Miracle-dz/UniFAR-FTUs huggingface dataset:
Accumulation of Seminolipid in Sertoli Cells Is Associated with Increased Levels of Reactive Oxygen Species and Male Subfertility: Studies in Aging Arsa Null Male Mice

Seminolipid (also known as sulfogalactosylglycerolipid-SGG), present selectively in male germ cells, plays important roles in spermatogenesis and sperm–egg interaction. The proper degradation of SGG in apoptotic germ cells is also as important. Sertoli cells first phagocytose apoptotic germ cells, then Sertoli lysosomal arylsulfatase A (ARSA) desulfates SGG, the first step of SGG degradation. We have reported that aging male Arsa−/− mice become subfertile with SGG accumulation in Sertoli cell lysosomes, typical of a lysosomal storage disorder (LSD). Since reactive oxygen species (ROS) levels are increased in other glycolipid-accumulated LSDs, we quantified ROS in Arsa−/− Sertoli cells. Our analyses indicated increases in superoxide and H2O2 in Arsa−/− Sertoli cells with elevated apoptosis rates, relative to WT counterparts. Excess H2O2 from Arsa−/− Sertoli cells could travel into testicular germ cells (TGCs) to induce ROS production. Our results indeed indicated higher superoxide levels in Arsa−/− TGCs, compared with WT TGCs. Increased ROS levels in Arsa−/− Sertoli cells and TGCs likely caused the decrease in spermatogenesis and increased the abnormal sperm population in aging Arsa−/− mice, including the 50% decrease in sperm SGG with egg binding ability. In summary, our study indicated that increased ROS production was the mechanism through which subfertility manifested following SGG accumulation in Sertoli cells.
Recent Advances in Experimental Burn Models

Simple Summary Human burns are diverse and the most difficult injuries to study in clinical settings. Numerous experimental burn models designed to study and compare different aspects of burns and their consequences and treatment are steadily progressing. This review summarizes the latest advances in experimental burn research as a guide to aid in the future design of studies. Abstract Experimental burn models are essential tools for simulating human burn injuries and exploring the consequences of burns or new treatment strategies. Unlike clinical studies, experimental models allow a direct comparison of different aspects of burns under controlled conditions and thereby provide relevant information on the molecular mechanisms of tissue damage and wound healing, as well as potential therapeutic targets. While most comparative burn studies are performed in animal models, a few human or humanized models have been successfully employed to study local events at the injury site. However, the consensus between animal and human studies regarding the cellular and molecular nature of systemic inflammatory response syndrome (SIRS), scarring, and neovascularization is limited. The many interspecies differences prohibit the outcomes of animal model studies from being fully translated into the human system. Thus, the development of more targeted, individualized treatments for burn injuries remains a major challenge in this field. This review focuses on the latest progress in experimental burn models achieved since 2016, and summarizes the outcomes regarding potential methodological improvements, assessments of molecular responses to injury, and therapeutic advances.
Gene Polymorphisms of NOD2, IL23R, PTPN2 and ATG16L1 in Patients with Crohn’s Disease: On the Way to Personalized Medicine?

Genetic and environmental factors are involved in the pathogenesis of inflammatory bowel diseases (IBD). The study aimed at investigating the potential influence of single nucleotide polymorphisms (SNPs) NOD2 rs2066844, NOD2 rs2066845, NOD2 rs2066847, IL23R rs11209026, PTPN2 rs2542151, PTPN2 rs7234029, and ATG16L1 rs2241880 on the response to immunomodulatory therapies and disease course in Crohn’s disease (CD). This is an uncontrolled retrospective monocentric study including patients from the IBD outpatient clinic of Heidelberg University Hospital. Therapy responses and disease courses were related to genetic findings. 379 patients with CD were included. The presence of at least one PTPN2 rs7234029 risk allele was associated with nonresponse to anti-interleukin-12/23 treatment (89.9% vs. 67.6%, p = 0.005). The NOD2 rs2066844 risk allele was associated with a first-degree family history of colon cancer (12.7% vs. 4.7%, p = 0.02), the ATG16L1 rs2241880 risk allele with ileal CD manifestation (p = 0.027), and the IL23R rs11209026 risk allele with a higher rate of CD-related surgeries per disease year (0.08 vs. 0.02, p = 0.025). The results of this study underline the relevance of genetic influences in CD. The association of the PTPN2 rs7234029 risk allele with nonresponse to anti-interleukin-12/23 treatment in CD patients is a novel finding and requires further investigation.
Genetic Aspects of Somatic Cell Count in Holstein Dairy Cows in Iran

