Miracle-dz/UniFAR-FTUs huggingface dataset:
Habitual intake of dietary advanced glycation end products is not associated with generalized microvascular function—the Maastricht Study

ABSTRACT Background Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat. Objectives We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort. Methods In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC–tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light–induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors. Results Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light–induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: −0.04 SD; 95% CI: −0.08, −0.00 SD), the effect sizes were small and their biological relevance can be questioned. Conclusions We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions.
Evaluation of small molecule kinase inhibitors as novel antimicrobial and antibiofilm agents

Antibiotic resistance is a global and pressing concern. Our current therapeutic arsenal is increasingly limited as bacteria are developing resistance at a rate that far outpaces our ability to create new treatments. Novel approaches to treating and curing bacterial infections are urgently needed. Bacterial kinases have been increasingly explored as novel drug targets and are poised for development into novel therapeutic agents to combat bacterial infections. This review describes several general classes of bacterial kinases that play important roles in bacterial growth, antibiotic resistance, and biofilm formation. General features of these kinase classes are discussed and areas of particular interest for the development of inhibitors will be highlighted. Small molecule kinase inhibitors are described and organized by phenotypic effect, spotlighting particularly interesting inhibitors with novel functions and potential therapeutic benefit. Finally, we provide our perspective on the future of bacterial kinase inhibition as a viable strategy to combat bacterial infections and overcome the pressures of increasing antibiotic resistance.
Lens and cornea limit UV vision of birds – a phylogenetic perspective

ABSTRACT Most vertebrates have UV-sensitive vision, but the UV sensitivity of their eyes is limited by the transmittance of the ocular media, and the specific contribution of the different media (cornea, lens) has remained unclear. Here, we describe the transmittance of all ocular media (OMT), as well as that of lenses and corneas of birds. For 66 species belonging to 18 orders, the wavelength at which 50% of light is transmitted through the ocular media to the retina (λT0.5) ranges from 310 to 398 nm. Low λT0. 5 corresponds to more UV light transmitted. Corneal λT0. 5 varies only between 300 and 345 nm, whereas lens λT0. 5 values are more variable (between 315 and 400 nm) and tend to be the limiting factor, determining OMT in the majority of species. OMT λT0. 5 is positively correlated with eye size, but λT0. 5 of corneas and lenses are not correlated with their thickness when controlled for phylogeny. Corneal and lens transmittances do not differ between birds with UV- and violet-sensitive SWS1 opsin when controlling for eye size and phylogeny. Phylogenetic relatedness is a strong predictor of OMT, and ancestral state reconstructions suggest that from ancestral intermediate OMT, highly UV-transparent ocular media (low λT0.5) evolved at least five times in our sample of birds. Some birds have evolved in the opposite direction towards a more UV-opaque lens, possibly owing to pigmentation, likely to mitigate UV damage or reduce chromatic aberration.
On a new piecewise regression model with cure rate: Diagnostics and application to medical data

In this article, we discuss an extension of the classical negative binomial cure rate model with piecewise exponential distribution of the time to event for concurrent causes, which enables the modeling of monotonic and non‐monotonic hazard functions (ie, the shape of the hazard function is not assumed as in traditional parametric models). This approach produces a flexible cure rate model, depending on the choice of time partition. We discuss local influence on this negative binomial power piecewise exponential model. We report on Monte Carlo simulation studies and application of the model to real melanoma and leukemia datasets.
Cyp17a1 is required for female sex determination and male fertility by regulating sex steroid biosynthesis in fish.

In teleost fish, sex steroids are involved in sex determination, sex differentiation, and fertility. Particularly, Cyp17a1 (Cytochrome P450 family 17 subfamily A member 1) is thought to play essential roles in fish steroidogenesis. Therefore, to further understand its roles in steroidogenesis, sex determination, and fertility in fish, we constructed a cyp17a1 gene mutant in Nile tilapia (Oreochromis niloticus). In XX fish, mutation of cyp17a1 gene led to a female-to-male sex reversal with a significant decline in 17β-estradiol (E2) and testosterone (T) production, and ectopic expression of male-biased markers (Dmrt1 and Gsdf) in gonads from the critical window of sex determination. Sex reversal was successfully rescued via T or E2 administration, and ovarian characteristics were maintained after termination of E2 supplementation in the absence of endogenous estrogen production in cyp17a1 -/--XX fish. Likewise, deficiencies in T and 11-KT production in both cyp17a1 -/--XX sex reversed males and cyp17a1 -/--XY mutants resulted in meiotic initiation delays, vas deferens obstruction and sterility due to excessive apoptosis and abnormal mitochondrial morphology. However, 11-KT treatment successfully rescued the dysspermia to produce normal sperm in cyp17a1 -/- male fish. Significant increases in fshβ, lhβ, and gth receptors in cyp17a1 -/- mutants may excessively upregulate steroidogenic gene expression in Leydig cells through a feedback loop. Taken together, our findings demonstrate that Cyp17a1 is indispensable for E2 production, which is fundamental for female sex determination and differentiation in XX tilapia. Additionally, Cyp17a1 is essential for T and 11-KT production, which further promotes spermatogenesis and fertility in XY males.
Co-Occurring Opioid Use and Depressive Disorders: Patient Characteristics and Co-Occurring Health Conditions

