Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel BMP1, CRTAP, and SERPINF1 variants causing autosomal recessive osteogenesis imperfecta

Dear Editor, Most patients with osteogenesis imperfecta (OI) have COL1A1 or COL1A2 variants. However, OI with autosomal recessive (AR) inheritance are uncommon. Here, we reported three unrelated AR-OI patients and, with parental written consent, successfully identified six pathogenic alleles in BMP1, CRTAP, or SERPINF1. Patient-1, a 6-year-old boy born to non-consanguineous parents, began having fractures of both humeri and right femur at 3 months old. At 3 years old, he had experienced more than 10 fractures involving femurs, humeri, and vertebrae. Radiographs demonstrated multiple fractures and long bone and vertebrae deformities (Figure 1A–C), and intravenous pamidronate was started that resulted in no further fractures. At age 6, he had a small head (head circumference [HC] 47 cm, <3rd percentile), dentinogenesis imperfecta, with normal sclerae and hearing. He could not walk due to leg deformities. Next generation sequencing (NGS) revealed that he was compound heterozygous for c.584dupG, p.(Gln197Profs*10) (SCV001960983,ACMG:PVS1,PM2) and c.965G>A, p.(Cys322Tyr) (SCV001960984,ACMG:PM1,PM2,PP2, PP3) in BMP1 (NM_006129.5), indicating OI type XIII (Figure 1D). Both variants affect BMP1 and mammalian tolloid protein (mTLD) isoforms. Variants affecting both isoforms have more severe phenotypes than those affecting one. Similar to previous observations that most BMP1 individuals had fewer fractures after being treated with bisphosphonate, Patient-1 responded well. Patient-2, a 7-year-old girl born to consanguineous parents, had bowed femurs antenatally. Multiple fractures were found at birth and a
The creation of radiation and the relic of inflaton potential

Recently, we have performed research on the subject of the cosmological constant problem. The scenario is based on two postulates for inflationary theory: one is that inflaton $\phi$ can interact with radiation (relativistic particles); the other is that radiation will be created continuously during and after the epoch of inflation. According to these postulates and from a "macroscopic perspective", we discover that radiation can be viewed as a product of the interaction between $\dot{\phi}$ and some "effective kinetic frictional force" that exists in inflaton dynamics. Deducing and surmising from "effective friction", we obtain conclusions of two special types of expanding universe: A Type I universe will finally enter an expanding course after a special time $t_{*}$ with uniformly rolling $\dot{\phi}(t_{*})$ due to the balance between $V^{'}(\phi(t))$, 3H(t)\dot{\phi}(t_{*}) and the "effective kinetic frictional force". In this result, the expanding course will see particles created continuously. Additionally, for a Type II universe, $\phi$ will be at rest after $t_{r}$ inside a region named the "stagnant zone" that is formed by the "maximum effective static frictional force". Consistent with this, inflaton potential will survive as a relic $V(\phi(t_{r}))$, playing the role of the effective cosmological constant $\Lambda$ .
A tunable gelatin-hyaluronan dialdehyde/methacryloyl gelatin interpenetrating polymer network hydrogel for additive tissue manufacturing

Methacryloyl gelatin (GelMA) is a versatile material for bioprinting because of its tunable physical properties and inherent bioactivity. Bioprinting of GelMA is often met with challenges such as lower viscosity of GelMA inks due to higher methacryloyl substitution and longer physical gelation time at room temperature. In this study, a tunable interpenetrating polymer network (IPN) hydrogel was prepared from gelatin-hyaluronan dialdehyde (Gel-HDA) Schiff’s polymer, and 100% methacrylamide substituted GelMA for biofabrication through extrusion based bioprinting. Temperature sweep rheology measurements show a higher sol-gel transition temperature for IPN (30 °C) compared to gold standard GelMA (27 °C). Furthermore, to determine the tunability of the IPN hydrogel, several IPN samples were prepared by combining different ratios of Gel-HDA and GelMA achieving a compressive modulus ranging from 20.6 ± 2.48 KPa to 116.7 ± 14.80 KPa. Our results showed that the mechanical properties and printability at room temperature could be tuned by adjusting the ratios of GelMA and Gel-HDA. To evaluate cell response to the material, MC3T3-E1 mouse pre-osteoblast cells were embedded in hydrogels and 3D-printed, demonstrating excellent cell viability and proliferation after 10 d of 3D in vitro culture, making the IPN an interesting bioink for the fabrication of 3D constructs for tissue engineering applications.
Waitlist mortality of young patients with biliary atresia: Impact of allocation policy and living donor liver transplantation