Simple Summary Holstein Friesian is the dominant breed of modern dairy cattle in Iran, therefore the development of a genetic evaluation system for economically important traits for this population is needed. Genetic parameters for SCS and its genetic correlations with production traits were estimated in Iranian Holstein cows. The moderate heritability for SCS and its low negative genetic correlations with yield traits indicate that genetic selection for decreasing SCS would have a relatively medium genetic progress with no necessarily antagonistic effects on lactation performance. The estimates found in this study can be considered as the first step to include SCS in the national genetic evaluations in Iranian Holsteins using a multiple-trait, multiple-lactation random regression model. Abstract The aim of this study was to estimate the genetic parameters of somatic cell count (SCC) and its relationship with production traits in the first three parities in Iranian Holstein dairy cows. Data were 1,891,559 test-day records of SCC, milk yield, and milk compositions on 276,217 lactations on 147,278 cows distributed in 134 herds. The number of test-day records in the first, second and third parities were 995,788 (on 147,278 cows), 593,848 (on 85,153 cows), and 301,923 (on 43,786 cows), respectively. Test-day SCCs were transformed to somatic cell scores (SCS). A random regression test-day animal model through four-trait three-lactation was used to estimate variance components for test-day records of SCS and lactation traits were included. Gibbs sampling was used to obtain marginal posterior distributions for the various parameters using a single chain of 200,000 iterates in which the first 50,000 iterates of each chain were regarded as a burn-in period. The mean heritability estimates for SCS (0.15 to 0.18) were lower than those for milk yield (0.36 to 0.38), fat yield (0.30 to 0.31), protein yield (0.31 to 0.32), fat percentage (0.21 to 0.25), and protein percentage (0.21 to 0.22). Low negative genetic correlations ranging from −0.05 to −0.30 were found between SCS and yield traits (milk, fat, and protein yields). The genetic correlation found between SCS and fat percentage was close to zero, however, a low positive genetic correlation ranging from 0.12 to 0.17 was found between SCS and protein percentage. Based on the results, it can be concluded that genetic selection for decreasing SCS would also increase lactation yield. The estimates found in this study can be used to perform breeding value estimations for national genetic evaluations in Iranian Holsteins using a multiple-trait, multiple-lactation random regression model.
Co-expression Network Analysis Reveals Key Genes Related to Ankylosing spondylitis Arthritis Disease: Computational and Experimental Validation

Background: Ankylosing spondylitis (AS) is a type of arthritis which can cause inflammation in the vertebrae and joints between the spine and pelvis. However, our understanding of the exact genetic mechanisms of AS is still far from being clear. Objective: To study and find the mechanisms and possible biomarkers related to AS by surveying inter-gene correlations of networks. Materials and Methods: A weighted gene co-expression network was constructed among genes identified by microarray analysis, gene co-expression network analysis, and network clustering. Then receiver operating characteristic (ROC) curves were conducted to identify a significant module with the genes implicated in the AS pathogenesis. Real-time PCR was performed to validate the results of microarray analysis. Results: In the significant module obtained from the network analysis there were eight AS related genes (LSM3, MRPS11, NSMCE2, PSMA4, UBL5, RPL17, MRPL22 and RPS17) which have been reported in previous studies as hub genes. Further, in this module, eight significant enriched pathways were found with adjusted p-values < 0.001 consisting of oxidative phosphorylation, ribosome, nonalcoholic fatty liver disease, Alzheimer's, Huntington's, and Parkinson's diseases, spliceosome, and cardiac muscle contraction pathways which have been linked to AS. Furthermore, we identified nine AS related genes (UQCRB, UQCRH, UQCRHL, UQCRQ, COX7B, COX5B, COX6C, COX6A1 and COX7C) in these pathways which can play essential roles in controlling mitochondrial activity and pathogenesis of autoimmune diseases. Real-time PCR results showed that three genes including UQCRH, MRPS11, and NSMCE2 in AS patients were significantly differentially expressed compared with normal controls. Conclusions: The results of the present study may contribute to understanding of AS molecular pathogenesis, thereby aiding the early prognosis, diagnosis, and effective therapies of the disease.
A Respiratory Motion Estimation Method Based on Inertial Measurement Units for Gated Positron Emission Tomography