Abstract Objective Among persons with opioid use disorder (OUD), co-occurring depression is linked to a greater risk of opioid misuse, overdose and suicide. Less is known about characteristics and other comorbid health conditions of persons with co-occurring opioid use and depressive disorders. Methods This study used electronic health record (EHR) encounters from the Geisinger Health System prior to the fall of 2019. Adult patients were recruited from a medication-based treatment clinic and had an OUD diagnosis (N = 692). Co-occurring depression was defined by a depression diagnosis in the EHR. Multivariable logistic regression was performed to assess differences in characteristics, behavioral health and medical diagnoses, as well as opioid overdose and suicide attempt or ideation between individuals with and without comorbid depression. Results Forty-seven percent of patients with OUD had a lifetime depression diagnosis. Individuals with co-occurring depression were more likely to be female and have comorbid chronic pain or other medical conditions. Co-occurring depression was associated with an increased likelihood of other mental health and substance use disorders, as well as opioid overdose and/or suicide attempt or ideation. Conclusions While it is established that co-occurring depression is associated with increased risk of overdose and suicide, this study adds that other health conditions, including chronic pain and common medical conditions, are more prevalent among persons with co-occurring depressive disorders. Results highlight the need to consider these complex health needs when developing treatment plans and services.
Pulmonary fibrosis in non‐mutation carriers of families with short telomere syndrome gene mutations

Diagnostic and predictive genetic testing for disease cause and risk estimation is common in many countries. For genetic diseases, predictive test results are commonly straightforward: presence of the mutation involves increased risk for disease and absence of the mutation involves no inherit risk for disease. Germline mutations in telomere‐related genes (TRGs) can lead to telomere shortening and are associated with short telomere syndrome (STS). Telomere length is heritable, and in families with STS due to a TRG mutation, progeny with and without the TRG mutation is known to have shorter than average telomeres. We hypothesize that progeny of TRG mutation carriers who did not inherit the TRG mutation may still develop pulmonary fibrosis.
Grhl3 promotes retention of epidermal cells under endocytic stress to maintain epidermal architecture in zebrafish

Epithelia such as epidermis cover large surfaces and are crucial for survival. Maintenance of tissue homeostasis by balancing cell proliferation, cell size, and cell extrusion ensures epidermal integrity. Although the mechanisms of cell extrusion are better understood, how epithelial cells that round up under developmental or perturbed genetic conditions are reintegrated in the epithelium to maintain homeostasis remains unclear. Here, we performed live imaging in zebrafish embryos to show that epidermal cells that round up due to membrane homeostasis defects in the absence of goosepimples/myosinVb (myoVb) function, are reintegrated into the epithelium. Transcriptome analysis and genetic interaction studies suggest that the transcription factor Grainyhead-like 3 (Grhl3) induces the retention of rounded cells by regulating E-cadherin levels. Moreover, Grhl3 facilitates the survival of MyoVb deficient embryos by regulating cell adhesion, cell retention, and epidermal architecture. Our analyses have unraveled a mechanism of retention of rounded cells and its importance in epithelial homeostasis.
Central retinal vein occlusion after mRNA SARS-CoV-2 vaccination: A case report

A central retinal vein occlusion (CRVO) case in a patient developed with sudden blurred vision in some hemifield areas of his left eye, maintaining 20/20 vision 15-days after the COVID-19 vaccination. Initial retinal findings were venous dilation and tortuosity with dispersing dot hemorrhages. Fluorescein angiography (FA) and optical coherence tomography (OCT) confirmed a non-ischemic CRVO diagnosis, and a complete blood panel was requested with average results. An intravitreal steroid dose was applied. A decrease in best-corrected visual acuity (BCVA) (20/30) with more intraretinal hemorrhages was documented. An intravitreal dose of bevacizumab and oral apixaban were added with a final BCVA of 20/20 with decreased hemorrhages. There is no specific causal relationship between COVID-19 vaccines and CRVO. Without previous risk factors and positive treatment response, this case may correlate the first COVID-19 vaccine dose and the event.
Green synthesis of pectin mediated hydroxyapatite nanoparticles from culinary banana bract and its characterization

