Miracle-dz/UniFAR-FTUs huggingface dataset:
SOX10-Cre-labeled Cells under the Tongue Epithelium Serve as Progenitors for Taste Bud Cells That Are Mainly Type III and Keratin 8-Low.

Taste bud cells are specialized epithelial cells that undergo continuous turnover, and thus require active progenitors for their renewal and an intact taste function. Our previous studies suggested that a population of taste bud cells originates from outside of the surrounding tongue epithelium - previously regarded sole source of taste bud progenitors. In this study, we demonstrated that SOX10-expressing cells, known to be in the migrating neural crest, were also distributed in taste bud-surrounding tissue compartments under the tongue epithelium, i.e., the connective tissue core of taste papillae and von Ebner's glands. By lineage tracing of SOX10-expressing cells using SOX10-Cre, a Cre model driven by the endogenous SOX10 promoter, crossing with a Cre reporter line R26-tdTomato (tdT), we found SOX10-Cre-labeled tdT+ cells within taste buds in all three types of taste papillae (fungiform, circumvallate, and foliate) as well as in the soft palate in postnatal mice. The tdT+ taste bud cells were progressively more abundant along the developmental stages, from virtually zero at birth to over 35% in adults. Most of tdT+ taste bud cells had a low intensity of immunosignals of Keratin 8 (a widely used taste bud cell marker). In circumvallate taste buds, tdT signals were co-localized principally with a type III taste bud cell marker, less so with type I and II cell makers. Together, our data demonstrate a novel progenitor source for taste buds of postnatal mice -- SOX10-Cre-labeled cells in the connective tissue core and/or von Ebner's glands.
Dabigatran Treatment of Acute Noncardioembolic Ischemic Stroke

Supplemental Digital Content is available in the text. Background and Purpose— Patients with transient ischemic attack (TIA) and minor ischemic stroke are at risk for early recurrent cerebral ischemia. Anticoagulants are associated with reduced recurrence but also increased hemorrhagic transformation (HT). The safety of the novel oral anticoagulant dabigatran in acute stroke has not been evaluated. Methods— DATAS II (Dabigatran Treatment of Acute Stroke II) was a phase II prospective, randomized open label, blinded end point trial. Patients with noncardioembolic stroke/transient ischemic attack (National Institutes of Health Stroke Scale score, ≤9; infarct volume, ≤25 mL) were randomized to dabigatran or aspirin. Magnetic resonance imaging was performed before randomization and repeated at day 30. Imaging end points were ascertained centrally by readers blinded to treatment. The primary end point was symptomatic HT within 37 days of randomization. Results— A total of 305 patients, mean age 66.59±13.21 years, were randomized to dabigatran or aspirin a mean of 42.00±17.31 hours after symptom onset. The qualifying event was a transient ischemic attack in 21%, and ischemic stroke in 79% of patients. Median National Institutes of Health Stroke Scale (interquartile range) was 1 (0–2), and mean infarct volume 3.2±6.5 mL. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (relative risk, 2.301 [95% CI, 0.778–6.802]). Baseline infarct volume predicted incident HT (odds ratio, 1.07 [95% CI, 1.03–1.12]; P=0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran-assigned and 14/142 (9.8%) of aspirin-assigned patients (relative risk, 0.62 [95% CI, 0.26, 1.48]). Conclusions— Dabigatran was associated with a risk of HT similar to aspirin in acute minor noncardioembolic ischemic stroke/transient ischemic attack. Registration— URL: https://www.clinicaltrials. gov; Unique identifier: NCT02295826.
Methylation of Daptomycin Leading to the Discovery of Kynomycin, a Cyclic Lipodepsipeptide Active Against Resistant Pathogens.

Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the non-proteinogenic amino acid kynurenine in daptomycin could result in significant enhancement of antibacterial activity. Termed 'kynomycin', this new antibiotic exhibits higher antibacterial activity than daptomycin and is able to eradicate MRSA and VRE strains, including daptomycin-resistant strains. The improved antimicrobial activity of kynomycin was demonstrated in in vitro time killing assay, in vivo wax worm model and different mouse infection models. The increased antibacterial activity, improved pharmacokinetics and lower cytotoxicity of kynomycin, compared to daptomycin, showed the promise of the future design and development of next-generation daptomycin-based antibiotics.
Evaluation of laser scanning confocal microscopy as a method for characterizing reef-building coral tissue thickness and Symbiodiniaceae fluorescence

ABSTRACT Predicting the sensitivity of reef-building corals to disturbance, including bleaching, requires an understanding of physiological responses to stressors, which may be limited by destructive sampling and the capacity of common methodologies to characterize early life history stages. We developed a new methodology using laser scanning confocal microscopy (LSCM) to measure and track the physiological condition of corals. In a thermal stress experiment, we used LSCM to track coral condition during bleaching in adults and juveniles of two species, Montipora capitata and Pocillopora acuta. Depth of fluorescence in coral tissues provides a proxy measure of tissue thickness, whereas Symbiodiniaceae population fluorescence relates to both population density and chlorophyll a content. In response to thermal stress, there were significant shifts in tissue thickness and Symbiodiniaceae fluorescence with differences between life stages. This method is particularly well suited for detecting shifts in physiological condition of living corals in laboratory studies, especially in small juvenile colonies. Summary: Description and evaluation of the utility of laser scanning confocal microscopy to measure physiological condition (Symbiodiniaceae fluorescence and tissue thickness) in reef-building corals.
Inactivation of NF1 Promotes Resistance to EGFR Inhibition in KRAS/NRAS/BRAFV600-Wild-Type Colorectal Cancer

Through the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in NRAS/KRAS/BRAFV600-wild-type colorectal cancer cells. Reduced NF1 expression permitted sustained signaling through the MAPK pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition leads to synergistic antiproliferative activity. Human KRAS/NRAS/BRAFV600-wild-type colorectal cancer cell lines with NF1 mutations displayed reduced NF1 mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in PTEN were associated with resistance to dual EGFR/MEK inhibition but cotreatment with a PI3K inhibitor further suppressed proliferation. Loss of NF1 may be a useful biomarker to identify patients that are less likely to benefit from single-agent anti-EGFR therapy in colorectal cancer and may direct potential combination strategies. Implications: This study suggests that further clinical validation of NF1 status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with KRAS/NRAS/BRAFV600-wild-type tumors is warranted.
The human factor: does the operator performing the embryo transfer significantly impact the cycle outcome?

Abstract STUDY QUESTION Is Ongoing Pregnancy Rate (OPR) operator-dependent, and can experience improve embryo transfer efficiency? SUMMARY ANSWER OPR is influenced by the operators who perform the embryo transfer (ET), and experience does not assure proficiency for everyone. WHAT IS KNOWN ALREADY ET remains the critical step in assisted reproduction. Although many other factors such as embryo quality and uterine receptivity impact embryo implantation, the proper ET technique is clearly an operator-dependent variable and as such it should be objectively standardized. STUDY DESIGN, SIZE, DURATION Retrospective comparative analysis including all fresh ETs performed between January 1996 and December 2016 at the Humanitas Fertility Center after IVF—ICSI cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS IVF/ICSI fresh ETs performed by 32 operators, 19 824 cycles in all, were analyzed. All transfers consisting of freehand insertion of a preloaded soft catheter into the uterine cavity under transabdominal ultrasound guidance were considered. Two different statistical analyses were performed. First, a logistic regression model with a random intercept for the operator was used to estimate the heterogeneity of the rate of success among operators, accounting for woman age, FSH, number of oocytes retrieved, fertilization rate, year of the procedure, number and stage of transferred embryos and operator’s experience. Second, the relationship between experience and pregnancy rate was estimated separately for each operator by logistic regression, and operator-specific results were combined and compared in a random-effects meta-analysis. In both analyses, the operator’s experience at time t was measured in terms of number of embryo transfers performed before t. MAIN RESULTS AND THE ROLE OF CHANCE The heterogeneity among operators was highly significant (P value <0.001) and explained 44.5% of the total variability. The odds ratio of success of the worst operator in respect to the mean was equal to 0.84. For the best operator, the odds ratio of success was equal to 1.13 in respect to the mean. Based on the meta-analysis of the relationship between operator’s experience and success rate, it resulted that, on average, the operators’ performance did not improve with additional transfers. LIMITATIONS, REASONS FOR CAUTION At our center, operators become independent for ET’s after performing between 30 and 50 transfers under supervision. It is also possible that other relevant factors, such as embryologists on duty for the ET, have not been included in the present analysis and this may represent a potential bias. Among these, it should be mentioned that the embryologists on duty for the ET were not taken into consideration. WIDER IMPLICATIONS OF THE FINDINGS Continued performance analysis and the use of a digital simulator could help operators to test their expertise over time and either correct poor performance or avoid doing transfers. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER NCT03561129.
A 21‐Month‐Old Boy with One‐Month History of Vomiting