We present a novel method for estimating respiratory motion using inertial measurement units (IMUs) based on microelectromechanical systems (MEMS) technology. As an application of the method we consider the amplitude gating of positron emission tomography (PET) imaging, and compare the method against a clinically used respiration motion estimation technique. The presented method can be used to detect respiratory cycles and estimate their lengths with state-of-the-art accuracy when compared to other IMU-based methods, and is the first based on commercial MEMS devices, which can estimate quantitatively both the magnitude and the phase of respiratory motion from the abdomen and chest regions. For the considered test group consisting of eight subjects with acute myocardial infarction, our method achieved the absolute breathing rate error per minute of 0.44 ± 0.23 1/min, and the absolute amplitude error of 0.24 ± 0.09 cm, when compared to the clinically used respiratory motion estimation technique. The presented method could be used to simplify the logistics related to respiratory motion estimation in PET imaging studies, and also to enable multi-position motion measurements for advanced organ motion estimation.
Cannabinoid Activity—Is There a Causal Connection to Spasmolysis in Clinical Studies?

Cannabinoid drugs are registered for postoperative nausea and emesis, Tourette syndrome and tumor-related anorexia, but are also used for spasticity and pain relief, among other conditions. Clinical studies for spasmolysis have been equivocal and even conclusions from meta-analyses were not consistent. This may be due to uncertainty in diagnostic criteria as well as a lack of direct spasmolytic activity (direct causality). In this review we used the Hill criteria to investigate whether a temporal association is causal or spurious. Methods: A systematic literature search was performed to identify all clinical trials of cannabinoids for spasticity. Studies were evaluated for dose dependency and time association; all studies together were analyzed for reproducibility, coherence, analogy and mechanistic consistency. A Funnel plot was done for all studies to identify selection or publication bias. Results: Twenty-seven studies were included in this meta-analysis. The spasmolytic activity (effect strength) was weak, with a nonsignificant small effect in most studies and a large effect only in a few studies (“enriched” studies, low patient numbers). No dose dependency was seen and plotting effect size vs. daily dose resulted in a slope of 0.004. Most studies titrated the cannabinoid to the optimum dose, e.g., 20 mg/d THC. The effect decreased with longer treatment duration (3–4 months). The spasmolytic effect is consistent for different European countries but not always within a country, nor is the effect specific for an etiology (multiple sclerosis, spinal cord injury, others). For other criteria like plausibility, coherence or analogous effects, no data exist to support or refute them. In most studies, adverse effects were frequently reported indicating a therapeutic effect only at high doses with relevant side effects. Conclusions: Current data do not support a specific spasmolytic effect; a general decrease in CNS activity analogous to benzodiazepines appears more likely. Whether individual patients or specific subgroups benefit from cannabinoids is unclear. Further studies should compare cannabinoids with other, nonspecific spasmolytic drugs like benzodiazepines.
Intrinsic and Chemotherapeutic Stressors Modulate ABCC-Like Transport in Trypanosoma cruzi

Trypanosoma cruzi is the etiologic agent for Chagas disease, which affects 6–7 million people worldwide. The biological diversity of the parasite reflects on inefficiency of benznidazole, which is a first choice chemotherapy, on chronic patients. ABC transporters that extrude xenobiotics, metabolites, and mediators are overexpressed in resistant cells and contribute to chemotherapy failure. An ABCC-like transport was identified in the Y strain and extrudes thiol-conjugated compounds. As thiols represent a line of defense towards reactive species, we aimed to verify whether ABCC-like transport could participate in the regulation of responses to stressor stimuli. In order to achieve this, ABCC-like activity was measured by flow cytometry using fluorescent substrates. The present study reveals the participation of glutathione and ceramides on ABCC-like transport, which are both implicated in stress. Hemin modulated the ABCC-like efflux which suggests that this protein might be involved in cellular detoxification. Additionally, all strains evaluated exhibited ABCC-like activity, while no ABCB1-like activity was detected. Results suggest that ABCC-like efflux is not associated with natural resistance to benznidazole, since sensitive strains showed higher activity than the resistant ones. Although benznidazole is not a direct substrate, ABCC-like efflux increased after prolonged drug exposure and this indicates that the ABCC-like efflux mediated protection against cell stress depends on the glutathione biosynthesis pathway.
Dehydroabietic Acid Microencapsulation Potential as Biofilm-Mediated Infections Treatment

