Miracle-dz/UniFAR-FTUs huggingface dataset:
Transcriptional Profiling Reveals the Importance of RcrR in the Regulation of Multiple Sugar Transportation and Biofilm Formation in Streptococcus mutans

The human oral cavity is a constantly changing environment. Tooth decay is a commonly prevalent chronic disease mainly caused by the cariogenic bacterium Streptococcus mutans. S. mutans is an oral pathogen that metabolizes various carbohydrates into extracellular polysaccharides (EPSs), biofilm, and tooth-destroying lactic acid. ABSTRACT The ability of Streptococcus mutans to survive and cause dental caries is dependent on its ability to metabolize various carbohydrates, accompanied by extracellular polysaccharide synthesis and biofilm formation. Here, the role of an rel competence-related regulator (RcrR) in the regulation of multiple sugar transportation and biofilm formation is reported. The deletion of the rcrR gene in S. mutans caused delayed growth, decreased biofilm formation ability, and affected the expression level of its multiple sugar transportation-related genes. Transcriptional profiling revealed 17 differentially expressed genes in the rcrR mutant. Five were downregulated and clustered with the sugar phosphotransferase (PTS) systems (mannitol- and trehalose-specific PTS systems). The conserved sites bound by the rcrR promoter were then determined by electrophoretic mobility shift assays (EMSAs) and DNase I footprinting assays. Furthermore, a potential binding motif in the promoters of the two PTS operons was predicted using MEME Suite 5.1. 1. RcrR could bind to the promoter regions of the two operons in vitro, and the sugar transporter-related genes of the two operons were upregulated in an rcrR-overexpressing strain. In addition, when RcrR-binding sites were deleted, the growth rates and final yield of S. mutans were significantly decreased in tryptone-vitamin (TV) medium supplemented with different sugars, but not in absolute TV medium. These results revealed that RcrR acted as a transcription activator to regulate the two PTS systems, accompanied by multiple sugar transportation and biofilm formation. Collectively, these results indicate that RcrR is a critical transcription factor in S. mutans that regulates bacterial growth, biofilm formation, and multiple sugar transportation. IMPORTANCE The human oral cavity is a constantly changing environment. Tooth decay is a commonly prevalent chronic disease mainly caused by the cariogenic bacterium Streptococcus mutans. S. mutans is an oral pathogen that metabolizes various carbohydrates into extracellular polysaccharides (EPSs), biofilm, and tooth-destroying lactic acid. The host diet strongly influences the availability of multiple carbohydrates. Here, we showed that the RcrR transcription regulator plays a significant role in the regulation of biofilm formation and multiple sugar transportation. Further systematic evaluation of how RcrR regulates the transportation of various sugars and biofilm formation was also conducted. Notably, this study decrypts the physiological functions of RcrR as a potential target for the better prevention of dental caries.
The genetic structure of the Turkish population reveals high levels of variation and admixture

Significance We delineated the fine-scale genetic structure of the Turkish population by using sequencing data of 3,362 unrelated Turkish individuals from different geographical origins and demonstrated the position of Turkey in terms of human migration and genetic drift. The results show that the genetic structure of present-day Anatolia was shaped by historical and modern-day migrations, high levels of admixture, and inbreeding. We observed that modern-day Turkey has close genetic relationships with the neighboring Balkan and Caucasus populations. We generated a Turkish Variome which defines the extent of variation observed in Turkey, listed homozygous loss-of-function variants and clinically relevant variants in the cohort, and generated an imputation panel for future genome-wide association studies. The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 50% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes.
Pancreatic solid pseudopapillary neoplasm: a single‐institution study

Solid pseudopapillary neoplasms (SPNs) are a distinct but rare form of low‐grade pancreatic neoplasia, accounting for 0.3%–2.7% of all pancreatic tumours. They are most common in young females. Local recurrence and distant metastasis are reported but extremely rare, and are usually resectable with curative intent. We report the clinicopathological features and long‐term outcomes of SPNs following surgical resection from a single institution.
The Fibronectin–ILT3 Interaction Functions as a Stromal Checkpoint that Suppresses Myeloid Cells

