Miracle-dz/UniFAR-FTUs huggingface dataset:
Using Canine Olfaction to Detect Bovine Respiratory Disease: A Pilot Study

Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in feedlot cattle and is a major welfare and economic concern. Identification of BRD-affected cattle using clinical illness scores is problematic, and speed and cost constraints limit the feasibility of many diagnostic approaches. Dogs can rapidly identify humans and animals affected by a variety of diseases based on scent. Canines' olfactory systems can distinguish between patterns of volatile organic compounds produced by diseased and healthy tissue. In this pilot study, two dogs (“Runnels” and “Cheaps”) were trained for 7 months to discriminate between nasal swabs from cattle that developed signs of BRD within 20 days of feedlot arrival and swabs from cattle that did not develop BRD signs within 3 months at the feedlot. Nasal swabs were collected during cattle processing upon arrival to the feedlot and were stored at −80°C. Dogs were presented with sets of one positive and two negative samples and were trained using positive reinforcement to hold their noses over the positive sample. The dogs performed moderately well in the final stage of training, with accuracy for Runnels of 0.817 and Cheaps of 0.647, both greater than the 0.333 expected by chance. During a double-blind detection test, dogs evaluated 123 unique and unfamiliar samples that were presented as 41 sets (3 samples per set), with both the dog handler and data recorder blinded to the positive sample location. Each dog was tested twice on each set of samples. Detection test accuracy was slightly better than chance for Cheaps at 0.451 (95% CI: 0.344–0.559) and was no better than chance for Runnels at 0.390 (95% CI: 0.285–0.496. Overall accuracy was 0.421 (95% CI: 0.345–0.496). When dogs' consensus response on each sample set was considered, accuracy was 0.537 (95% CI: 0.384–0.689). Detection accuracy also varied by sample lot. While dogs showed some ability to discriminate between BRD-affected and healthy cattle using nasal swabs, the complexity of this task suggests that more testing is needed before determining whether dogs could be effective as a screening method for BRD.
Mapping the Tumor Microenvironment in TNBC and Deep Exploration for M1 Macrophages-Associated Prognostic Genes

Triple negative breast cancer (TNBC) remains the worst molecular subtype due to high heterogeneity and lack of effective therapeutic targets. Here we investigated the tumor and immune microenvironment heterogeneity of TNBC using scRNA-seq and bulk RNA-seq data from public databases and our cohort. Macrophage subpopulations accounted for a high proportion of tumor immune microenvironment (TIME), and M1 macrophages were associated with better clinical outcomes. Furthermore, three maker genes including IFI35, PSMB9, and SAMD9L showed a close connection with M1 macrophages. Specifically, IFI35 was positively associated with macrophage activation, chemotaxis, and migration. Also, patients with high IFI35 expression had a better prognosis. In vitro studies subsequently demonstrated that IFI35 was upregulated during the M1 subtype differentiation of macrophages. In summary, our data suggested that IFI35 maybe a promising novel target that helps to reshape macrophage polarization towards the M1 subtype for anti-tumor effects.
RNA-SSNV: A Reliable Somatic Single Nucleotide Variant Identification Framework for Bulk RNA-Seq Data

The usage of expressed somatic mutations may have a unique advantage in identifying active cancer driver mutations. However, accurately calling mutations from RNA-seq data is difficult due to confounding factors such as RNA-editing, reverse transcription, and gap alignment. In the present study, we proposed a framework (named RNA-SSNV, https://github.com/pmglab/RNA-SSNV) to call somatic single nucleotide variants (SSNV) from tumor bulk RNA-seq data. Based on a comprehensive multi-filtering strategy and a machine-learning classification model trained with comprehensively curated features, RNA-SSNV achieved the best precision–recall rate (0.880–0.884) in a testing dataset and robustly retained 0.94 AUC for the precision–recall curve in three validation adult-based TCGA (The Cancer Genome Atlas) datasets. We further showed that the somatic mutations called by RNA-SSNV tended to have a higher functional impact and therapeutic power in known driver genes. Furthermore, VAF (variant allele fraction) analysis revealed that subclonal harboring expressed mutations had evolutional selection advantage and RNA had higher detection power to rescue DNA-omitted mutations. In sum, RNA-SSNV will be a useful approach to accurately call expressed somatic mutations for a more insightful analysis of cancer drive genes and carcinogenic mechanisms.
Dietary Supplementation of Chitosan Oligosaccharide–Clostridium butyricum Synbiotic Relieved Early-Weaned Stress by Improving Intestinal Health on Pigeon Squabs (Columba livia)

