Miracle-dz/UniFAR-FTUs huggingface dataset:
Lentiviral Gene Therapy Combined with Low‐Dose Busulfan in Infants with SCID‐X1

BACKGROUND Allogeneic hematopoietic stem‐cell transplantation for X‐linked severe combined immunodeficiency (SCID‐X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high‐dose chemotherapy is given. In previous studies, autologous gene therapy with γ‐retroviral vectors failed to reconstitute B‐cell and NK‐cell immunity and was complicated by vector‐related leukemia. METHODS We performed a dual‐center, phase 1–2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low‐exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID‐X1. RESULTS Eight infants with SCID‐X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T‐cell count initially, but T cells developed in this infant after a boost of gene‐corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion‐site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven. CONCLUSIONS Lentiviral vector gene therapy combined with low‐exposure, targeted busulfan conditioning in infants with newly diagnosed SCID‐X1 had low‐grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK‐cell counts during a median follow‐up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID‐ND ClinicalTrials.gov number, NCT01512888.)
Hysteresis in solar wind power input to the magnetosphere

We examine the clock angle dependence of the solar wind power input into the magnetosphere using the Grand Unified Magnetosphere Ionosphere Coupling Simulation (GUMICS‐4). We compute the power input through the magnetopause systematically in four events where the solar wind parameters are otherwise kept constant, but the interplanetary magnetic field (IMF) clock angle θ is rotated from 0° to 360°. We find that when the clock angle rotates from north to south, the power input is well represented by sin2(θ/2). However, during the return rotation from south to north, the power input in the simulation remains enhanced longer than a sin2(θ/2) dependence would indicate. We suggest that the enhanced energy input during the return rotation may be a consequence of the nature of the reconnection process at the magnetopause.
Inhibiting cardiac autophagy suppresses Zika virus replication

Zika Virus (ZIKV) infection is a global threat. Other than the congenital neurological disorders it causes, ZIKV infection has been reported to induce cardiac complications. However, the precise treatment plans are unclear. Thus, illustrating the pathogenic mechanism of ZIKV in the heart is critical to providing effective prevention and treatment of ZIKV infection. The mechanism of autophagy has been reported recently in Dengue virus infection. Whether or not autophagy participates in ZIKV infection and its role remains unrevealed. This study successfully established the in vitro cardiomyocytes and in vivo mouse models of ZIKV infection to investigate the involvement of autophagy in ZIKV infection. The results showed that ZIKV infection is both time and gradient‐dependent. The key autophagy protein, LC3B, increased remarkably after ZIKV infection. Meanwhile, autophagic flux was detected by immunofluorescence. Applying autophagy inhibitors decreased the LC3B levels. Furthermore, the number of viral copies was quantified to evaluate the influence of autophagy during infection. We found that autophagy was actively involved in the ZIKV infection and the inhibition of autophagy could effectively reduce the viral copies, suggesting a potential intervention strategy for reducing ZIKV infection and the undesired complications caused by ZIKV.
Stimulation‐induced entrainment of hippocampal network activity: Identifying optimal input frequencies

The hippocampus contains rich oscillatory activity, with continuous ebbs and flows of rhythmic currents that constrain its ability to integrate inputs. During associative learning, the hippocampus must integrate inputs from a range of sources carrying information about events and the contexts in which they occur. Under these circumstances, temporal coordination of activity between sender and receiver is likely essential for successful communication. Previously, it has been shown that the coordination of rhythmic activity between the lateral entorhinal cortex (LEC) and the CA1 region of the hippocampus is tightly correlated with the onset of learning in an associative learning task. We aimed to examine whether rhythmic inputs from the LEC in specific frequency ranges were sufficient to enhance the temporal coordination of activity in downstream CA1. In urethane‐anesthetized rats, we applied extracellular low‐intensity alternating current stimulation across the length of the LEC. Using this method, we aimed to phase‐bias ongoing neuronal activity in LEC at a range of different frequencies (from 1.25 to 55 Hz). Rhythmic stimulation of LEC at both 35 and 50 Hz increased the proportion of CA1 neurons significantly entrained to the phase of the applied stimulation current. A subset of stimulation frequencies modified CA1 spiking relationships to the phase of local ongoing CA1 oscillations, with each stimulation frequency exerting a unique influence upon downstream CA1, often in frequency ranges outside the target stimulation frequency. These results suggest there are optimal frequencies for LEC–CA1 communication, and that different profiles of LEC rhythms likely have distinct outcomes upon CA1 processing.
The methylation status of GATA3 potentially predicts the outcomes of assisted reproductive technologies

