Miracle-dz/UniFAR-FTUs huggingface dataset:
The Thymidine-Dependent Small-Colony-Variant Phenotype Is Associated with Hypermutability and Antibiotic Resistance in Clinical Staphylococcus aureus Isolates

ABSTRACT Thymidine-dependent small-colony variants (TD-SCVs) of Staphylococcus aureus can be isolated from the airway secretions of patients suffering from cystic fibrosis (CF) and are implicated in persistent and treatment-resistant infections. These characteristics, as well as the variety of mutations in the thymidylate synthase-encoding thyA gene which are responsible for thymidine dependency, suggest that these morphological variants are hypermutable. To prove this hypothesis, we analyzed the mutator phenotype of different S. aureus phenotypes, in particular CF-derived TD-SCVs, CF-derived isolates with a normal phenotype (NCVs), and non-CF NCVs. The comparative analysis revealed that the CF isolates had significantly higher mutation rates than the non-CF isolates. The TD-SCVs, in turn, harbored significantly more strong hypermutators (mutation rate ≥ 10−7) than the CF and non-CF NCVs. In addition, antimicrobial resistance to non-beta-lactam antibiotics, including gentamicin, ciprofloxacin, erythromycin, fosfomycin, and rifampin, was significantly more prevalent in TD-SCVs than in CF and non-CF NCVs. Interestingly, macrolide resistance, which is usually mediated by mobile genetic elements, was conferred in half of the macrolide-resistant TD-SCVs by the point mutation A2058G or A2058T in the genes encoding the 23S rRNA. Sequence analysis of mutS and mutL, which are involved in DNA mismatch repair in gram-positive bacteria, revealed that in hypermutable CF isolates and especially in TD-SCVs, mutL was often truncated due to frameshift mutations. In conclusion, these data provide direct evidence that TD-SCVs are hypermutators. This hypermutability apparently favors the acquisition of antibiotic resistance and facilitates bacterial adaptation during long-term persistence.
Isolation by Distance.

important S line of attack on the evolutionary problem. While such differences can only rarely represent first steps toward speciation in the sense of the splitting of the species, they are important for the evolution of the species as a whole. They provide a possible basis for intergroup selection of genetic systems, a process that provides a more effective mechanism for adaptive advance of the species as a whole than does the mass selection which is all that can occur under panmixia. TUDY of statistical differences among local populations is
Transient Receptor Potential Channel 1 Deficiency Impairs Host Defense and Proinflammatory Responses to Bacterial Infection by Regulating Protein Kinase Cα Signaling

ABSTRACT Transient receptor potential channel 1 (TRPC1) is a nonselective cation channel that is required for Ca2+ homeostasis necessary for cellular functions. However, whether TRPC1 is involved in infectious disease remains unknown. Here, we report a novel function for TRPC1 in host defense against Gram-negative bacteria. TRPC1−/− mice exhibited decreased survival, severe lung injury, and systemic bacterial dissemination upon infection. Furthermore, silencing of TRPC1 showed decreased Ca2+ entry, reduced proinflammatory cytokines, and lowered bacterial clearance. Importantly, TRPC1 functioned as an endogenous Ca2+ entry channel critical for proinflammatory cytokine production in both alveolar macrophages and epithelial cells. We further identified that bacterium-mediated activation of TRPC1 was dependent on Toll-like receptor 4 (TLR4), which induced endoplasmic reticulum (ER) store depletion. After activation of phospholipase Cγ (PLC-γ), TRPC1 mediated Ca2+ entry and triggered protein kinase Cα (PKCα) activity to facilitate nuclear translocation of NF-κB/Jun N-terminal protein kinase (JNK) and augment the proinflammatory response, leading to tissue damage and eventually mortality. These findings reveal that TRPC1 is required for host defense against bacterial infections through the TLR4-TRPC1-PKCα signaling circuit.
α‐Synuclein pathology in the cranial and spinal nerves in Lewy body disease

