Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of Different Bone Grafting Materials and Mesenchymal Stem Cells on Bone Regeneration: A Micro-Computed Tomography and Histomorphometric Study in a Rabbit Calvarial Defect Model

This study evaluated the new bone formation potential of micro–macro biphasic calcium phosphate (MBCP) and Bio-Oss grafting materials with and without dental pulp-derived mesenchymal stem cells (DPSCs) and bone marrow-derived mesenchymal stem cells (BMSCs) in a rabbit calvarial bone defect model. The surface structure of the grafting materials was evaluated using a scanning electron microscope (SEM). The multipotent differentiation characteristics of the DPSCs and BMSCs were assessed. Four circular bone defects were created in the calvarium of 24 rabbits and randomly allocated to eight experimental groups: empty control, MBCP, MBCP+DPSCs, MBCP+BMSCs, Bio-Oss+DPSCs, Bio-Oss+BMSCs, and autogenous bone. A three-dimensional analysis of the new bone formation was performed using micro-computed tomography (micro-CT) and a histological study after 2, 4, and 8 weeks of healing. Homogenously porous structures were observed in both grafting materials. The BMSCs revealed higher osteogenic differentiation capacities, whereas the DPSCs exhibited higher colony-forming units. The micro-CT and histological analysis findings for the new bone formation were consistent. In general, the empty control showed the lowest bone regeneration capacity throughout the experimental period. By contrast, the percentage of new bone formation was the highest in the autogenous bone group after 2 (39.4% ± 4.7%) and 4 weeks (49.7% ± 1.5%) of healing (p < 0.05). MBCP and Bio-Oss could provide osteoconductive support and prevent the collapse of the defect space for new bone formation. In addition, more osteoblastic cells lining the surface of the newly formed bone and bone grafting materials were observed after incorporating the DPSCs and BMSCs. After 8 weeks of healing, the autogenous bone group (54.9% ± 6.1%) showed a higher percentage of new bone formation than the empty control (35.3% ± 0.5%), MBCP (38.3% ± 6.0%), MBCP+DPSC (39.8% ± 5.7%), Bio-Oss (41.3% ± 3.5%), and Bio-Oss+DPSC (42.1% ± 2.7%) groups. Nevertheless, the percentage of new bone formation did not significantly differ between the MBCP+BMSC (47.2% ± 8.3%) and Bio-Oss+BMSC (51.2% ± 9.9%) groups and the autogenous bone group. Our study results demonstrated that autogenous bone is the gold standard. Both the DPSCs and BMSCs enhanced the osteoconductive capacities of MBCP and Bio-Oss. In addition, the efficiency of the BMSCs combined with MBCP and Bio-Oss was comparable to that of the autogenous bone after 8 weeks of healing. These findings provide effective strategies for the improvement of biomaterials and MSC-based bone tissue regeneration.
Core Histones Are Constituents of the Perinuclear Theca of Murid Spermatozoa: An Assessment of Their Synthesis and Assembly during Spermiogenesis and Function after Gametic Fusion

The perinuclear theca (PT) of the eutherian sperm head is a cytoskeletal-like structure that houses proteins involved in important cellular processes during spermiogenesis and fertilization. Building upon our novel discovery of non-nuclear histones in the bovine PT, we sought to investigate whether this PT localization was a conserved feature of eutherian sperm. Employing cell fractionation, immunodetection, mass spectrometry, qPCR, and intracytoplasmic sperm injections (ICSI), we examined the localization, developmental origin, and functional potential of histones from the murid PT. Immunodetection localized histones to the post-acrosomal sheath (PAS) and the perforatorium (PERF) of the PT but showed an absence in the sperm nucleus. MS/MS analysis of selectively extracted PT histones indicated that predominately core histones (i.e., H3, H3.3, H2B, H2A, H2AX, and H4) populate the murid PT. These core histones appear to be de novo-synthesized in round spermatids and assembled via the manchette during spermatid elongation. Mouse ICSI results suggest that early embryonic development is delayed in the absence of PT-derived core histones. Here, we provide evidence that core histones are de novo-synthesized prior to PT assembly and deposited in PT sub-compartments for subsequent involvement in chromatin remodeling of the male pronucleus post-fertilization.
Primary Nephrotic Syndrome and Risks of ESKD, Cardiovascular Events, and Death: The Kaiser Permanente Nephrotic Syndrome Study