Patients with biliary atresia (BA) below 2 years of age in need of a transplantation largely rely on partial grafts from deceased donors (deceased donor liver transplantation [DDLT]) or living donors (living donor liver transplantation [LDLT]). Because of high waitlist mortality in especially young patients with BA, the Eurotransplant Liver Intestine Advisory Committee (ELIAC) has further prioritized patients with BA listed before their second birthday for allocation of a deceased donor liver since 2014. We evaluated whether this Eurotransplant (ET) allocation prioritization changed the waitlist mortality of young patients with BA. We used a pre–post cohort study design with the implementation of the new allocation rule between the two periods. Participants were patients with BA younger than 2 years who were listed for liver transplantation in the ET database between 2001 and 2018. Competing risk analyses were performed to assess waitlist mortality in the first 2 years after listing. We analyzed a total of 1055 patients with BA, of which 882 had been listed in the preimplementation phase (PRE) and 173 in the postimplementation phase (POST). Waitlist mortality decreased from 6.7% in PRE to 2.3% in POST (p = 0.03). Interestingly, the proportion of young patients with BA undergoing DDLT decreased from 32% to 18% after ET allocation prioritization (p = 0.001), whereas LDLT increased from 55% to 74% (p = 0.001). The proportional increase in LDLT decreased the median waitlist duration of transplanted patients from 1.5 months in PRE to 0.85 months in POST (p = 0.003). Since 2014, waitlist mortality in young patients with BA has strongly decreased in the ET region. Rather than associated with prioritized allocation of deceased donor organs, the decreased waitlist mortality was related to a higher proportion of patients undergoing LDLT.
Protective effect of indole-3-carbinol on testis of a high fat diet induced obesity

ABSTRACT We investigated the effects of obesity caused by a high fat diet (HFD) on rat testes and evaluated the possible protective effects of indole-3-carbinol (IND). We used 24 8–10-week-old 200 g male rats randomly assigned to 4 groups: non-obese control (NC), obese control (OC), non-obese IND group (NI), obese + IND group (OI). Testis samples were examined using stereological, immunohistochemical, biochemical and histological methods. The number of spermatogenic cells, Leydig cells, mean volume of testes and seminiferous tubules was significantly decreased in the OC group compared to the NC group, but these values were increased significantly in the OI group compared to the OC group. We found a significant increase in catalase and myeloperoxidase activities in the OC group compared to the NC group. In the OI group, catalase and myeloperoxidase levels were decreased compared to the OC group. TUNEL-positive cells also were increased in the OC group compared to the NC group (p < 0.05), but these were fewer in the OI group than the OC group. We found marked morphological changes in testicular tissues between the NC and OC groups, as well as between the OI and OC groups. We found that HFD induced obesity was detrimental to rat testes and that administration of IND ameliorated testicular changes caused by obesity.
Outcomes reporting in systematic reviews on vital pulp treatment: A scoping review for the development of a core outcome set

Abstract Background A large number of research reports on vital pulp treatment (VPT) has been published over the last two decades. However, heterogeneity in reporting outcomes of VPT is a significant challenge for evidence synthesis and clinical decision‐making. Objectives To identify outcomes assessed in VPT studies and to evaluate how and when outcomes are measured. A subsidiary aim was to assess evidence for selective reporting bias in the included studies. The results of this review will be used to inform the development of a core outcome set (COS) for endodontic treatments. Methods Multiple healthcare bibliographic databases, including PubMed/MEDLINE, Ovid EMBASE, Scopus, Cochrane Database of Systematic Reviews and Web of Science were searched for systematic reviews published between 1990 and 2020, reporting on VPT. Screening, data extraction and risk of bias assessment were completed independently by two reviewers. Outcomes' information was extracted and aligned with a healthcare taxonomy into five core areas: survival, clinical/physiological changes, life impact, resource use and adverse events. Results Thirty‐six systematic reviews were included, 10 reporting on indirect pulp capping or selective caries removal, nine on direct pulp capping, eight on pulpotomy and nine on combined VPTs. There was considerable variation in the outcomes reported in these reviews and their included studies. Clinician‐reported outcomes were used considerably more often than patient‐reported outcomes. A range of instruments and time points were used for measuring outcomes. Several of the reviews were assessed as having low risk of selective reporting bias, but many did not specifically report this domain, whilst others did not provide risk of bias assessment at all. Discussion Considerable variation in selection of outcomes and how and when they are measured and reported was evident, and this heterogeneity has implications for evidence synthesis and clinical decision‐making. Conclusions Whilst there is a lack of consistency, several potentially important outcomes for VPT, including pulp survival, incidence of post‐operative pain and need for further intervention, have been identified which could inform the development of a COS for endodontic treatment. Registration Core Outcome Measures in Effectiveness Trials (COMET) (No. 1879).
Fermionic response in a zero entropy state of N = 4 super-Yang-Mills