Accumulation of phosphorylated α‐synuclein in neurons and glial cells is a histological hallmark of Lewy body disease (LBD) and multiple system atrophy (MSA). Recently, filamentous aggregations of phosphorylated α‐synuclein have been reported in the cytoplasm of Schwann cells, but not in axons, in the peripheral nervous system in MSA, mainly in the cranial and spinal nerve roots. Here we conducted an immunohistochemical investigation of the cranial and spinal nerves and dorsal root ganglia of patients with LBD. Lewy axons were found in the oculomotor, trigeminal and glossopharyngeal‐vagus nerves, but not in the hypoglossal nerve. The glossopharyngeal‐vagus nerves were most frequently affected, with involvement in all of 20 subjects. In the spinal nerve roots, Lewy axons were found in all of the cases examined. Lewy axons in the anterior nerves were more frequent and numerous in the thoracic and sacral segments than in the cervical and lumbar segments. On the other hand, axonal lesions in the posterior spinal nerve roots appeared to increase along a cervical‐to‐sacral gradient. Although Schwann cell cytoplasmic inclusions were found in the spinal nerves, they were only minimal. In the dorsal root ganglia, axonal lesions were seldom evident. These findings indicate that α‐synuclein pathology in the peripheral nerves is axonal‐predominant in LBD, whereas it is restricted to glial cells in MSA.
Hypothyroidism and obesity: An intriguing link

According to common perception, hypothyroidism is held responsible for obesity. However, linking them causally is controversial. Overt hypothyroidism is associated with modest weight gain, but there is a lack of clarity regarding subclinical hypothyroidism. Novel view indicates that changes in thyroid-stimulating hormone (TSH) could well be secondary to obesity. The increasing prevalence of obesity further confounds definition of normal TSH range in population studies. Thyroid autoantibody status may help in establishing the diagnosis of subclinical hypothyroidism in obesity. High leptin levels may play a role in the hyperthyrotropinemia of obesity and also increase susceptibility to thyroid autoimmunity and subsequent hypothyroidism. There is at most a modest effect of L-T4 treatment in overt hypothyroidism in inducing weight loss; benefit in subclinical hypothyroidism is not established with no data supporting thyroid hormone use in euthyroid obese patients.
5‐Fluorouracil treatment alters the expression of intestinal transporters in rats

5‐Fluorouracil (5‐FU), an anticancer drug, causes severe gastrointestinal damage, which may affect the absorption of orally administered drugs including the substrates of intestinal uptake and efflux transporters. This study aimed to investigate quantitatively the effect of 5‐FU‐induced intestinal damage on the expression of intestinal transporters: P‐glycoprotein (P‐gp), breast cancer resistance protein (BCRP) and peptide transporter 1 (PEPT1) in rats. The rats were treated with 5‐FU (30 mg/kg/day, p.o.) for 5 days to induce intestinal damage, and then the upper, middle and lower intestinal segments were removed. The mRNA and protein expression levels of these transporters in each segment were determined using quantitative real‐time PCR and Western blotting, respectively. In the 5‐FU‐treated rats, the protein levels of P‐gp and Bcrp in the upper segment were significantly increased to 15‐ and 2.6‐fold of the control, respectively, while those in other segments were unaffected. Pept1 expression was increased by 5‐FU in almost all segments. A remarkable increase in P‐gp expression was shown, the uptake of digoxin, a P‐gp substrate, in each intestinal segment was measured using a rat everted sac. As a result, the uptake of digoxin in the upper segments of 5‐FU‐treated rats was decreased compared with that of the control. In conclusion, 5‐FU‐induced intestinal damage was shown to alter the expression of these transporters, especially in the upper intestinal segment, while the characteristics of the influence varied among the transporters. The 5‐FU‐induced intestinal damage may affect transporter‐mediated drug absorption of orally administered drugs in the clinical setting.
Effects of hot extrusion and heat treatment on microstructure and properties of industrial large-scale spray-deposited 7055 aluminum alloy