According to a previous study, we had found that early weaning causes harm to growth performance, intestinal morphology, activity of digestive enzymes, and antioxidant status in pigeon squabs (Columba livia). Chitosan oligosaccharides (COS) and Clostridium butyricum have been reported to have great potential to improve the growth performance and intestinal health of early-weaned animals. Therefore, the aim of this study is to explore whether dietary supplementation with COS-C. butyricum synbiotic could relieve early-weaned stress by evaluating its effects on growth performance and intestinal health in pigeon squabs. A total of 160 squabs (weaned at 7 days of age) were randomly divided into 5 groups: the control group, fed with artificial crop milk; the COS supplementation group, fed with artificial crop milk + 150 mg/kg COS; and three synbiotic supplementation groups, fed with artificial crop milk + 150 mg/kg COS + 200, 300, and 400 mg/kg C. butyricum. The results showed that a diet supplemented with COS-C. butyricum synbiotic benefitted the growth performance of early-weaned squabs; even so the differences were not significant among the five groups (p > 0.05). In addition, dietary supplementation of 150 mg/kg COS + 300~400 mg/kg C. butyricum significantly improved the intestinal morphology (especially villus surface area and the ratio of villus height to crypt depth), the activity of digestive enzymes (lipase, trypsin, and leucine aminopeptidase) in duodenum contents, and the production of total short-chain fatty acids and acetic acid in ileum content (p < 0.05). Additionally, dietary supplementation of 150 mg/kg COS + 400 mg/kg C. butyricum benefitted gut health by improving the antioxidant capacity (glutathione peroxidase and total antioxidant capacity) and cytokine status (IL-4 and IL-10) (p < 0.05), as well as by improving the intestinal microbiota diversity. In conclusion, our results revealed that dietary supplementation with synbiotic (150 mg/kg COS + 300~400 mg/kg C. butyricum) could relieve early-weaned stress by maintaining intestinal health in pigeon squabs.
5FU/Oxaliplatin-Induced Jagged1 Cleavage Counteracts Apoptosis Induction in Colorectal Cancer: A Novel Mechanism of Intrinsic Drug Resistance

Colorectal cancer (CRC) is characterized by early metastasis, resistance to anti-cancer therapy, and high mortality rate. Despite considerable progress in the development of new treatment options that improved survival benefits in patients with early-stage or advanced CRC, many patients relapse due to the activation of intrinsic or acquired chemoresistance mechanisms. Recently, we reported novel findings about the role of Jagged1 in CRC tumors with Kras signatures. We showed that Jagged1 is a novel proteolytic target of Kras signaling, which induces Jagged1 processing/activation resulting in Jag1-ICD release, which favors tumor development in vivo, through a non-canonical mechanism. Herein, we demonstrate that OXP and 5FU cause a strong accumulation of Jag1-ICD oncogene, through ERK1/2 activation, unveiling a surviving subpopulation with an enforced Jag1-ICD expression, presenting the ability to counteract OXP/5FU-induced apoptosis. Remarkably, we also clarify the clinical ineffectiveness of γ-secretase inhibitors (GSIs) in metastatic CRC (mCRC) patients. Indeed, we show that GSI compounds trigger Jag1-ICD release, which promotes cellular growth and EMT processes, functioning as tumor-promoting agents in CRC cells overexpressing Jagged1. We finally demonstrate that Jagged1 silencing in OXP- or 5FU-resistant subpopulations is enough to restore the sensitivity to chemotherapy, confirming that drug sensitivity/resistance is Jag1-ICD-dependent, suggesting Jagged1 as a molecular predictive marker for the outcome of chemotherapy.
High Prolyl 4-Hydroxylase Subunit Alpha 3 Expression as an Independent Prognostic Biomarker and Correlated With Immune Infiltration in Gastric Cancer