Green synthesis of hydroxyapatite (HA) nanoparticles was followed using various concentrations of pectin extracted from the culinary banana bract. The effect of pectin concentrations on purity, crystallinity, particle size, and morphology of synthesized HA nanoparticles were studied. The extracted pectin was characterized by proton-1 nuclear magnetic resonance spectroscopy (1H NMR) and Fourier transform infrared (FT-IR) spectroscopy. FT-IR results revealed that increased concentration (0–0.075 % w/w) of pectin substantially improved the purity level of synthesized HA nanoparticles. In addition, higher concentration of pectin also reduced the crystallinity and size of the synthesized HA nanoparticles, which was confirmed by X-ray diffraction (XRD) and SEM results, respectively. The synthesized HA nanoparticles at increased pectin concentration (HA0.075) evinced high purity, less crystallinity, and discrete uniform shape. Results of TEM images have the credence to reveal the presence of nanosized discrete p.
A biallelic SNIP1 Amish founder variant causes a recognizable neurodevelopmental disorder

SNIP1 (Smad nuclear interacting protein 1) is a widely expressed transcriptional suppressor of the TGF-β signal-transduction pathway which plays a key role in human spliceosome function. Here, we describe extensive genetic studies and clinical findings of a complex inherited neurodevelopmental disorder in 35 individuals associated with a SNIP1 NM_024700. 4:c.1097A>G, p.(Glu366Gly) variant, present at high frequency in the Amish community. The cardinal clinical features of the condition include hypotonia, global developmental delay, intellectual disability, seizures, and a characteristic craniofacial appearance. Our gene transcript studies in affected individuals define altered gene expression profiles of a number of molecules with well-defined neurodevelopmental and neuropathological roles, potentially explaining clinical outcomes. Together these data confirm this SNIP1 gene variant as a cause of an autosomal recessive complex neurodevelopmental disorder and provide important insight into the molecular roles of SNIP1, which likely explain the cardinal clinical outcomes in affected individuals, defining potential therapeutic avenues for future research.
Negative-sense RNA viruses: An underexplored platform for examining virus–host lipid interactions

Viruses are pathogenic agents that can infect all varieties of organisms, including plants, animals, and humans. These microscopic particles are genetically simple as they encode a limited number of proteins that undertake a wide range of functions. While structurally distinct, viruses often share common characteristics that have evolved to aid in their infectious life cycles. A commonly underappreciated characteristic of many deadly viruses is a lipid envelope that surrounds their protein and genetic contents. Notably, the lipid envelope is formed from the host cell the virus infects. Lipid-enveloped viruses comprise a diverse range of pathogenic viruses, which often lead to high fatality rates and many lack effective therapeutics and/or vaccines. This perspective primarily focuses on the negative-sense RNA viruses from the order Mononegavirales, which obtain their lipid envelope from the host plasma membrane. Specifically, the perspective highlights the common themes of host cell lipid and membrane biology necessary for virus replication, assembly, and budding.
Factors associated with livebirth in couples undergoing their first in vitro fertilization cycle: An internally validated prediction model

Objective: The aim of the study is to create a new model to predict successful outcome in assisted reproductive techniques. Materials and Methods: A retrospective cohort study was conducted in tertiary fertility center between 2010 and 2017. Nulliparous women younger than 45 years-old undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) for the first time were included; frozen embryo transfers, canceled induction cycles, freeze-all cycles were excluded. Two prediction models were built using multivariate logistic regression with a subset of the dataset and then were internally validated using bootstrapping methods. Results: Four hundred eighty eight women were included with 136 (27.9%) live births. The basal model was built using variable age, antral follicle count (AFC), and basal luteinizing hormone (LH) levels. Age over 37 years [odds ratio (OR): 0.07, 95% confidence interval (CI): 0.00-0.36] and AFC below 5 (OR: 0.15, 95% CI: 0.02-0.53) was associated with poorer outcomes whereas an LH level above 6 mIU/mL (OR: 2.24, 95% CI: 1.27-3.94) was associated with better outcomes. Optimism adjusted area under the curve (AUC) of this model was 0.68 (95% CI: 0.62-0.74). Combined model in addition to basal model variables included the length of induction cycle, the endometrial thickness at the day of transfer, grade and count of the transferred embryo. Cycles lasting more than ten days (OR: 2.23, 95% CI: 1.17-4.42), an endometrial thickness greater than 9 mm (OR: 2.07, 95% CI: 1.00-4.53) were associated with better outcomes. Optimism adjusted AUC of this model was 0.76 (95% CI: 0.70-0.81). Calibration of both models was good according to Hosmer Lemeshow test (p=0.979 and p=0.848, respectively). Conclusion: This internally validated prediction model has good calibration and can be used predicting outcomes in first time IVF/ICSI cycles with modest sensitivity.
Navigating the uncertainty of health advocacy teaching and evaluation from the trainee’s perspective