Visual Abstract Significance Statement Little population-based data exist about adults with primary nephrotic syndrome and risks of kidney, cardiovascular, and mortality outcomes. In a cohort of 907 adults with nephrologist-confirmed primary nephrotic syndrome attributed to minimal change disease, FSGS, and membranous nephropathy, adjusted rates of ESKD, acute coronary syndrome, heart failure, ischemic stroke, venous thromboembolism, and death were significantly higher than in 89,593 matched adults with no diabetes or known proteinuria. Adults with FSGS had the highest rate of ESKD, followed by adults with membranous nephropathy and adults with minimal change disease. Additional research is needed to understand the mechanisms underlying these excess risks, and population-level identification strategies on the basis of electronic health records should be implemented to identify and optimize personalized care of patients with primary nephrotic syndrome. Background Little population-based data exist about adults with primary nephrotic syndrome. Methods To evaluate kidney, cardiovascular, and mortality outcomes in adults with primary nephrotic syndrome, we identified adults within an integrated health care delivery system (Kaiser Permanente Northern California) with nephrotic-range proteinuria or diagnosed nephrotic syndrome between 1996 and 2012. Nephrologists reviewed medical records for clinical presentation, laboratory findings, and biopsy results to confirm primary nephrotic syndrome and assigned etiology. We identified a 1:100 time-matched cohort of adults without diabetes, diagnosed nephrotic syndrome, or proteinuria as controls to compare rates of ESKD, cardiovascular outcomes, and death through 2014, using multivariable Cox regression. Results We confirmed 907 patients with primary nephrotic syndrome (655 definite and 252 presumed patients with FSGS [40%], membranous nephropathy [40%], and minimal change disease [20%]). Mean age was 49 years; 43% were women. Adults with primary nephrotic syndrome had higher adjusted rates of ESKD (adjusted hazard ratio [aHR], 19.63; 95% confidence interval [95% CI], 12.76 to 30.20), acute coronary syndrome (aHR, 2.58; 95% CI, 1.89 to 3.52), heart failure (aHR, 3.01; 95% CI, 2.16 to 4.19), ischemic stroke (aHR, 1.80; 95% CI, 1.06 to 3.05), venous thromboembolism (aHR, 2.56; 95% CI, 1.35 to 4.85), and death (aHR, 1.34; 95% CI, 1.09 to 1.64) versus controls. Excess ESKD risk was significantly higher for FSGS and membranous nephropathy than for presumed minimal change disease. The three etiologies of primary nephrotic syndrome did not differ significantly in terms of cardiovascular outcomes and death. Conclusions Adults with primary nephrotic syndrome experience higher adjusted rates of ESKD, cardiovascular outcomes, and death, with significant variation by underlying etiology in the risk for developing ESKD.
Rapamycin Plus Doxycycline Combination Affects Growth Arrest and Selective Autophagy-Dependent Cell Death in Breast Cancer Cells

Metabolic alteration is characteristic during tumour growth and therapy; however, targeting metabolic rewiring could overcome therapy resistance. mTOR hyperactivity, autophagy and other metabolic processes, including mitochondrial functions, could be targeted in breast cancer progression. We investigated the growth inhibitory mechanism of rapamycin + doxycycline treatment in human breast cancer model systems. Cell cycle and cell viability, including apoptotic and necrotic cell death, were analysed using flow cytometry, caspase activity measurements and caspase-3 immunostainings. mTOR-, autophagy-, necroptosis-related proteins and treatment-induced morphological alterations were analysed by WesTM, Western blot, immunostainings and transmission electron microscopy. The rapamycin + doxycycline combination decreased tumour proliferation in about 2/3rd of the investigated cell lines. The continuous treatment reduced tumour growth significantly both in vivo and in vitro. The effect after short-term treatment was reversible; however, autophagic vacuoles and degrading mitochondria were detected simultaneously, and the presence of mitophagy was also observed after the long-term rapamycin + doxycycline combination treatment. The rapamycin + doxycycline combination did not cause apoptosis or necrosis/necroptosis, but the alterations in autophagy- and mitochondria-related protein levels (LC3-B-II/I, p62, MitoTracker, TOM20 and certain co-stainings) were correlated to autophagy induction and mitophagy, without mitochondria repopulation. Based on these results, we suggest considering inducing metabolic stress and targeting mTOR hyperactivity and mitochondrial functions in combined anti-cancer treatments.
Production of Functional Buttermilk and Soymilk Using Pediococcus acidilactici BD16 (alaD+)

