the concurrent activation of the prefrontal region mainly depends on the frequency of cyclic force production, which was associated with the strength of stability indices and performance errors. The current study is the first work to uncover the effect of frequency on the multi-finger synergies as to the hemodynamic response in the prefrontal cortex, which possibly provides a clue of the neural mechanism of synergy formation and its changes.