Background: Gastric cancer (GC) has a high mortality rate and is particularly prevalent in China. The extracellular matrix protein, prolyl 4-hydroxylase subunit alpha 3 (P4HA3), has been implicated in various cancers. We aimed to assess the diagnostic and prognostic value of P4HA3 in GC and investigate its correlation with immune cell infiltration. Methods: The present study used microarray data from the Cancer Genome Atlas (TCGA) to analyze the association of P4HA3 expression with clinicopathological features. Data from the Gene Expression Omnibus (GEO) were used for validation. Receiver operating characteristic (ROC) and Kaplan–Meier curves were constructed to determine the diagnostic and prognostic value of P4HA3 in GC. Univariate and multivariate regression analyses were performed to assess the impact of P4HA3 on overall survival (OS) rates. A protein–protein interaction (PPI) network was generated and functional enrichment evaluated. Single-sample gene set enrichment analysis (ssGSEA) was conducted to correlate P4HA3 expression with immune cell infiltration. The correlation between P4HA3 and immune check point genes was studied. Results: P4HA3 was over-expressed in GC, along with 15 other types of cancer, including breast invasive carcinoma and cholangiocarcinoma. P4HA3 showed high diagnostic and prognostic value in GC and was an independent prognostic factor. P4HA3, TNM (tumor, node, metastases) stage, pathological stage and age all correlated with OS rates. Genes related to P4HA3 were enriched in the lumen of the endoplasmic reticulum and included procollagen-proline 3-dioxygenase activity. P4HA3 expression correlated with numbers of macrophages, natural killer (NK) cells, immature dendritic cells (iDC), mast cells, eosinophils, effective memory T cells (Tem), T-helper 1 (Th1) cells and dendritic cells (DC). P4HA3 was positively correlated with hepatitis A virus cellular receptor 2 (HAVCR2) and programmed cell death 1 ligand 2 (PDCD1LG2). Conclusion: P4HA3 is a potential independent biomarker for prognosis of GC and may be an immunotherapy target in the treatment of GC.
Mobile Smartphone-Based Digital Pupillometry Curves in the Diagnosis of Traumatic Brain Injury

Objective The pupillary light reflex (PLR) and the pupillary diameter over time (the PLR curve) is an important biomarker of neurological disease, especially in the diagnosis of traumatic brain injury (TBI). We investigated whether PLR curves generated by a novel smartphone pupillometer application could be easily and accurately interpreted to aid in the diagnosis of TBI. Methods A total of 120 PLR curves from 42 healthy subjects and six patients with TBI were generated by PupilScreen. Eleven clinician raters, including one group of physicians and one group of neurocritical care nurses, classified 48 randomly selected normal and abnormal PLR curves without prior training or instruction. Rater accuracy, sensitivity, specificity, and interrater reliability were calculated. Results Clinician raters demonstrated 93% accuracy, 94% sensitivity, 92% specificity, 92% positive predictive value, and 93% negative predictive value in identifying normal and abnormal PLR curves. There was high within-group reliability (k = 0.85) and high interrater reliability (K = 0.75). Conclusion The PupilScreen smartphone application-based pupillometer produced PLR curves for clinical provider interpretation that led to accurate classification of normal and abnormal PLR data. Interrater reliability was greater than previous studies of manual pupillometry. This technology may be a good alternative to the use of subjective manual penlight pupillometry or digital pupillometry.
Using Auditory Characteristics to Select Hearing Aid Compression Speeds for Presbycusic Patients