The industrial large-scale 7055 aluminum alloy fabricated by spray forming technology was subjected to hot extrusion and heat treatment to achieve high strength and ductility. Microstructure of the as-deposited alloy indicates that higher density billets with equiaxed grains (20–40 μm) were fabricated rather than a typical dendritic microstructure of the as-cast alloy. The grains of the as-extruded alloy exhibit fibrous morphology, the original boundaries disappear and fined second phases with size about 0.5–5 μm distribute along with extrusion direction. Meanwhile, the defects could be eliminated by hot extrusion, which resulted in good strength as well as ductility. The ultimate tensile strength, yield strength and elongation of the as-extruded alloy are 345 MPa, 236 MPa and 18.5%, respectively. After heat treatment, the partial recrystallization is observed around the un-recrystallized grains and sub-grains. And the platelet/rod-shaped precipitates (MgZn2) show a uniform distribution in the matrix alloy. The alloy reaches the maximum tensile strength of 730 MPa after T6 temper treatment, associated with a fine precipitation (MgZn2). However, with further deepen aging degree (from T6 to T73 temper), the size of dominant precipitated phases (MgZn2) grows obviously, the grain boundary precipitates transform from continuous to individual ones and the width of precipitate free zone increases. The result shows that the alloy after T7X temper treatment exhibits higher electrical conductivity (>35 %IACS) and facture toughness (>25.6 MPa m1/2) although a 8%–17% reduction in strength compared with that at T6 temper.
Varicella Prevention in the United States: A Review of Successes and Challenges

OBJECTIVE. In 1995, the United States was the first country to introduce a universal 1-dose childhood varicella vaccination program. In 2006, the US varicella vaccine policy was changed to a routine 2-dose childhood program, with catchup vaccination for older children. The objective of this review was to summarize the US experience with the 1-dose varicella vaccination program, present the evidence considered for the policy change, and outline future challenges of the program. METHODS. We conducted a review of publications identified by searching PubMed for the terms “varicella,” “varicella vaccine,” and “herpes zoster. ” The search was limited to US publications except for herpes zoster; we reviewed all published literature on herpes zoster incidence. RESULTS. A single dose of varicella vaccine was 80% to 85% effective in preventing disease of any severity and >95% effective in preventing severe varicella and had an excellent safety profile. The vaccination program reduced disease incidence by 57% to 90%, hospitalizations by 75% to 88%, deaths by >74%, and direct inpatient and outpatient medical expenditures by 74%. The decline of cases plateaued between 2003 and 2006, and outbreaks continued to occur, even among highly vaccinated school populations. Compared with children who received 1 dose, in 1 clinical trial, 2-dose vaccine recipients developed in a larger proportion antibody titers that were more likely to protect against breakthrough disease and had a 3.3-fold lower risk for breakthrough disease and higher vaccine efficacy. Two studies showed no increase in overall herpes zoster incidence, whereas 2 others showed an increase. CONCLUSIONS. A decade of varicella prevention in the United States has resulted in a dramatic decline in disease; however, even with high vaccination coverage, the effectiveness of 1 dose of vaccine did not generate sufficient population immunity to prevent community transmission. A 2-dose varicella vaccine schedule, therefore, was recommended for children in 2006. Data are inconclusive regarding an effect of the varicella vaccination program on herpes zoster epidemiology.
Pooled Analysis of 2,408 Cases of Acute Adult Purulent Meningitis from Turkey