In this study, the fibronectin–ILT3 interaction is shown to represent a “stromal checkpoint” through which the extracellular matrix actively suppresses tumor-associated myeloid cells. Therapeutics targeting this interaction can potentially reprogram suppressive myeloid cells, increasing antitumor immune responses. Suppressive myeloid cells inhibit antitumor immunity by preventing T-cell responses. Immunoglobulin-like transcript 3 (ILT3; also known as LILRB4) is highly expressed on tumor-associated myeloid cells and promotes their suppressive phenotype. However, the ligand that engages ILT3 within the tumor microenvironment and renders tumor-associated myeloid cells suppressive is unknown. Using a screening approach, we identified fibronectin as a functional ligand for ILT3. The interaction of fibronectin with ILT3 polarized myeloid cells toward a suppressive state, and these effects were reversed with an ILT3-specific antibody that blocked the interaction of ILT3 with fibronectin. Furthermore, ex vivo treatment of human tumor explants with anti-ILT3 reprogrammed tumor-associated myeloid cells toward a stimulatory phenotype. Thus, the ILT3–fibronectin interaction represents a “stromal checkpoint” through which the extracellular matrix actively suppresses myeloid cells. By blocking this interaction, tumor-associated myeloid cells may acquire a stimulatory phenotype, potentially resulting in increased antitumor T-cell responses.
Genetic Sequencing of Attwater's Prairie Chicken Avian Poxvirus and Evaluation of Its Potential Role in Reticuloendotheliosis Virus Outbreaks

SUMMARY. Efforts to breed Attwater's prairie chickens (APC; Tympanuchus cupido attwateri) in captivity to supplement wild populations of this endangered bird have been negatively affected by infections with Avipoxvirus and reticuloendotheliosis virus (REV). Because REV can be integrated into the genome of fowlpox virus (FPV) and may be transmitted in that manner, identifying the source of avipox disease in APC is important to mitigate the impact of this virus. Tissue samples from APC were collected from breeding programs in Texas from 2016 to 2020. These samples consisted of 11 skin lesions and three internal organs from a total of 14 different birds that died of unknown causes or were euthanized. Avipoxvirus was detected by PCR and isolation in embryonating chicken eggs in all skin lesion samples but was not detected in internal organs. Using sequence analysis of FPV polymerase and 4b genes, we determined that 10 out of 11 Avipoxvirus detections resided within the fowlpox clade and a single sample resided within the canarypox clade. REV sequences were detected in all FPV positive samples and in all internal organ tissues but were not detected in the sample matching the canarypox clade. Analysis of REV sequences and PCR detection showed the REV infecting APC was consistent with REV-A and had little variability on analysis of the U3 region of the long terminal repeat. The results of this study indicate control of REV in APC breeding colonies may benefit by a vaccination program targeting FPV and REV. However, a commercially available vaccine for REV is not available at this time.
Phosphoenolpyruvate depletion mediates both growth arrest and drug tolerance of Mycobacterium tuberculosis in hypoxia

Significance Nonreplicating (NR) Mycobacterium tuberculosis (Mtb) was thought to be drug tolerant due to its low metabolic activity. However, drug tolerance often gradually increases by exposure to antibiotics, inferring the role of an adaptive strategy. This study established that drug tolerance of NR Mtb is associated with phosphoenolpyruvate (PEP) anabolic down-regulation. PEP is a substrate of multiple pathways needed for replication; in NR Mtb, their functions were abolished due to PEP depletion. Intriguingly, PEP supplementation partly restored drug sensitivity and prevented the emergence of drug resistance (DR). The results expand our knowledge of how NR Mtb remodels its metabolic networks and propose potential Mtb metabolites as a source of therapeutic adjuvants to synthetically kill NR Mtb and prevent development of DR. Mycobacterium tuberculosis (Mtb) infection is difficult to treat because Mtb spends the majority of its life cycle in a nonreplicating (NR) state. Since NR Mtb is highly tolerant to antibiotic effects and can mutate to become drug resistant (DR), our conventional tuberculosis (TB) treatment is not effective. Thus, a novel strategy to kill NR Mtb is required. Accumulating evidence has shown that repetitive exposure to sublethal doses of antibiotics enhances the level of drug tolerance, implying that NR Mtb is formed by adaptive metabolic remodeling. As such, metabolic modulation strategies to block the metabolic remodeling needed to form NR Mtb have emerged as new therapeutic options. Here, we modeled in vitro NR Mtb using hypoxia, applied isotope metabolomics, and revealed that phosphoenolpyruvate (PEP) is nearly completely depleted in NR Mtb. This near loss of PEP reduces PEP-carbon flux toward multiple pathways essential for replication and drug sensitivity. Inversely, supplementing with PEP restored the carbon flux and the activities of the foregoing pathways, resulting in growth and heightened drug susceptibility of NR Mtb, which ultimately prevented the development of DR. Taken together, PEP depletion in NR Mtb is associated with the acquisition of drug tolerance and subsequent emergence of DR, demonstrating that PEP treatment is a possible metabolic modulation strategy to resensitize NR Mtb to conventional TB treatment and prevent the emergence of DR.
Anaplasma phagocytophilum in Multiple Tissue Samples of Wild Carnivores in Romania