Objectives This study aimed to select the optimal hearing aid compression speeds (fast-acting and slow-acting) for presbycusic patients by using auditory characteristics including temporal modulation and speech-in-noise performance. Methods In total, 24 patients with unilateral or bilateral moderate sensorineural hearing loss who scored higher than 21 on the Montreal Cognitive Assessment (MoCA) test participated in this study. The electrocochleogram (ECochG) results, including summating potentials (SP) and action potentials (AP), were recorded. Subjects' temporal modulation thresholds and speech recognition at 4 individualized signal-to-noise ratios were measured under three conditions, namely, unaided, aided with fast-acting compression (FAC), and aided with slow-acting compression (SAC). Results The results of this study showed that modulation discrimination thresholds in the unaided (−8.14 dB) and aided SAC (−8.19 dB) conditions were better than the modulation thresholds in the FAC (−4.67 dB) conditions. The speech recognition threshold (SRT75%) for FAC (5.21 dB) did not differ significantly from SAC (3.39 dB) (p = 0.12). A decision tree analysis showed that the inclusion of the AP, unaided modulation thresholds, and unaided SRT75% may correctly identify the optimal compression speeds (FAC vs. SAC) for individual presbycusic patients with up to 90% accuracy. Conclusion Both modes of compression speeds improved a presbycusic patient's speech recognition ability in noise. The SAC hearing aids may better preserve the modulation thresholds than the FAC hearing aids. The measurement of AP, along with the unaided modulation thresholds and unaided SRT75%, may help guide the selection of optimal compression speeds for individual presbycusic patients.
Clinicopathological Features, Staging Classification, and Clinical Outcomes of Esophageal Melanoma: Evaluation of a Pooled Case Series

Studies that have attempted to validate the staging systems and the predictors of survival for patients with primary malignant melanoma of the esophagus (PMME) have been underpowered given their scarcity and small scale. We aimed to review a large number of PMME cases to know more about its clinicopathological features, TNM staging systems, and survival predictors of PMME. Case reports on PMME were extracted from PubMed/Medline through bibliography search and our center. A total of 287 PMME cases were identified. The majority of the patient population was male (72.08%). The most common location of PMME was the lower esophagus (50.62%) and middle esophagus (35.39%). Among the patients, 82.28% received surgical intervention. The median overall survival (OS) duration was 15 months (0.5–244). The American Joint Commission on Cancer staging classification (AJCC) for the mucosal melanoma of the upper aerodigestive tract with stage IVB and IVC integrated in stage IVA showed better distribution of OS than that for esophageal carcinoma. T stage, N stage, and surgery had significant impacts on OS duration in univariate analysis. However, only T stage and N stage were identified as independent factors for OS duration in the multivariate Cox models. PMME is an aggressive tumor with poor prognosis. The AJCC staging system for mucosal melanoma with stage IVB and IVC integrated in stage IVA may be a better option for staging PMME patients. T stage and N stage are independent factors for OS.
Natural Killer Cells in SARS-CoV-2 Infection: Pathophysiology and Therapeutic Implications

Natural Killer (NK) cells are lymphocytes of the innate immunity that play a crucial role in the control of viral infections in the absence of a prior antigen sensitization. Indeed, they display rapid effector functions against target cells with the capability of direct cell killing and antibody-dependent cell-mediated cytotoxicity. Furthermore, NK cells are endowed with immune-modulatory functions innate and adaptive immune responses via the secretion of chemokines/cytokines and by undertaking synergic crosstalks with other innate immune cells, including monocyte/macrophages, dendritic cells and neutrophils. Recently, the Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally. Although the specific role of NK cells in COVID-19 pathophysiology still need to be explored, mounting evidence indicates that NK cell tissue distribution and effector functions could be affected by SARS-CoV-2 infection and that a prompt NK cell response could determine a good clinical outcome in COVID-19 patients. In this review, we give a comprehensive overview of how SARS-CoV-2 infection interferes with NK cell antiviral effectiveness and their crosstalk with other innate immune cells. We also provide a detailed characterization of the specific NK cell subsets in relation to COVID-19 patient severity generated from publicly available single cell RNA sequencing datasets. Finally, we summarize the possible NK cell-based therapeutic approaches against SARS-CoV-2 infection and the ongoing clinical trials updated at the time of submission of this review. We will also discuss how a deep understanding of NK cell responses could open new possibilities for the treatment and prevention of SARS-CoV-2 infection.
Induction of Autophagy Promotes Clearance of RHOP23H Aggregates and Protects From Retinal Degeneration