Functional foods or drinks prepared using lactic acid bacteria (LAB) have recently gained considerable attention because they can offer additional nutritional and health benefits. The present study aimed to develop functional drinks by the fermentation of buttermilk and soymilk preparations using the Pediococcus acidilactici BD16 (alaD+) strain expressing the L-alanine dehydrogenase enzyme. LAB fermentation was carried out for 24 h and its impact on the physicochemical and quality attributes of the fermented drinks was evaluated. Levels of total antioxidants, phenolics, flavonoids, and especially L-alanine enhanced significantly after LAB fermentation. Further, GC-MS-based metabolomic fingerprinting was performed to identify the presence of bioactive metabolites such as 1,2-benzenedicarboxylic acid, 1-dodecene, 2-aminononadecane, 3-octadecene, 4-octen-3-one, acetic acid, azanonane, benzaldehyde, benzoic acid, chloroacetic acid, colchicine, heptadecanenitrile, hexadecanal, quercetin, and triacontane, which could be accountable for the improvement of organoleptic attributes and health benefits of the drinks. Meanwhile, the levels of certain undesirable metabolites such as 1-pentadecene, 2-bromopropionic acid, 8-heptadecene, formic acid, and propionic acid, which impart bitterness, rancidity, and unpleasant odor to the fermented drinks, were reduced considerably after LAB fermentation. This study is probably the first of its kind that highlights the application of P. acidilactici BD16 (alaD+) as a starter culture candidate for the production of functional buttermilk and soymilk.
Lung Ultrasound Examination in Patients with SARS-CoV-2 Infection: Multicenter Study

Background: The COVID-19 pandemic has, by necessity, contributed to rapid advancements in medicine. Owing to the necessity of following strict anti-epidemic sanitary measures when taking care of infected patients, the accessibility of standard diagnostic methods may be limited. Consequently, the significance and potential of bedside diagnostic modalities increase, including lung ultrasound (LUS). Method: Multicenter registry study involving adult patients with confirmed COVID-19, for whom LUS was performed. Results: A total of 228 patients (61% males) qualified for the study. The average age was 60 years (±14), 40% were older than 65 years of age. In 130 from 173 hospitalized patients, HRCT (high-resolution computed tomography) was performed. In 80% of patients, LUS findings indicated interstitial pneumonia. In hospitalized patients multifocally located single B-lines, symmetrical B-lines, and areas of white lung were significantly more frequent as compared to ambulatory patients. LUS findings, both those indicating interstitial syndrome and consolidations, were positively correlated with HRCT images. As compared to HRCT, the sensitivity and specificity of LUS in detecting interstitial pneumonia were 97% and 100%, respectively. Conclusions: As compared to HRCT, LUS is characterized by a very high sensitivity and specificity in detecting interstitial pneumonia in COVID-19 patients. Potentially, LUS can be a particularly useful diagnostic modality for COVID-19 patients pneumonia.
Occurrence of Calcium Oscillations in Human Spermatozoa Is Based on Spatial Signaling Enzymes Distribution