Abstract Evaluation of methylation status of genes in sperm samples has been suggested for diagnosis of male infertility as well as prognosis of assisted reproductive technologies (ART) outcomes. In this study, we compared the methylation pattern of the GATA3 gene in infertile and fertile men as well as in infertile men with positive and negative ART outcome based on clinical pregnancy. Ejaculates were obtained from 42 infertile men with a negative ART outcome (group 1), 30 infertile men with a positive ART outcome (group 2), and 21 fertile men (control). Then, samples were subjected to genomic DNA isolation and subsequent TUNEL assay and methylation-specific PCR. The number of infertile men with at least one methylated allele of GATA3 was significantly higher compared to the control group (p = 0.022). Also, the number of patients with at least one methylated allele was significantly higher in group 1 compared to group 2 (p = 0.013). Moreover, the TUNEL assay revealed that the amount of sperm DNA fragmentation is higher in group 1 compared to group 2 (p = 0.008). The findings of our study demonstrated that the degree of GATA3 methylation can potentially differentiate between infertile and fertile men and more importantly can potentially predict the outcome of ART.
Repeat-associated non-AUG translation induces cytoplasmic aggregation of CAG repeat-containing RNAs

Significance Several degenerative diseases are caused by expansions of CAG trinucleotide repeats. The repeat-containing RNAs contribute to cellular pathology in two unusual ways. These RNAs may agglomerate in the nucleus as foci or undergo aberrant repeat-associated non-AUG (RAN) translation. We show that RAN translation is preceded by prolonged retention of repeat-containing RNAs at nuclear foci, chronologically connecting these two pathomechanisms. Upon RAN translation, the repeat-containing RNAs coaggregate with the cognate RAN translation products. This cytoplasmic RNA–RAN protein aggregation correlates with the mislocalization of various RNA-binding proteins and cell toxicity, while accumulation of nuclear foci alone does not produce these defects. Our findings suggest that cytoplasmic RNA aggregation may be a common feature of diseases caused by CAG trinucleotide repeat expansions.
The New Oncologic Diagnosis Discussion: Perspectives of Pediatric Oncologists

PURPOSE: We aimed to understand how new diagnosis discussions are conducted in pediatric oncology, and the training provided for their conduct. METHODS: This mixed-methods study used a sequential exploratory design. Qualitative interviews (n = 20) were conducted with pediatric oncologists (n = 15) and fellows (n = 5) at a single institution, focusing on the process used to convey the diagnosis and treatment plan to the family. Accreditation Council for Graduate Medical Education–accredited pediatric oncology fellowship program directors (n = 38) and fellows (n = 70) were subsequently surveyed to confirm qualitative results and elucidate the training that fellows receive in conducting new diagnosis discussions. RESULTS: Our findings suggest that new diagnosis discussions in pediatric oncology are typically conducted in three stages: (1) concern for cancer; (2) confirmation of diagnosis; and (3) treatment plan/consent, and are fundamentally similar across settings; however, pediatric oncologists skillfully tailor their approach on the basis of clinical circumstances and parental needs. Decisions regarding inclusion of the child are primarily determined by parental preference, whereas inclusion of health care team members is driven by physician role (ie, trainee v program director) and health care organization–related factors. Physician preparation for discussions involves logistical, intellectual, and emotional components. Disclosure of prognosis is nuanced. There is variability across pediatric oncology fellowship programs in the provision of training for these discussions. CONCLUSION: We identified common practices of pediatric oncologists as they prepare for and lead new diagnosis discussions in pediatric oncology. We found variability in the training that pediatric oncology fellows receive regarding how to conduct these discussions, highlighting a need for standardized training curricula.
Modes of action of lysophospholipids as endogenous activators of the TRPV4 ion channel