We analyze fermionic response in the geometry holographically dual to zero-temperature N=4 Super-Yang-Mills theory with two equal nonvanishing chemical potentials, which is characterized by a singular horizon and zero ground state entropy. We show that fermionic fluctuations are completely stable within a gap in energy around a Fermi surface singularity, beyond which non-Fermi liquid behavior returns. This gap disappears abruptly once the final charge is turned on, and is associated to a discontinuity in the corresponding chemical potential. We also show that the singular near-horizon geometry lifts to a smooth AdS_3 x R^3, and interpret the gap as a region where the quasiparticle momentum is spacelike in six dimensions due to the momentum component in the Kaluza-Klein direction, corresponding to the final charge.
HSA-MnO2-131I Combined Imaging and Treatment of Anaplastic Thyroid Carcinoma

Purpose Compelling evidence suggests that nanoparticles (NPs) play a crucial role in cancer therapy. NPs templated with human serum albumin (HSA) has good retention in tumors. Manganese dioxide (MnO2) has been used to enhance the effect of radiotherapy. In this study, synthesized NPs using HSA-MnO2 labeled 131I to perform both imaging and therapy for anaplastic thyroid carcinoma (ATC). Method HSA-MnO2 was synthesized via HSA using a simple biomineralization method, and then labeled with Na131I by the chloramine T method. The cytotoxicity and biosafety of HSA-MnO2 were evaluated by the MTT test. The proliferation-inhibiting effect of HSA-MnO2-131I was evaluated in papillary thyroid cancer cell lines (K1, BCPAP, and KTC) and anaplastic thyroid carcinoma cell lines (Cal62, THJ16T, and ARO). For further translational application in medicine, we established a model of transplantable subcutaneously tumors in BALB\c-nu mice to assess the anti-tumor effect of HSA-MnO2-131I. The imaging effects of NPs were evaluated by MRI and SPECT/CT. Results The MTT test proved that the HSA-MnO2 had low toxicity. HSA-MnO2-131I significantly inhibited the proliferation of PTC and ATC cell lines. In addition, the results unveiled that HSA-MnO2-131I exhibited dual-modality MR/SPECT imaging for thyroid cancer visualization. In particular, HSA-MnO2-131I had an enhanced T1 signal in MR. Using SPECT/CT, we observed that HSA-MnO2-131I had good retention in tumor tissue, which was helpful for the diagnosis and treatment of tumor. In vivo assays indicated that the NPs led to a reduction in radioresistance in the tumor hypoxic microenvironment. Conclusion The nanomaterial had a simple synthesis method, good water solubility and biosafety, and good retention in tumor tissue. Hence, it could be used for SPECT/CT and MR dual mode imaging and therapy with radioiodine of tumor cells. The experimental results provided a feasible solution for combining radiotherapy and dual-model imaging by NPs for cancer diagnosis and treatment.
Inhibition of Nitrosative Stress Attenuates Myocardial Injury and Improves Outcomes after Cardiac Arrest and Resuscitation