Objectives: The aim of this study was to systematically review the Turkish literature of acute adult purulent meningitis. Materials and Methods: The published series of three national databases and two international databases were searched to perform the review. In addition to the databases, abstracts of congresses held between 1994 and 2003 by the Turkish Clinical Microbiology and Infectious Diseases Association, Turkish Microbiology Association, and the Antibiotic and Chemotherapy Association were searched for reports about acute purulent meningitis. Results: Data for 2,408 patients with a diagnosis of acute purulent meningitis were obtained from 30 reports. In terms of clinical findings, 1,254 of 1,570 (79.8%) had fever (>38°C), 1,408 of 1,595 (88.2%) headache, 1,403 of 1,562 (89.8%) stiffness of the neck, and 649 of 784 (82.7%) leukocytosis (>10,000/mm3). Cerebrospinal fluid culture yielded a pathogen in 873 of 2,260 (38.6%) patients. The most common pathogen was Streptococcus pneumoniae, followed by Neisseria meningitidis and Staphylococcus aureus. Overall mortality was 425 of 2,408 (17.6%). Pathogen-specific mortality was 60 of 202 (29.7%) for S. pneumoniae and 6 of 100 (6%) for N. meningitidis. Conclusion: Meningitis is a serious, life-threatening disease. More preventive measures should be sought to further decrease the mortality and morbidity related to acute purulent meningitis.
Development of a drug-eluting microstent for micro-invasive glaucoma surgery

Abstract Glaucoma represents the leading cause of irreversible blindness worldwide. Therapeutic approaches are based on the lowering of intraocular pressure (IOP). Micro-invasive glaucoma surgery (MIGS) offers perspectives for implant based IOP-reduction with reduced complication rates compared to conventional surgical approaches. Nevertheless, available devices suffer from complications like hypotony and fibrotic encapsulation. The current work focuses on the development of a minimally invasive implantable drugeluting microstent for the drainage of aqueous humour into suprachoroidal or subconjunctival space. Technical feasibility of a micro-scale resorbable nonwoven for the prevention of hypotony and of a drug-eluting coating for the prevention of fibrosis is assessed. Microstent base bodies with a length of 10 mm and an inner/outer diameter of 0.20 mm / 0.35 mm were manufactured. For the prevention of hypotony, resorbable nonwovens with an adequate flow resistance of 1.543 mmHg/μl min-1 were manufactured in the inflow area of microstents. A drug-eluting coating in the outflow area of microstents was developed based on the model drug fluorescein diacetate. Micro-invasive ab interno implantation of a microstent prototype into suprachoroidal space of a porcine eye post mortem was successfully performed, using an injector device. Future studies will focus on the development of an antifibrotic drug-eluting coating and further in vitro, ex vivo and in vivo testing of the devices.
Textbook of Endocrinology

"ExcEPT ye utter by the tongue words easy to be understood,how shall it be known what is spoken? "(I Corinthians, XIV:9). The author follows the principle of this quotation in his preface for four of the five chaptersof this book. However, he departs from this principle in Chapter IV, although the five chaptersrepresentinformal talks rather than formal text-book descriptions. If Chapter IV is informal we must indeed ask to be saved from tormalttv. It is a pity that the authorslays so much stresson complex immunophysiologicalaspectsin a book devoted mainly to treatment. The pure atoptstswill agree with most of Dr. Hill's theorizing in ChapterIV, but the cynical non-atopists will feel justified in their cynicism after reading this chapter. The first three chaptersare really excellent, however, and show clearly the wide extent of the author's experienceas the former Director of the ·EczemaClinic and the Allergy Clinic at the Children's Medical Centre, Boston. His treatmentis sound and all would agree that admission of children to hospital with infantile eczemamayor may not be a wise procedure. Each, casemust be decidedon its merits. Local treatment combined with sedation and bandagingand with an understanding'of the child's supersensitivenaturewill give relief in most cases. This will help more thanall the skin testsin the world, and Dr. Hill realizes tbis, although he considersskin testing a guide to treatment in some instances. However, mostly It is not justifiable, and all physiciansknow those patientswith multiple sensitivities (as revealed by skin tests) who do not benefit by removal of the specified allergens. Infantile eczemadoes not seemto be a reaction to any specific allergen. The role of such substancesas Dr. Hill suggests appears to be aggravating,not causal.
Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration

Citrobacter rodentium uses a type III secretion system (T3SS) to induce colonic crypt hyperplasia in mice, thereby gaining an edge during its competition with the gut microbiota through an unknown mechanism. Here, we show that by triggering colonic crypt hyperplasia, the C. rodentium T3SS induced an excessive expansion of undifferentiated Ki67-positive epithelial cells, which increased oxygenation of the mucosal surface and drove an aerobic C. rodentium expansion in the colon. Treatment of mice with the γ-secretase inhibitor dibenzazepine to diminish Notch-driven colonic crypt hyperplasia curtailed the fitness advantage conferred by aerobic respiration during C. rodentium infection. We conclude that C. rodentium uses its T3SS to induce histopathological lesions that generate an intestinal microenvironment in which growth of the pathogen is fueled by aerobic respiration.
Digital pathology and anatomic pathology laboratory information system integration to support digital pathology sign-out

Background: The adoption of digital pathology offers benefits over labor-intensive, time-consuming, and error-prone manual processes. However, because most workflow and laboratory transactions are centered around the anatomical pathology laboratory information system (APLIS), adoption of digital pathology ideally requires integration with the APLIS. A digital pathology system (DPS) integrated with the APLIS was recently implemented at our institution for diagnostic use. We demonstrate how such integration supports digital workflow to sign-out anatomical pathology cases. Methods: Workflow begins when pathology cases get accessioned into the APLIS (CoPathPlus). Glass slides from these cases are then digitized (Omnyx VL120 scanner) and automatically uploaded into the DPS (Omnyx; Integrated Digital Pathology (IDP) software v.1. 3). The APLIS transmits case data to the DPS via a publishing web service. The DPS associates scanned images with the correct case using barcode labels on slides and information received from the APLIS. When pathologists remotely open a case in the DPS, additional information (e.g. gross pathology details, prior cases) gets retrieved from the APLIS through a query web service. Results: Following validation of this integration, pathologists at our institution have signed out more than 1000 surgical pathology cases in a production environment. Integration between the APLIS and DPS enabled pathologists to review digital slides while simultaneously having access to pertinent case metadata. The introduction of a digital workflow eliminated costly manual tasks involving matching of glass slides and avoided delays waiting for glass slides to be delivered. Conclusion: Integrating the DPS and APLIS were instrumental for successfully implementing a digital solution at our institution for pathology sign-out. The integration streamlined our digital sign-out workflow, diminished the potential for human error related to matching slides, and improved the sign-out experience for pathologists.
Stability of Mann Iterative Process with Random Errors for the Fixed Point of Strongly-Pseudocontractive Mapping in Arbitrary Banach Spaces

Suppose that X is a arbitrary real Banach space and T : X → X is a Strongly pseudocontractive mapping. It is proved that certain Mann iterative process with random errors for the fixed point of T is stable(almost stable) with respect to T with(without) Lipschitz condition. And, two related results are obtained that deals with stability(or almost stability) of Mann iterative process for solution of nonlinear equations with strongly accretive mapping. Consequently, the corresponding results of Osilike are improved.
Racial IQ Differences among Transracial Adoptees: Fact or Artifact?

Some academic publications infer from studies of transracial adoptees’ IQs that East Asian adoptees raised in the West by Whites have higher IQs than Western Whites, and that White adoptees raised by Whites have higher IQs than Black adoptees raised by Whites. Those publications suggest that this is because genetic differences give East Asians a higher mean IQ than Whites, and Whites a higher mean IQ than Blacks. This paper proposes a parsimonious alternative explanation: the apparent IQ advantage of East Asian adoptees is an artifact caused by ignoring the Flynn effect and adoption’s beneficial effect on IQ, and most of the IQ disadvantage of Black adoptees disappears when one allows for attrition in the Minnesota Transracial Adoption Study, and acknowledges the results of other studies. Diagnosing these artifacts suggests a nil hypothesis: East Asian, White, and Black adoptees raised in the same environment would have similar IQs, hinting at a minimal role for genes in racial IQ differences.