The Transient Receptor Potential Vanilloid 4 (TRPV4) channel has been shown to function in many physiological and pathophysiological processes. Despite abundant information on its importance in physiology, very few endogenous agonists for this channel have been described, and very few underlying mechanisms for its activation have been clarified. TRPV4 is expressed by several types of cells, such as vascular endothelial, and skin and lung epithelial cells, where it plays pivotal roles in their function. In the present study, we show that TRPV4 is activated by lysophosphatidic acid (LPA) in both endogenous and heterologous expression systems, pinpointing this molecule as one of the few known endogenous agonists for TRPV4. Importantly, LPA is a bioactive glycerophospholipid, relevant in several physiological conditions, including inflammation and vascular function, where TRPV4 has also been found to be essential. Here we also provide mechanistic details of the activation of TRPV4 by LPA and another glycerophospholipid, lysophosphatidylcholine (LPC), and show that LPA directly interacts with both the N‐ and C‐terminal regions of TRPV4 to activate this channel. Moreover, we show that LPC activates TRPV4 by producing an open state with a different single‐channel conductance to that observed with LPA. Our data suggest that the activation of TRPV4 can be finely tuned in response to different endogenous lipids, highlighting this phenomenon as a regulator of cell and organismal physiology.
High body energy reserve influences extracellular vesicles miRNA contents within the ovarian follicle

Aiming to evaluate the effects of increased body energy reserve (BER) in Nellore cows’ reproductive efficiency, cows were fed with different nutritional plans to obtain animals with high BER (HBER; Ad libitum diet) and moderate BER (MBER: cows fed 70% of HBER group ingestion). To evaluate the BER, cows were weekly weighted and evaluated for subcutaneous fat thickness and insulin serum concentration along the experimental period. At the end of the experimental period, animals were submitted to estrous synchronization and artificial insemination. Animals were slaughtered approximately 120 h after ovulation induction and the reproductive tracts were collected for embryo recovery and samples collection. Cumulus-oocyte-complexes (COC) and follicular fluid were collected from 3–6 mm in diameter ovarian follicles to perform miRNA analysis of cumulus cells (CC) and extracellular vesicles from follicular fluid (EV FF). As expected, differences were observed among MBER and HBER groups for body weight, fat thickness, and insulin serum concentration. HBER animals showed lower ovulation and embryo recovery rates compared to MBER animals. Different miRNAs were found among CC and EV FF within groups, suggesting that the BER may influence follicular communication. This suggests that small follicles (3–6 mm diameter) are already under BER effects, which may be greater on later stages of follicular development.
Charge carrier velocity distributions in field-effect transistors

The measurement of the distribution of charge carrier velocities in a field-effect transistor can provide considerable insight into charge transport mechanisms and structure-property relationships. We have developed such a method and have applied it to study temperature-dependent velocity distributions in solution-processed zinc-tin oxide thin-film transistors. Two distinct transport pathways, each with a different activation energy, have been observed, in contrast to a single activation energy yielded by steady-state measurements. Our results show that more insight into charge transport behavior and phenomena can be obtained with such time-resolved transport measurements.
The association of fatty liver and risk of hepatocellular carcinoma in HBV or HCV infected individuals: a systematic review and meta-analysis