1 Department of Hematology/Oncology, Saitama Children’s Medical Center, Saitama, Japan. 2 Department of Clinical Laboratory, Saitama Children’s Medical Center, Saitama, Japan. 3 Department of Pathology, Gunma University Hospital, Maebashi, Japan. 4 Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan. 5 Department of Neurosurgery, Saitama Children’s Medical Center, Saitama, Japan. 6 Department of Radiology, Saitama Children’s Medical Center, Saitama, Japan.
rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application

Over the last decade, pioneering molecular gene therapy for inner-ear disorders have achieved experimental hearing improvements after a single local or systemic injection of adeno-associated, virus-derived vectors (rAAV for recombinant AAV) encoding an extra copy of a normal gene, or ribozymes used to modify a genome. These results hold promise for treating congenital or later-onset hearing loss resulting from monogenic disorders with gene therapy approaches in patients. In this review, we summarize the current state of rAAV-mediated inner-ear gene therapies including the choice of vectors and delivery routes, and discuss the prospects and obstacles for the future development of efficient clinical rAAV-mediated cochlear gene medicine therapy.
Inflammatory and stress markers predicting pneumonia, outcome, and etiology in patients with stroke

Objective Prognosis of stroke is negatively affected by complications, in particular stroke-associated pneumonia (SAP). We hypothesized that inflammatory and stress biomarkers predict SAP during hospitalization and outcome 3 months after stroke. Methods We pooled the clinical data of 2 acute stroke studies with identical assessment: the STRoke Adverse outcome is associated WIth NoSoKomial Infections (STRAWINSKI) and PREDICT studies. Measurement of biomarkers (ultrasensitive procalcitonin [PCTus]; midregional pro-adrenomedullin; midregional pro-atrial natriuretic peptide [MRproANP]; ultrasensitive copeptin [CPus]; C-terminal pro-endothelin) was performed from serum samples drawn on the first 4 days of hospital admission. Results The combined cohort consists of 573 cases with available backup samples to perform the analysis. SAP was associated with increased admission and maximum levels of all biomarkers. Furthermore, all biomarkers were associated with death and correlated with functional outcome 3 months after stroke. The multivariate logistic regression model retained ultrasensitive CPus and PCTus beyond clinical risk factors for predicting SAP, improving the receiver operating characteristic area under the curve (AUC) from 0.837 to 0.876. In contrast, the biomarkers did not improve the prediction of death and functional outcome in the multivariate model. Cardioembolic strokes were significantly associated with higher values of all biomarkers, whereas discrimination was best for MRproANP (AUC = 0.811 for maximum value). Conclusions The tested biomarkers are associated with SAP and poor functional outcome. However, these biomarkers only slightly improve prediction of SAP and do not improve long-term outcome prediction over clinical parameters. MRproANP showed the best discrimination for identifying cardioembolic stroke, warranting further studies to confirm our finding. Clinical trial registration clinicaltrials.gov NCT01264549 and NCT01079728.
Dietary Habits of Saharawi Type II Diabetic Women Living in Algerian Refugee Camps: Relationship with Nutritional Status and Glycemic Profile