Abstract: Wild vertebrate hosts can serve as reservoirs or amplification hosts for tick-borne pathogens (TBPs). Wild carnivores due to their large size have an increased risk for harboring large numbers of ticks. Moreover, their large home ranges and long lives may increase the risk of exposure to ticks and TBPs. Wild carnivores therefore may be good sentinel species with which to monitor the distribution of TBPs. We aimed to evaluate the presence of rickettsial DNA in wild carnivores and to compare its presence in different types of samples. In total, 95 wild carnivores from nine species, originating from 17 counties of Romania collected during 2014–18, were included in the study. From each animal, DNA was extracted from multiple tissue samples, including blood clot, heart, liver, lungs, spleen, kidney, lymph node, and bone marrow, and screened for the presence of rickettsial pathogen DNA (Anaplasma phagocytophilum, Ehrlichia canis, and Rickettsia spp.). Samples from 10 animals from six species (Canis aureus, Ursus arctos, Canis lupus, Felis sylvestris, Lutra lutra, and Martes foina) were found to be positive for A. phagocytophilum. The most frequently positive sample was the spleen. No animal was positive for Ehrlichia spp. or Rickettsia spp. Wild carnivores may be involved in the ecoepidemiology of A. phagocytophilum by maintaining the infection in synanthropic environments.
Amendments suggested for zoo medical research strategies with focus on the D-A-CH region

Abstract Objective Scientific exploration of zoo animals is one of the main missions of modern zoos. As scientific achievements are best reflected within scientific literature, we screened appropriate literature search outcomes from the 5 highest ranked zoos in the D-A-CH region (Germany-Austria-Switzerland) in order to deduce suggestions for optimizations of future research strategies. Material and methods Literature search was done by entering ”Zoo Vienna”, “Tiergarten Schönbrunn”, “Zoo Berlin”, “Tiergarten Berlin”, “Tierpark Hellabrunn”, “Tierpark Hagenbeck”, and “Zoo Zurich” on PubMed and Scopus for the period 2000–2020. These 5 European zoos were chosen due to their broad public recognition and international importance. Inclusion criterion for the literature list was the description/mentioning of analysed animals or samples with a clear affiliation to the respective zoo in the materials and methods or acknowledgements sections. Search hits were then allocated to the following 7 areas: animal nutrition, biology, ethology, infectiology, reproduction, phylogenetics, and clinical medicine. Also, portions of higher animal taxa (and species, if appropriate) were recorded. Results and conclusions A total of 142 papers has been published. Mammals, especially large ones, were clearly over-represented in literature with 2 thirds of analysed papers dealing with them. Sauropsids (birds and reptiles) were treated in 28 % and non-amniotic vertebrates (amphibians and fish) as well as invertebrates in only 3 % each. This apportionment is in no relation to the species numbers of the respective higher animal taxa. The predominating research areas (covered by approximately 75 % of papers) were ethological studies, followed by papers on infectious diseases, and finally papers on biology with morphological, physiological, and molecular biological themes. Research on reproductive biology/medicine, which is considered to be of tremendous importance for the establishment of ex-situ populations and thus for the conservation of endangered species, has been covered by only 6 % of papers. Future research should more intensely keep an eye on that discipline, especially in non-mammalian vertebrates.
HIV and syphilis prevalence among transgender women and men who have sex with men, Silom Community Clinic, Bangkok, Thailand, 2017–2019

ABSTRACT We assessed HIV and syphilis infection among MSM and TGW attending Silom Community Clinic from 2017 to 2019. Walk-in and referral clients completed a registration application including a question on gender identity. We compared the prevalence of HIV, syphilis, and HIV and syphilis coinfection among TGW and MSM. In a total of 1050 clients, 276 (26.3%) were TGW and 774 (74.7%) were MSM. Among TGW clients, HIV prevalence was 29.8%, syphilis prevalence was 38.4%, and coinfection prevalence was 18.5%. Comparing prevalence among TGW to MSM, the adjusted prevalence ratio (aPR) for HIV was 1.8 (95% CI:1.4–2.3), for syphilis was 1.2 (95% CI:1.0–1.4), and for HIV and syphilis coinfection was 2.1 (95% CI:1.4–2.9). The prevalence of syphilis was higher than HIV among TGW, with a PR of 1.3 (95% CI:1.1–1.6), and among MSM, with a PR of 1.4 (95% CI:1.2–1.7). TGW age 15–21 years had an HIV prevalence of 16.9% and syphilis prevalence of 30.8%. After adjusting for age, referral, and sexual behaviors, TGW remain significantly associated with HIV and syphilis prevalence. There is a substantial burden of HIV and HIV/syphilis co-infection among TGW. HIV/STI prevention are needed for TGW, including linkage to HIV care.
Assessment of TLR3 and MDA5-Mediated Immune Responses Using Knockout Quail Fibroblast Cells