ABSTRACT Background Fatty liver (FL) is reportedly a risk factor for hepatocellular carcinoma (HCC) in individuals affected with Hepatitis C (HCV) or B (HBV) virus. However, the results are contradictory, necessitating a meta-analysis. Research design and methods Sixteen relevant studies involving 88,618 individuals were retrieved from the Cochrane Library, PubMed, MEDLINE, Embase, and Scopus databases from their inception to 10 December 2022. The hazard ratios (HR) and 95% confidence intervals (CI) were analyzed. Results Liver biopsy-proven FL may be a significant risk factor for HCC in individuals affected with HBV (univariate analyses: HR = 3.13, 95% CI = 1.69–5.79; multivariate analyses: HR = 3.42, 95% CI = 0.83–14.09) as well as HCV (univariate analyses: HR = 1.64, 95% CI = 0.93–2.90; multivariate analyses: HR = 1.75, 95% CI = 1.02–3.00). However, the presence of FL confirmed using reasonable methods other than liver biopsy may not indicate a risk for HCC in HBV-infected individuals (univariate analyses: HR = 0.90, 95% CI = 0.44–1.81; multivariate analyses: HR = 0.69, 95% CI = 0.45–1.08). Conclusions Biopsy-proven FL may be a significant risk factor for HCC in HCV/HBV-infected individuals. Thus, such individuals should receive suitable interventions to prevent HCC formation or at least attenuate the risk of HCC.
Recent advances in VECSELs for laser projection applications

Laser projectors integrated in portable devices offer a new platform for media display but put strong demands on the laser sources in terms of efficiency, modulation band width, operating temperature range and device cost. Osram Opto Semiconductors has developed and produces synthetic green lasers for projection applications on which the latest results are reported. Based on vertical external cavity surface emitting laser (VECSEL) technology and second harmonic generation an output power of >75mW has been achieved. The maximum output power is to a large extent limited by the high thermal resistance of the monolithic VECSEL chip used. To overcome the thermal limitations a new thinfilm VECSEL chip design is proposed where the epitaxial layers are transferred to a silicon carrier and processed on wafer level, thus significantly lowering the thermal resistance and improving the maximum output power.
Adaptation to glucose starvation is associated with molecular reorganization of the circadian clock in Neurospora crassa

The circadian clock governs rhythmic cellular functions by driving the expression of a substantial fraction of the genome and thereby significantly contributes to the adaptation to changing environmental conditions. Using the circadian model organism Neurospora crassa, we show that molecular timekeeping is robust even under severe limitation of carbon sources, however, stoichiometry, phosphorylation and subcellular distribution of the key clock components display drastic alterations. Protein kinase A, protein phosphatase 2 A and glycogen synthase kinase are involved in the molecular reorganization of the clock. RNA-seq analysis reveals that the transcriptomic response of metabolism to starvation is highly dependent on the positive clock component WC-1. Moreover, our molecular and phenotypic data indicate that a functional clock facilitates recovery from starvation. We suggest that the molecular clock is a flexible network that allows the organism to maintain rhythmic physiology and preserve fitness even under long-term nutritional stress.
Changes in symptom burden from 2019 to 2021 amongst community-dwelling older adults in Finland

Abstract Background Symptom burden causes suffering amongst older adults and is associated with healthcare visits and prognosis. Aims We evaluated the prevalence of 10 symptoms and changes in symptom burden amongst home-dwelling older adults in 2019 and 2021 using Finnish cohort data. We analysed factors associated with symptom burden increase during follow-up. Methods Altogether 1,637 people aged 75+ participated in the Helsinki Ageing Study postal survey in 2019, where they reported the presence of 10 common symptoms over the past 2 weeks. Of them, 785 participated in a follow-up in 2021, where the same symptoms were queried. We compared the prevalence of various symptoms and symptom burden scores in the 2-year interval and evaluated factors associated with increased symptom burden during this time. Results Of participants, 33% reported at least one daily symptom in 2019 versus 44% in 2021. Symptom burden increased by a mean ratio of 1.29 between 2019 and 2021. The most common symptoms were joint pain, back pain, urinary incontinence and fatigue. The prevalence of four symptoms increased between 2019 and 2021: joint pain, urinary incontinence, dizziness and shortness of breath. Higher age, reduced functional capacity and comorbidities were associated with higher odds of symptom burden increase during follow-up. Psychological well-being (PWB) was strongly associated with lower odds of symptom burden increase in the logistic regression model. Conclusions Symptom burden increased in our cohort aged 75+ between 2019 and 2021 before and during the COVID-19 pandemic. PWB was associated with lower odds of acquiring additional symptoms over time.
SPECTROSCOPIC CONSTANTS FOR 13C AND DEUTERIUM ISOTOPOLOGUES OF CYCLIC AND LINEAR C3H3+