Diabetes is one of the main health problems among Saharawi refugees living in Algerian camps, especially for women. As is known, diet plays an important role in the management of diabetes. However, the dietary habits of Saharawi diabetic women are unknown. Therefore, we investigated the dietary habits and established their relationship with the nutritional status and glycemic profile of such women. We recruited 65 Saharawi type II diabetic women taking orally glucose-lowering drugs only. Dietary habits were investigated using qualitative 24 h recall carried out over three non-consecutive days. Anthropometric measurements were taken and blood parameters were measured. About 80% of the women were overweight and about three out of four women had uncompensated diabetes and were insulin resistant. The Saharawi diet was found to mainly include cereals, oils, sugars, vegetables (especially onions, tomatoes, and carrots), tea, and meat. Principal component analysis identified two major dietary patterns, the first one “healthy” and the second one “unhealthy”. Women in the higher tertile of adherence to the unhealthy dietary pattern had a higher homeostatic model assessment for insulin resistance (HOMA) index (b = 2.49; 95% CI: 0.41–4.57; p = 0.02) and circulating insulin (b = 4.52; 95% CI: 0.44–8.60; p = 0.03) than the women in the lowest tertile. Food policies should be oriented to improve the quality of diet of Saharawi diabetic women.
Developing Nanostructured Ti Alloys for Innovative Implantable Medical Devices

Recent years have witnessed much progress in medical device manufacturing and the needs of the medical industry urges modern nanomaterials science to develop novel approaches for improving the properties of existing biomaterials. One of the ways to enhance the material properties is their nanostructuring by using severe plastic deformation (SPD) techniques. For medical devices, such properties include increased strength and fatigue life, and this determines nanostructured Ti and Ti alloys to be an excellent choice for the engineering of implants with improved design for orthopedics and dentistry. Various reported studies conducted in this field enable the fabrication of medical devices with enhanced functionality. This paper reviews recent development in the field of nanostructured Ti-based materials and provides examples of the use of ultra-fine grained Ti alloys in medicine.
Visual determinants of prey chasing behavior in a mudflat crab

ABSTRACT The crab Neohelice granulata inhabits mudflats where it is preyed upon by gulls and, conversely, preys on smaller crabs. Therefore, on seeing moving stimuli, this crab can behave as prey or predator. The crab escape response to visual stimuli has been extensively investigated from the behavioral to the neuronal level. The predatory response (PR), however, has not yet been explored. Here, we show that this response can be reliably elicited and investigated in a laboratory arena. By using dummies of three different sizes moved on the ground at three different velocities over multiple trials, we identified important stimulation conditions that boost the occurrence of PR and its chances of ending in successful prey capture. PR probability was sustained during the first 10 trials of our experiments but then declined. PR was elicited with high probability by the medium size dummy, less effectively by the small dummy, and hardly brought about by the large dummy, which mostly elicited avoidance responses. A GLMM analysis indicated that the dummy size and the tracking line distance were two strong determinants for eliciting PR. The rate of successful captures, however, mainly depended on the dummy velocity. Our results suggest that crabs are capable of assessing the distance to the dummy and its absolute size. The PR characterized here, in connection with the substantial knowledge of the visual processing associated with the escape response, provides excellent opportunities for comparative analyses of the organization of two distinct visually guided behaviors in a single animal. Summary: The crab Neohelice chases after smaller crabs; manipulating prey dummies in the lab allowed identification of a combination of visual features that guide the crab's predatory behavior.
Volumetric mapping of the functional neuroanatomy of the respiratory network in the perfused brainstem preparation of rats