ABSTRACT Objectives: Nitrosative stress is widely involved in cell injury via inducing the nitration modification of a variety of proteins. This study aimed to investigate whether inhibition of nitrosative stress attenuated myocardial injury and improved outcomes in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Methods: Adult male Wistar rats were subjected to asphyxia-induced cardiac arrest and subsequently resuscitation. One minute after return of spontaneous circulation (ROSC), rats were randomized and administered the nitrosative stress inhibitor, FeTMPyP (1 or 3 mg/kg), or normal saline as a placebo. 3-Nitrotyrosine (3-NT), mean arterial pressure (MAP), heart rate (HR), mortality, electrocardiogram (ECG), left ventricular ejection fraction (EF) and fractional shortening (FS), and levels of myocardial apoptosis were evaluated. The concentrations of lactate, creatine kinase MB isoenzyme (CK-MB), and angiotensin II (Ang II), were measured in blood samples. Results: 3-NT level was significantly increased in the heart after ROSC. Administration of FeTMPyP (1 or 3 mg/kg) attenuated the increase of 3-NT in the myocardium. Inhibition of nitrosative stress improved survival and attenuated CA/CPR-induced reperfusion injury by maintaining the stability of MAP and HR, and reducing the accumulation of lactic acid. Post-cardiac arrest rats had higher serum CK-MB and Ang II than healthy rats, while EF and FS were lower in healthy rats. Inhibition of nitrosative stress not only alleviated ischemic heart injury but also reduced the occurrence of CA/CPR-induced of arrhythmias. Moreover, nitrosative stress mediated the upregulation of Cleaved caspase-3 and downregulation Bcl-2, which was abolished by FeTMPyP. Conclusions: Inhibition of nitrosative stress is a novel molecular target to alleviate myocardial injury and improve outcomes in a rat model of CA/CPR.
Pulmonary exposure of mice to ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX) suppresses the innate immune response to carbon black nanoparticles and stimulates lung cell proliferation

Abstract Background Per- and polyfluoroalkyl substances (PFAS) have been associated with respiratory diseases in humans, yet the mechanisms through which PFAS cause susceptibility to inhaled agents is unknown. Herein, we investigated the effects of ammonium perfluoro(2-methyl-3-oxahexanoate) (GenX), an emerging PFAS, on the pulmonary immune response of mice to carbon black nanoparticles (CBNP). We hypothesized that pulmonary exposure to GenX would increase susceptibility to CBNP through suppression of innate immunity. Methods Male C57BL/6 mice were exposed to vehicle, 4 mg/kg CBNP, 10 mg/kg GenX, or CBNP and GenX by oropharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) was collected at 1 and 14 days postexposure for cytokines and total protein. Lung tissue was harvested for histopathology, immunohistochemistry (Ki67 and phosphorylated (p)-STAT3), western blotting (p-STAT3 and p-NF-κB), and qRT-PCR for cytokine mRNAs. Results CBNP increased CXCL-1 and neutrophils in BALF at both time points evaluated. However, GenX/CBNP co-exposure reduced CBNP-induced CXCL-1 and neutrophils in BALF. Moreover, CXCL-1, CXCL-2 and IL-1β mRNAs were increased by CBNP in lung tissue but reduced by GenX. Western blotting showed that CBNP induced p-NF-κB in lung tissue, while the GenX/CBNP co-exposed group displayed decreased p-NF-κB. Furthermore, mice exposed to GenX or GenX/CBNP displayed increased numbers of BALF macrophages undergoing mitosis and increased Ki67 immunostaining. This was correlated with increased p-STAT3 by western blotting and immunohistochemistry in lung tissue from mice co-exposed to GenX/CBNP. Conclusions Pulmonary exposure to GenX suppressed CBNP-induced innate immune response in the lungs of mice yet promoted the proliferation of macrophages and lung epithelial cells.
Functional Outcomes of Patients ≥85 Years With Acute Ischemic Stroke Following EVT: A HERMES Substudy

Background: Observational studies have shown endovascular treatment (EVT) for acute ischemic stroke to be effective in the elderly, despite resulting in poorer outcomes and higher rates of mortality compared with younger patients. Randomized data on the effect of advanced age on outcomes following EVT are, however, lacking. Our aim was to assess the EVT effect for ischemic stroke in patients aged ≥85 years and the influence of age on outcome in a large, randomized trial dataset. Methods: Data were from the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration, a meta-analysis of 7 randomized trials published between January 1, 2010, and May 31, 2017, that tested the efficacy of EVT. A possible multiplicative interaction effect of age on the relationship between treatment and outcome was investigated. Ordinal logistic regression tested the association between EVT and 90-day functional outcome (modified Rankin Scale, primary outcome) in patients ≥85 years. Multivariable binary logistic regression was performed to compare primary and secondary outcomes (modified Rankin Scale score of 0–2/5–6) of patients ≥85 years versus those <85 years. Results: We included 1764 patients in the analysis, of whom 77 (4.4%) were ≥85 years old. A significant interaction of age and treatment on poor outcome (modified Rankin Scale score of 5–6, P=0.020) and mortality (P=0.031) was observed, with older adults having worse functional outcomes at 90 days compared with younger patients (adjusted common odds ratio, 0.20 [95% CI, 0.13–0.33]). However, a benefit of EVT was observed in the ≥85-year-old patient subgroup (common odds ratio, 4.20 [95% CI, 1.56–11.32]). Age ≥85 years was not significantly associated with differing rates of symptomatic intracerebral hemorrhage or reperfusion (adjusted odds ratio, 1.92 [95% CI, 0.71–5.15] and adjusted odds ratio, 0.91 [95% CI, 0.40–2.06], respectively). Conclusions: Patients ≥85 years old with independent premorbid function more often achieve good functional outcomes and have lower rates of mortality when treated with EVT compared with conservative management, with an observed treatment effect modification of age on outcome. EVT should therefore not be withheld in this subgroup.
Tirofiban potentiates agonist-induced platelet activation and degranulation, despite effectively inhibiting aggregation