In human spermatozoa, calcium dynamics control most of fertilization events. Progesterone, present in the female reproductive system, can trigger several types of calcium responses, such as low-frequency oscillations. Here we aimed to identify the mechanisms of progesterone-induced calcium signaling in human spermatozoa. Progesterone-induced activation of fluorophore-loaded spermatozoa was studied by fluorescent microscopy. Two computational models were developed to describe the spermatozoa calcium responses: a homogeneous one based on a system of ordinary differential equations and a three-dimensional one with added space dimensions and diffusion for the cytosolic species. In response to progesterone, three types of calcium responses were observed in human spermatozoa: a single transient rise of calcium concentration in cytosol, a steady elevation, or low-frequency oscillations. The homogenous model provided qualitative description of the oscillatory and the single spike responses, while the three-dimensional model captured the calcium peak shape and the frequency of calcium oscillations. The model analysis demonstrated that an increase in the calcium diffusion coefficient resulted in the disappearance of the calcium oscillations. Additionally, in silico analysis suggested that the spatial distribution of calcium signaling enzymes governs the appearance of calcium oscillations in progesterone-activated human spermatozoa.
Moderate–Vigorous Physical Activity and Clinical Outcomes in Adults with Nondialysis Chronic Kidney Disease

The health benefits of physical activity (PA) are well known. However, the association between an adequate amount of moderate–vigorous PA (MVPA) and clinical outcomes has limited evidence in chronic kidney disease (CKD). We assessed PA using a self-administered questionnaire. The amount of MVPA was categorized into four groups: none, low, moderate, and high (0, <7.5, 7.5–14.9, and 15.0–29.9 metabolic equivalent-hours/week, respectively). We analyzed the association between the amount of MVPA and clinical outcomes. Among a total of 1909 adults with CKD, adults with MVPA showed various beneficial outcomes compared to those with no MVPA in a Kaplan–Meier curve followed over a median of 5.9 years. In multivariable-adjusted Cox proportional hazard models, a low and a moderate amount of MVPA was associated with a lower risk of all-cause death. A moderate amount of MVPA was associated with a lower risk of cardiovascular events. A high amount of MVPA was associated with a lower risk of end-stage kidney disease in ESKD in 1324 adults with eGFR <60 mL/min/1.73 m2. Age and sex modified the relationships between MVPA and clinical outcomes. MVPA is associated with various beneficial outcomes across the amount of MVPA. PA plans should be tailored for individual adults with CKD.
Effects of Transcatheter Mitral Valve Repair Using MitraClip® Device on Sleep Disordered Breathing in Patients with Mitral Valve Regurgitation

Sleep disordered breathing (SDB) is common among patients with valvular heart disease, and successful valve surgery could reduce SDB severity. However, data about the effects of transcatheter mitral valve repair on SDB are scarce. Therefore, mitral regurgitation (MR) patients undergoing MitraClip-placement were prospectively enrolled. Before MitraClip-placement, daytime sleepiness and sleep quality were assessed using the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI), respectively; and all patients underwent SDB screening using five-channel respiratory polygraphy. After 3–6 months, patients had a similar reassessment including: ESS, PSQI, and respiratory polygraphy. 67 patients were included (77 ± 8years). Despite normal sleepiness scores, 41 patients (61%) had SDB with apnea-hypopnea-index (AHI) ≥ 15 h before MitraClip-placement, of whom only three patients had known SDB previously. Compared to patients without SDB, patients with SDB had similar sleepiness scores but higher NT-proBNP values at baseline (4325 vs. 1520 pg/mL, p < 0.001). At follow-up, there were significant AHI improvements among patients with SDB (p = 0.013). However, there were no significant sleepiness score changes. In conclusion, the prevalence of SDB among MitraClip candidates is very high even in those without daytime sleepiness. MR patients with SDB have higher NT-proBNP values, which may reflect a worse prognosis. MitraClip-placement may improve the underlying SDB, which could be an additional benefit of the procedure.
Germacranolides from Carpesium divaricatum: Some New Data on Cytotoxic and Anti-Inflammatory Activity