The functional neuroanatomy of the mammalian respiratory network is far from being understood since experimental tools that measure neural activity across this brainstem‐wide circuit are lacking. Here, we use silicon multi‐electrode arrays to record respiratory local field potentials (rLFPs) from 196–364 electrode sites within 8–10 mm3 of brainstem tissue in single arterially perfused brainstem preparations with respect to the ongoing respiratory motor pattern of inspiration (I), post‐inspiration (PI) and late‐expiration (E2). rLFPs peaked specifically at the three respiratory phase transitions, E2–I, I–PI and PI–E2. We show, for the first time, that only the I–PI transition engages a brainstem‐wide network, and that rLFPs during the PI–E2 transition identify a hitherto unknown role for the dorsal respiratory group. Volumetric mapping of pontomedullary rLFPs in single preparations could become a reliable tool for assessing the functional neuroanatomy of the respiratory network in health and disease.
Atrial Fibrillation-Associated Ischemic Stroke Patients With Prior Anticoagulation Have Higher Risk for Recurrent Stroke

Supplemental Digital Content is available in the text. Background and Purpose— Ischemic stroke associated with nonvalvular atrial fibrillation (NVAF) despite prior anticoagulation may indicate underlying problems that nullify the stroke-preventing effects of oral anticoagulants. We aimed to evaluate the risk for recurrent stroke in patients with NVAF with prior anticoagulation, compared with that in patients without prior anticoagulation. Methods— This study comprised pooled individual patient data on NVAF-associated acute ischemic stroke or transient ischemic attack from 2011 to 2014 arising from the Clinical Research Collaboration for Stroke in Korea (15 South Korean stroke centers) and the Stroke Acute Management With Urgent Risk-Factor Assessment and Improvement-NVAF registry (18 Japanese stroke centers). Data on 4841 eligible patients from the Clinical Research Collaboration for Stroke in Korea registry were pooled with data on all patients (n=1192) in the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-NVAF registry. The primary outcome was recurrent ischemic stroke. The secondary outcomes were hemorrhagic stroke and all-cause death. Outcome events were captured up to 1 year after the index event. Results— Among the 6033 patients in the full cohort, 5645 patients were analyzed, of whom 1129 patients (20.0%) had received prior anticoagulation. Median age was 75 years (interquartile range, 69–81 years), and 2649 patients (46.9%) were women. Follow-up data of 4617 patient-years (median follow-up 365 days, interquartile range 335–365 days) were available. The cumulative incidence of recurrent ischemic stroke in patients with prior anticoagulation was 5.3% (60/1129), compared with the 2.9% (130/4516) incidence in patients without prior anticoagulation. The risk for recurrent ischemic stroke was higher in patients with prior anticoagulation than in those without (multivariable Cox shared-frailty model, hazard ratio 1.50 [95% CI, 1.02–2.21]). No significant differences in the risks for hemorrhagic stroke and mortality were seen between the 2 groups. Conclusions— The risk for recurrent ischemic stroke may be higher in NVAF-associated stroke patients with prior anticoagulation than in those without prior anticoagulation. Registration— URL: https://www.clinicaltrials. gov; Unique identifier: NCT01581502.
Risk Factors Associated with Carious Lesions in Permanent First Molars in Children: A Seven-Year Retrospective Cohort Study

The aim of this study was to evaluate the risk factors associated with the occurrence of caries in permanent teeth (PT) and in the permanent first molar (PFM) seven years after their eruption. Children born in 2005 who were enrolled in a Community Dental Program were included. A total of 278 children were enrolled. Evaluated risk factors were parental caries experience, educational level of the mother, routine medications, systemic diseases, dietary habits, toothbrushing frequency, existence of molar incisor hypomineralization (MIH) in the PT, and caries in the temporary teeth (TT). Associations between independent variables and the DMF-T (decayed, missing, and filled teeth in PT) and DMF-M (DMF in PFM) indices, only considering cavitated and non-cavitated carious lesions or cavitated carious lesions as outcomes, were evaluated by Poisson regression with robust variance analysis. A cariogenic diet (sweets and soft drinks), toothbrushing frequency of <1 a day, a presence of df-t (decayed and filled temporary teeth) score of >0, low educational level of the mother, and existence of MIH were associated with high DMF-T or DMF-M values (p < 0.05). We can conclude that the intake of sweets and soft drinks, toothbrushing frequency, the presence of caries in TT, and MIH in PT were the best predictors of the occurrence of caries in PT and PFM.