Autophagy is a critical metabolic process that acts as a major self-digestion and recycling pathway contributing to maintain cellular homeostasis. An emerging field of research supports the therapeutic modulation of autophagy for treating human neurodegenerative disorders, in which toxic aggregates are accumulated in neurons. Our previous study identified Ezrin protein as an inhibitor of autophagy and lysosomal functions in the retina; thus, in turn, identifying it as a potential pharmacological target for increasing retinal cell clearance to treat inherited retinal dystrophies in which misfolded proteins have accumulated. This study aimed to verify the therapeutic inhibition of Ezrin to induce clearance of toxic aggregates in a mouse model for a dominant form of retinitis pigmentosa (i.e., RHOP23H/+). We found that daily inhibition of Ezrin significantly decreased the accumulation of misfolded RHOP23H aggregates. Remarkably, induction of autophagy, by a drug-mediated pulsatile inhibition of Ezrin, promoted the lysosomal clearance of disease-linked RHOP23H aggregates. This was accompanied with a reduction of endoplasmic reticulum (ER)-stress, robust decrease of photoreceptors' cell death, amelioration in both retinal morphology and function culminating in a better preservation of vision. Our study opens new perspectives for a pulsatile pharmacological induction of autophagy as a mutation-independent therapy paving the way toward a more effective therapeutic strategy to treat these devastating retinal disorders due to an accumulation of intracellular toxic aggregates.
Willingness and Perceptions Regarding COVID-19 Vaccine Booster Dose in Pakistani Vaccinated Population: A Cross-Sectional Survey

Objectives This study was conducted to evaluate COVID-19 vaccine booster dose willingness and identify predictors and factors of willingness and hesitance in the vaccinated population of Pakistan. Methods A cross-sectional web-based survey was undertaken between January and February 2022 to highlight the public perceptions regarding the COVID-19 booster dose and evaluate the willingness to get the additional dose. Demographic information and booster dose willingness were recorded through the questionnaire. Additionally, a 5-point Likert scale was employed to explore fears and beliefs regarding COVID-19 vaccinations. Univariate and multivariate regression was performed to identify booster dose willingness and hesitance factors. Results Of the 787 respondents, 69.6% were females, 75.3% fell in the 18–30 years age group, 53.5% were university students or had a Bachelor's degree. Overall, a 77.8% booster dose willingness was reported. Participants showed absence or low fear levels associated with a booster dose (47.3%). 60.1% agreed it was safe to receive an additional vaccine dose, with 44.1% agreeing that boosters are effective against coronavirus variants. Independent predictors of willingness included the absence of comorbidities, whereas not being willing to pay for the booster dose was a predictor of hesitance. Conclusion This study showed a suboptimal willingness level of booster dose uptake among the vaccinated Pakistani population. Public health policymakers must undertake necessary awareness campaigns to strategize vaccination drives and dispel myths.
Estimating Nitrogen Use Efficiency, Profitability, and Greenhouse Gas Emission Using Different Methods of Fertilization

Fertilization is a way to better use nitrogen fertilizers and increase productivity, but in another way, fertilization is also a source of anthropogenic greenhouse gas emissions. The study was carried out to measure the profitability ratio, technical efficiency, and CO2 from the top dressing (TD) and deep placement (DP) fertilization. The study was based on primary data, which were collected from different respondents and areas through a well-designed questionnaire. The study finds that DP fertilization is more profitable, least costly, and more efficient than TD fertilization. The finding observed that the yield of the TD growers is 727.82 kg/ha more than that of TD respondents. The efficiency score shows that to reach the 90% efficiency level, the farmers of TD need to use DP fertilization. The farmers of TD and DP can still increase their efficiency up to 12% and 9% by using the same inputs. The findings also clarify that manufacturing of synthetic nitrogen (N), direct use of N, Yield, and Area-Scaled greenhouse gas (GHG) emissions from the use of synthetic N through TD fertilization are greater than that of the DP group. The farming community needs to be aware of greenhouse gas emissions and how they can be reduced. It is also suggested that farmers need to shift toward DP fertilization to increase yield, profit, efficiency, food security, and reduce GHG emissions.