Abstract Background There may be no competency more shrouded in uncertainty than health advocacy (HA), raising questions about the robustness of advocacy training in postgraduate medical education. By understanding how programs currently train HA, we can identify whether trainees’ learning needs are being met. Methods From 2017 to 2019, we reviewed curricular documents across nine direct-entry specialties at all Ontario medical schools, comparing content for the HA and communicator roles to delineate role-specific challenges. We then conducted semi-structured interviews with trainees (n = 9) and faculty (n = 6) to review findings and discuss their impact. Data were analyzed using thematic content analysis. Results Curricular documents revealed vague objectives and ill-defined modes of assessment for both intrinsic roles. This uncertainty was perceived as more problematic for HA, in part because HA seemed both undervalued in, and disconnected from, clinical learning. Trainees felt that the onus was on them to figure out how to develop and demonstrate HA competence, causing many to turn their learning attention elsewhere. Discussion Lack of curricular focus seems to create the perception that advocacy isn’t valuable, deterring trainees—even those keen to become competent advocates—from developing HA skills. Such ambivalence may have troubling downstream effects for both patient care and trainees’ professional development.
Development and characterization of a soymilk Kefir-based functional beverage

Kefir is a fermented beverage that deserves special attention, since it has probiotic activity and unique sensory, nutritional, and therapeutic properties. Given that both kefir and soymilk are beneficial to human health, this study aimed to assess the physicochemical characteristics and acceptability of soymilk Kefir-based functional beverages (SKB) properly inoculated with lactobacilli strain after 16h of incubation at 37 °C. Ot was monitored lactobacilli cell viability, yeasts count, pH, titratable acidity, lipids, proteins, ash, total solid, carbohydrates, caloric values and acceptability of the products. Additionally was conducted a shelf-life study of SKB added of peach-flavor. The lactobacilli cell count ranged from 7.0 to 8.0 Log 10 CFUmL -1 and pH values from 4.5 to 4.6. SKB samples with higher soymilk kefir percent presented higher lactobacilli cell count and lower lipid, ash, total solid, carbohydrate and caloric value. Results showed similar preferential rates for the SKB up to 30% of added soymilk kefir. The functional peach-flavored beverage presented appropriate pH value (4.3) and high viable cells count (7.0 Log 10 CFUmL -1 ) up to the 28 th day of cold storage, showed high acceptability (94.5%) and positive purchase intention (83.4%) among consumers.
CD137 Costimulation Counteracts TGFβ Inhibition of NK-cell Antitumor Function

TGFβ directly inhibits cytotoxic T and NK lymphocytes in the tumor microenvironment. In this study, CD137 is identified as an actionable target for enhancing NK-cell persistence and function by counteracting TGFβ suppression. Enhancing natural killer (NK) cell–based cancer immunotherapy by overcoming immunosuppression is an area of intensive research. Here, we have demonstrated that the anti-CD137 agonist urelumab can overcome TGFβ-mediated inhibition of human NK-cell proliferation and antitumor function. Transcriptomic, immunophenotypic, and functional analyses showed that CD137 costimulation modified the transcriptional program induced by TGFβ on human NK cells by rescuing their proliferation in response to IL2, preserving their expression of activating receptors (NKG2D) and effector molecules (granzyme B, IFNγ) while allowing the acquisition of tumor-homing/retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGFβ1 and CD137 agonist recovered CCL5 and IFNγ secretion and showed enhanced direct and antibody-dependent cytotoxicity upon restimulation with cancer cells. Trastuzumab treatment of fresh breast carcinoma–derived multicellular cultures induced CD137 expression on tumor-infiltrating CD16+ NK cells, enabling the action of urelumab, which fostered tumor-infiltrating NK cells and recapitulated the enhancement of CCL5 and IFNγ production. Bioinformatic analysis pointed to IFNG as the driver of the association between NK cells and clinical response to trastuzumab in patients with HER2-positive primary breast cancer, highlighting the translational relevance of the CD137 costimulatory axis for enhancing IFNγ production. Our data reveals CD137 as a targetable checkpoint for overturning TGFβ constraints on NK-cell antitumor responses.
Intravenous injection of mesenchymal stem cell spheroids improves the pulmonary delivery and prolongs in vivo survival

Because of the excellent therapeutic potential, mesenchymal stem cells (MSCs) have been used as cell therapeutics for various diseases. However, the survival rate and duration of MSCs after transplantation are extremely low and short, respectively. To solve these problems, in this study, we prepared multicellular spheroids of MSCs and investigated their survival and function after intravenous injection in mice.