The antimicrobial activity of dehydroabietic acid (DHA) for its use as an antibiofilm agent was tested in this work. DHA was assayed against a collection of Gram-positive, Gram-negative sensitive and resistant bacteria and yeasts through the minimum inhibitory concentration (MIC), MIC with Bioburden challenge, minimum bactericidal concentration (MBC), minimum biofilm inhibitory concentration (MBIC), MBIC with Bioburden challenge and growth curve studies. Toxicological studies (Artemia salina, sulforhodamine B (SRB) assay) were done to assess if the compound had antimicrobial and not cytotoxic properties. Furthermore, microencapsulation and stability studies were carried out to evaluate the chemical behavior and stability of DHA. On MIC results, Gram-positive bacteria Staphylococcus aureus ATCC 1228 and Mycobacterium smegmatis ATCC 607 presented a high efficiency (7.81 µg/mL), while on Gram-negative bacteria the highest MIC value of 125 µg/mL was obtained by all Klebsiella pneumoniae strains and Escherichia coli isolate strain HSM 303. Bioburden challenge showed that MIC, MBIC and percentage biofilm inhibition (BI) values suffered alterations, therefore, having higher concentrations. MBIC values demonstrated that DHA has a higher efficiency against S. aureus ATCC 43866 with a percentage of BI of 75.13 ± 0.82% at 0.49 µg/mL. Growth curve kinetic profiles of DHA against S. aureus ATCC 25923 were observed to be bacteriostatic. DHA-alginate beads had a average size of 2.37 ± 0.20 and 2.31 ± 0.17 × 103 µm2 with an encapsulation efficiency (EE%) around 99.49 ± 0.05%, a protection percentage (PP%) of 60.00 ± 0.05% in the gastric environment and a protection efficiency (PE%) around 88.12 ± 0.05% against UV light. In toxicological studies DHA has shown IC50 of 19.59 ± 7.40 µg/mL and a LC50 of 21.71 ± 2.18%. The obtained results indicate that DHA is a promising antimicrobial candidate against a wide range of bacteria and biofilm formation that must be further explored.
Visualization of Gene Reciprocity among Lactic Acid Bacteria in Yogurt by RNase H-Assisted Rolling Circle Amplification-Fluorescence In Situ Hybridization

Recently, we developed an in situ mRNA detection method termed RNase H-assisted rolling circle amplification-fluorescence in situ hybridization (RHa-RCA-FISH), which can detect even short mRNA in a bacterial cell. However, because this FISH method is sensitive to the sample condition, it is necessary to find a suitable cell permeabilization and collection protocol. Here, we demonstrate its further applicability for detecting intrinsic mRNA expression using lactic acid bacteria (LAB) as a model consortium. Our results show that this method can visualize functional gene expression in LAB cells and can be used for monitoring the temporal transition of gene expression. In addition, we also confirmed that data obtained from bulk analyses such as RNA-seq or microarray do not always correspond to gene expression in individual cells. RHa-RCA-FISH will be a powerful tool to compensate for insufficient data from metatranscriptome analyses while clarifying the carriers of function in microbial consortia. By extending this technique to capture spatiotemporal microbial gene expression at the single-cell level, it will be able to characterize microbial interactions in phytoplankton–bacteria interactions.
Deep Reinforcement Learning for Attacking Wireless Sensor Networks

Recent advances in Deep Reinforcement Learning allow solving increasingly complex problems. In this work, we show how current defense mechanisms in Wireless Sensor Networks are vulnerable to attacks that use these advances. We use a Deep Reinforcement Learning attacker architecture that allows having one or more attacking agents that can learn to attack using only partial observations. Then, we subject our architecture to a test-bench consisting of two defense mechanisms against a distributed spectrum sensing attack and a backoff attack. Our simulations show that our attacker learns to exploit these systems without having a priori information about the defense mechanism used nor its concrete parameters. Since our attacker requires minimal hyper-parameter tuning, scales with the number of attackers, and learns only by interacting with the defense mechanism, it poses a significant threat to current defense procedures.
Attitudes toward Menopause in HIV-Infected Cambodian Women