Carpesium divaricatum Sieb. & Zucc. , a traditional medicinal plant used as an inflammation-relieving remedy, is a rich source of terpenoids. At least 40 germacrane-type sesquiterpene lactones, representatives of four different structural groups, were isolated from the plant. Cytotoxicity against cancer cells in vitro is the most frequently described biological activity of the compounds. However, little is known about the selectivity of the cytotoxic effect. The anti-inflammatory activity of the germacranolides is also poorly documented. The objective of the present study was to assess the cytotoxic activity of selected C. divaricatum germacranolides-derivatives of 4,5,8,9-tetrahydroxy-3-oxo-germacran-6,12-olide towards cancer and normal cell lines (including cells of different p53 status). Moreover, to assess the anti-inflammatory effect of the compounds, the release of four proinflammatory cytokines/chemokines (IL-1β, IL-8, TNF-α and CCL2) by lipopolysaccharide-stimulated human neutrophils was measured by ELISA. The investigated sesquiterpene lactones demonstrated nonselective activity towards prostate cancer (Du145 and PC3) and normal prostate epithelial cells (PNT2) as well as against melanoma cells (A375 and HTB140) and keratinocytes (HaCaT). Cytotoxic activity against osteosarcoma cells was independent of their p53 status. In sub-cytotoxic concentrations (0.5–2.5 µM) the studied compounds significantly decreased cytokine/chemokine release by lipopolysaccharide-stimulated human leukocytes.
IFP35 family proteins promote neuroinflammation and multiple sclerosis

Significance Multiple sclerosis (MS) is a complex neuroinflammatory disorder that constitutes the major cause of nontraumatic disability in young adults. However, the underlying mechanism of this disease remains obscure. Here, we identified NMI and IFP35 as factors critical in the progress of MS and experimental autoimmune encephalomyelitis, as their dysregulation activates both microglia in the central nervous system and T cells in the periphery. This study expands our understanding of the pathogenesis of MS and aims to provide potential diagnostic and therapeutic targets. Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B–dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naïve T cell differentiation into Th1 and Th17 cells. Nmi−/−, Ifp35−/−, or administration of neutralizing antibodies against IFP35 alleviated the immune cells’ infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS.
1T-MoS2 Coordinated Bimetal Atoms as Active Centers to Facilitate Hydrogen Generation

Anchoring single metal atoms has been demonstrated as an effective strategy to boost the catalytic performance of non-noble metal 1T-MoS2 towards hydrogen evolution reaction (HER). However, the dual active sites on 1T-MoS2 still remain a great challenge. Here, first-principles calculations were performed to systematically investigate the electrocatalytic HER activity of single and dual transition metal (TM) atoms bound to the 1T-MoS2 monolayer (TM@1T-MoS2). The resulted Ti@1T-MoS2 exhibits excellent structural stability, near-thermoneutral adsorption of H* and ultralow reaction barrier (0.15 eV). It is a promising single metal atom catalyst for HER, outperformed the reported Co, Ni and Pd anchoring species. Surprisingly, by further introducing Pd atoms coordinated with S atoms or S vacancies on the Ti@1T-MoS2 surface, the resulted catalyst not only maintains the high HER activity of Ti sites, but also achieves new dual active moiety due to the appropriate H* adsorption free energy on Pd sites. This work is of great significance for realizing dual active centers on 1T-MoS2 nanosheets and offers new thought for developing high-performance electrocatalysts for HER.
Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for the treatment of FLT3-mutated AML. However, treatment response to FLT3 inhibitors may be short-lived, and resistance may emerge. Compounds targeting STAT5 may enhance and prolong effects of FLT3 inhibitors in this subset of patients with FLT3-mutated AML. Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inhibitor PTC596, MEK-inhibitor trametinib, MCL1-inhibitor S63845, and BCL-2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Synergistic effects on cell viability were detected in both FLT3-mutated and FLT3-wild-type AML cells treated with AC-4-130 in combination with the MCL1 inhibitor S63845. AML patient samples with a strong response to AC-4-130 and S63845 combination treatment were characterized by mutated FLT3 or mutated TET2 genes. Susceptibility of AML cells to AC-4-130, PTC596, trametinib, PKC412, and venetoclax was altered in the presence of HS-5 stroma. Only the MCL1 inhibitor S63845 induced cell death with equal efficacy in the absence or presence of bone marrow stroma. The combination of the STAT5-inhibitor AC-4-130 and the MCL1 inhibitor S63845 may be an effective treatment targeting FLT3-mutated or TET2-mutated AML.