SUMMARY. Toll-like receptor 3 (TLR3) and melanoma differentiation-associated gene 5 (MDA5) are double-stranded RNA (dsRNA)-recognizing receptors that mediate innate immune responses to virus infection. However, the roles played by these receptors in the pathogenesis of avian viruses are poorly understood. In this study, we generated TLR3 and MDA5 single knockout (SKO) and TLR3-MDA5 double knockout (DKO) quail fibroblast cells and examined dsRNA receptor-mediated innate immune responses in vitro. The knockout cells were then stimulated with a synthetic dsRNA ligand polyinosinic:polycytidylic acid [poly(I:C)] or influenza A virus. Endosomal stimulation of TLR3 by adding poly(I:C) in cell culture media or cytoplasmic stimulation of MDA5 by transfecting poly(I:C) resulted in significant increases of TLR3, MDA5, interferon (IFN) β, and interleukin 8 gene expression levels in wild type (WT) cells. Endosomal poly(I:C) treatment induced a higher level expression of most of the genes tested in MDA5 SKO cells compared with WT cells, but not in TLR3 SKO and DKO cells. Cytoplasmic transfection of poly(I:C) led to significant upregulation of all four genes in WT, TLR3 SKO, and MDA5 SKO cells at 8 hr posttransfection and negligible gene expression changes in TLR3-MDA5 DKO cells. Upon infection with a strain of influenza virus with compromised IFN antagonistic capability, WT cells produced the highest amount of biologically active type I IFN followed by TLR3 SKO and MDA5 SKO cells. DKO cells did not produce detectable amounts of type I IFN. However, the IFN did not induce an antiviral state fast enough to block virus replication, even in WT cells under the experimental conditions employed. In summary, our data demonstrate that TLR3 and MDA5 are the key functional dsRNA receptors in quail and imply their coordinated roles in the induction of innate immune responses upon virus infection.
Molecular Subtyping Combined with Biological Pathway Analyses to Study Regorafenib Response in Clinically Relevant Mouse Models of Colorectal Cancer

Purpose: Regorafenib (REG) is approved for the treatment of metastatic colorectal cancer, but has modest survival benefit and associated toxicities. Robust predictive/early response biomarkers to aid patient stratification are outstanding. We have exploited biological pathway analyses in a patient-derived xenograft (PDX) trial to study REG response mechanisms and elucidate putative biomarkers. Experimental Design: Molecularly subtyped PDXs were annotated for REG response. Subtyping was based on gene expression (CMS, consensus molecular subtype) and copy-number alteration (CNA). Baseline tumor vascularization, apoptosis, and proliferation signatures were studied to identify predictive biomarkers within subtypes. Phospho-proteomic analysis was used to identify novel classifiers. Supervised RNA sequencing analysis was performed on PDXs that progressed, or did not progress, following REG treatment. Results: Improved REG response was observed in CMS4, although intra-subtype response was variable. Tumor vascularity did not correlate with outcome. In CMS4 tumors, reduced proliferation and higher sensitivity to apoptosis at baseline correlated with response. Reverse phase protein array (RPPA) analysis revealed 4 phospho-proteomic clusters, one of which was enriched with non-progressor models. A classification decision tree trained on RPPA- and CMS-based assignments discriminated non-progressors from progressors with 92% overall accuracy (97% sensitivity, 67% specificity). Supervised RNA sequencing revealed that higher basal EPHA2 expression is associated with REG resistance. Conclusions: Subtype classification systems represent canonical “termini a quo” (starting points) to support REG biomarker identification, and provide a platform to identify resistance mechanisms and novel contexts of vulnerability. Incorporating functional characterization of biological systems may optimize the biomarker identification process for multitargeted kinase inhibitors.
Diagnosis Disclosure Preferences of Cancer Patients in Egypt: A Multi-Institutional Cross-Sectional Study

Background: Although diagnosis disclosure to cancer patients has important roles in cancer care, it is not a routine practice in countries like Egypt. Respecting patients’ autonomy and responding to their preferences are among the factors that should guide the practice of cancer diagnosis disclosure. Objectives: To assess the preferences of Egyptian cancer patients regarding the disclosure of cancer diagnosis and to determine factors that may affect their preferences. Methods: The study included 295 patients aware of their cancer diagnosis from 3 cancer care facilities in Egypt. Patients were asked if they would have preferred to be informed of the diagnosis or not, whom they would have preferred to receive the diagnosis information from, and if they would have preferred to tell their families or not. Results: The vast majority (91%) of the included patients preferred to be informed about their diagnosis, 59% preferred to disclose the diagnosis to their families and 66% preferred to receive the diagnosis information from a physician. In univariate analysis, male gender, higher education level and employment were significantly associated with the preference for disclosure. None of the studied variables associated significantly with the preferences in multivariate analysis. Conclusion: The majority of Egyptian cancer patients in our study preferred to be informed about their diagnosis, which should be respected. The results may help in changing the diagnosis disclosure practice of health care professionals and refuting the misconception of family caregivers about cancer diagnosis disclosure in Egypt and countries with similar culture.