(1) Background: Attitudes toward menopause are believed to play a potential role in the experience of menopause, including its perceived severity. However, the studies available on the perspectives of women living with human immunodeficiency virus (HIV) on menopause in Cambodia are very limited. This study aimed to evaluate the attitudes toward menopause of Cambodian women living with HIV. (2) Methods: A cross-sectional study was conducted among 189 women using a questionnaire titled Attitude toward Menopause Scale and socio-demographics. (3) Results: The study analysis showed that the participants had slightly negative attitudes toward menopause with the mean attitude score of 86.81 ± 10.79 (Range 35–140). Postmenopausal women displayed more positive attitudes than premenopausal women. Older age, higher education, and a non-drinking habit were independently associated with a positive attitude toward menopause. (4) Conclusions: The results suggest the need for a multidisciplinary team of health care experts that would address the special needs of this population marked by the menopausal transition.
Maternal Supplementation with Cow’s Milk Naturally Enriched with PUFA Alters the Metabolism of Sows and the Fatty Acid Profile of the Offspring

The study aimed to evaluate the supplementation of gilts with cow’s milk naturally enriched with n-3 and n-6 polyunsaturated fatty acids (PUFA) on reproductive outcomes, and the serum biochemical and FA profile of swine females and their offspring. During 316 days, 30 gilts were distributed into three groups: (1) Control, fed a basal diet + milk from cows without oil; (2) n-3, fed a basal diet + milk from cows fed a diet enriched with linseed oil; (3) n-6, fed a basal diet + milk from cows fed a diet enriched with soybean oil. The gilts receiving the diets containing PUFA had higher serum urea and very-low-density lipoprotein levels and lower serum total protein and low-density lipoprotein levels compared to the Control group. Females supplemented with n-3 presented higher serum palmitic acid and γ-linolenic acid levels than those fed n-6. Piglets from the Control group were heavier at birth than those from females supplemented with enriched milk. The piglets from females receiving enriched milk had 140 g higher body weight from 1 to 21 days old compared to the Control group, and greater average daily weight gain from 7 to 14 days old. The serum eicosapentaenoic acid level of piglets fed n-3 was 69% higher than those fed n-6, which reduced the AA/EPA ratio. Gilts supplemented with PUFA-enriched cow’s milk showed changes in their serum palmitic and γ-linolenic acid levels, in addition to improved performance, EPA concentration and consequently reduced AA/EPA ratio in their piglets, demonstrating beneficial results for their progeny.
Cost-Effectiveness Analysis of Dabrafenib Plus Trametinib and Vemurafenib as First-Line Treatment in Patients with BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma in China

Objective: To evaluate the cost-effectiveness of dabrafenib plus trametinib combination therapy versus vemurafenib as first-line treatment in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma from a healthcare system perspective in China. Methods: This study employed a partitioned survival model with three health states (progression-free survival, post-progression survival and dead) to parameterize the data derived from Combi-v trial and extrapolated to 30 years. Health states’ utilities were measured by EQ-5D-3L, also sourced from the Combi-v trial. Costs including drug acquisition costs, disease management costs and adverse event costs were based on the Chinese Drug Bidding Database and physician survey in China. The primary outcomes of the model were lifetime costs, life-years (LYs), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted, respectively. Result: Dabrafenib plus trametinib is projected to increase a patient’s life expectancy by 0.95 life-years over vemurafenib (3.03 vs. 2.08) and 1.09 QALY gains (2.48 vs. 1.39) with an incremental cost of $3833. The incremental cost-effectiveness ratio (ICER) was $3511 per QALY. In the probabilistic sensitivity analyses, at a threshold of $33,357 per QALY (three times the gross domestic product (GDP) per capita in China in 2020), the probability of dabrafenib plus trametinib being cost-effective was 90%. In the deterministic sensitivity analyses, the results were most sensitive to the dabrafenib plus trametinib drug costs, vemurafenib drug costs and discount rate of cost. Conclusion: Dabrafenib plus trametinib therapy yields more clinical benefits than vemurafenib. Using a threshold of $33,357 per QALY, dabrafenib plus trametinib is very cost-effective as compared with vemurafenib in China.