Recently, we reported ab initio quartic force fields (QFFs) for the cyclic and linear forms of the C3H3+ molecular cation, referred to as c-C3H3+ and l-C3H3+. These were computed using high levels of theory. Specifically the singles and doubles coupled-cluster method that includes a perturbational estimate of connected triple excitations, CCSD(T), was used in conjunction with extrapolation to the one-particle basis set limit, and corrections for scalar relativity and core correlation were included. In the present study, we use these QFFs to compute highly accurate fundamental vibrational frequencies and other spectroscopic constants for the c-13CC2H3+, c-C3H2D+, c-13CC2H2D+ isotoplogues of c-C3H3+, and the H2CCCD+, HDCCCH+, H213CCCH+, H2C13CCH+, and H2CC13CH+ isotopologues of l-C3H3+. Improvements in ab intitio methods have now made it possible to identify small molecules in an astronomical observation without the aid of high-resolution experimental data. We also report dipole moment values and show that the above-mentioned cyclic isotopologues have values of 0.094, 0.225, and 0.312 D, respectively, while the l-C3H3+ isotopologues have values that range between 0.325 and 0.811 D. Thus, it is hoped that the highly accurate spectroscopic constants and data provided herein for the 13C and deuterium isotopologues of the cyclic and linear forms of C3H3+ will enable their identification in astronomical observations from the Herschel Space Observatory, the Stratospheric Observatory for Infrared Astronomy, the Atacama Large Millimeter Array, and in the future, the James Webb Space Telescope.
PRTN3 variant correlates with increased autoantigen levels and relapse risk in PR3-ANCA versus MPO-ANCA disease

A GWAS of patients with anti-neutrophil cytoplasmic antibodies (ANCAs) found an association between proteinase-3 ANCA (PR3-ANCA) and a single nucleotide polymorphism (rs62132293) upstream of PRTN3, encoding PR3. The variant (G allele) was shown to be an expression quantitative trait locus in healthy controls, but the clinical impact remains unknown. Longitudinally followed patients with ANCA and healthy controls were genotyped. Gene expression was quantified by real-time quantitative PCR from leukocyte RNA. Plasma PR3 was quantified by ELISA. Among patients, variant carriers had elevated leukocyte PRTN3 expression compared with noncarriers (C/G vs. C/C and G/G vs. C/C). Healthy controls had low PRTN3 regardless of genotype. Myeloperoxidase (MPO) expression did not differ by genotype. PRTN3 expression correlated with circulating PR3, and variant carriers had higher plasma PR3 compared with noncarriers. Among variant carriers, there was an increased risk of relapse in patients with PR3-ANCA versus MPO-ANCA. The risk allele marked by rs62132293 is clinically significant as it is associated with increased autoantigen and may, in part, explain increased relapse in PR3-ANCA. Our results underscore the role of autoantigen availability in ANCA vasculitis.
Crystal structure of the polyketide cyclase from Mycobacterium tuberculosis

About 40% of proteins are classified as conserved hypothetical proteins in Mycobacterium tuberculosis (TB). Identification and characterization of these proteins are beneficial to understand the pathogenesis of TB and exploiting novel drugs for TB treatments. The polyketide cyclase, a protein from M. tuberculosis ( MtPC) has been annotated as a hypothetical protein in Uniprot database. Sequence analysis shows that the MtPC belongs to the NTF2-like superfamily proteins with diverse functions. Here, we determined the crystal structure of MtPC at a resolution of 2.4 Å and measured backbone relaxation parameters for the MtPC protein. MtPC exists as a dimer in solution, and each subunit contains a six-stranded mixed β-sheet and three α helixes which are arranged in the order α1-α2-β1-β2-α3-β3-β4-β5-β6. The NMR dynamics analysis showed that the overall structure of MtPC is highly rigid on ps-ns time scales. Furthermore, we predicted the potential function of MtPC based on the crystal structure. Our results lay the basis for further exploiting and mechanistically understanding the biological functions of MtPC.