Abstract We aimed to investigate the effects of integrin αIIbβ3 inhibitor tirofiban on hallmarks of platelet activation, degranulation, and aggregation during its use to analyze activated but non-complexed platelets via flow cytometry. To do so, we used washed platelets from healthy human donors. We combined aggregometry, an assay of platelet functionality, with flow cytometry and ELISA to detect and correlate, respectively, platelet aggregation, activation, and granule release. While tirofiban effectively inhibited agonist-induced platelet aggregation (thrombin receptor-activating peptide 6 (TRAP), convulxin (CVX), U46619 and IV.3), the surface expression of P-selectin and CD63 and granule release of RANTES were significantly increased, indicating that tirofiban enhances degranulation, uncoupled from aggregation. The results show that tirofiban alters the activation phenotype of platelets, something that should be considered when using tirofiban to enable flow cytometric analysis of activated but unaggregated platelet suspensions.
Conditional ablation of E‐cadherin in the oral epithelium progeny results in tooth anomalies

The objective of this study is to confirm the developmental origin of the enamel organ and evaluate the role of E‐cadherin in tooth development by conditional deletion in the oral epithelium and its enamel organ progeny. K5‐Cre;ROSA26 compound mice were included in this study in order to confirm the oral epithelial origin of the enamel organ, as well as of the action of the K5‐Cre transgene in ablating E‐cadherin in the enamel organ. K5‐Cre;Ecadfl/fl knockout mice were included to evaluate the effects of the conditional E‐cadherin ablation onto tooth development.
Distributed Neural Systems Support Flexible Attention Updating during Category Learning

Abstract To accurately categorize items, humans learn to selectively attend to the stimulus dimensions that are most relevant to the task. Models of category learning describe how attention changes across trials as labeled stimuli are progressively observed. The Adaptive Attention Representation Model (AARM), for example, provides an account in which categorization decisions are based on the perceptual similarity of a new stimulus to stored exemplars, and dimension-wise attention is updated on every trial in the direction of a feedback-based error gradient. As such, attention modulation as described by AARM requires interactions among processes of orienting, visual perception, memory retrieval, prediction error, and goal maintenance to facilitate learning. The current study explored the neural bases of attention mechanisms using quantitative predictions from AARM to analyze behavioral and fMRI data collected while participants learned novel categories. Generalized linear model analyses revealed patterns of BOLD activation in the parietal cortex (orienting), visual cortex (perception), medial temporal lobe (memory retrieval), basal ganglia (prediction error), and pFC (goal maintenance) that covaried with the magnitude of model-predicted attentional tuning. Results are consistent with AARM's specification of attention modulation as a dynamic property of distributed cognitive systems.
Longitudinal Retinal Changes in MOGAD

Patients with myelin oligodendrocyte glycoprotein antibody (MOG‐IgG)‐associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro‐axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON‐independent retinal atrophy can be detected in MOGAD.
Anterior nucleus of the thalamus deep brain stimulation vs temporal lobe responsive neurostimulation for temporal lobe epilepsy

Based on the promising results of randomized controlled trials, deep brain stimulation (DBS) and responsive neurostimulation (RNS) are used increasingly in the treatment of patients with drug‐resistant epilepsy. Drug‐resistant temporal lobe epilepsy (TLE) is an indication for either DBS of the anterior nucleus of the thalamus (ANT) or temporal lobe (TL) RNS, but there are no studies that directly compare the seizure benefits and adverse effects associated with these therapies in this patient population. We, therefore, examined all patients who underwent ANT‐DBS or TL‐RNS for drug‐resistant TLE at our center.