Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic, and there is limited data on effective therapies. Bacillus Calmette–Guérin (BCG) vaccine, a live-attenuated strain derived from ...an isolate of Mycobacterium bovis and originally designed to prevent tuberculosis, has shown some efficacy against infection with unrelated pathogens. In this study, we reviewed 120 consecutive adult patients (≥18 years old) with COVID-19 at a major federally qualified health centre in Rhode Island, United States from 19 March to 29 April 2020. Median age was 39.5 years (interquartile range, 27.0–50.0), 30% were male and 87.5% were Latino/Hispanics. Eighty-two (68.3%) patients had BCG vaccination. Individuals with BCG vaccination were less likely to require hospital admission during the disease course (3.7% vs. 15.8%, P = 0.019). This association remained unchanged after adjusting for demographics and comorbidities (P = 0.017) using multivariate regression analysis. The finding from our study suggests the potential of BCG in preventing more severe COVID-19.
We demonstrate the tunable enhancement of the zero phonon line of a single nitrogen-vacancy colour centre in diamond at cryogenic temperature. An open cavity fabricated using focused ion beam milling ...provides mode volumes as small as 1.24 m3 (4.7 ) and quality factor In situ tuning of the cavity resonance is achieved with piezoelectric actuators. At optimal coupling to a TEM00 cavity mode, the signal from individual zero phonon line transitions is enhanced by a factor of 6.25 and the overall emission rate of the NV− centre is increased by 40% compared with that measured from the same centre in the absence of cavity field confinement. This result represents a step forward in the realisation of efficient spin-photon interfaces and scalable quantum computing using optically addressable solid state spin qubits.
Preliminary studies suggest that maternal heat stress (HS) during late gestation exerts carryover effects on a calf’s insulin response after weaning, but a comprehensive evaluation of how maternal HS ...affects calf intake, growth, and metabolic response from birth to weaning is lacking. Our objective was to evaluate the effects of maternal HS during the dry period on dry matter intake, growth, and metabolism from birth to weaning. After birth, 20 heifers born to either HS (n=10) or cooled (CL, n=10) dry cows were immediately separated from their dams and fed 3.8 L of colostrum from a common pool within 4h of birth. All heifers were managed identically and weaned at 49 d of age (DOA). Calf starter intake was recorded daily, and body weight was assessed at birth and every 2 wk from birth to 56 DOA. Blood samples were collected twice a week until 56 DOA to assess hematocrit and concentrations of insulin and metabolites. To evaluate metabolic responses to maternal HS, a glucose tolerance test, insulin, and epinephrine challenge were performed on 3 consecutive days for all heifers at 8, 29, and 57 DOA. Maternal HS during the dry period did not affect heifer birth weight. Compared with HS, CL calves consumed more starter (0.53 vs. 0.34kg/d) from birth to 56 DOA and were heavier (71.7 vs. 61.4kg) at 56 DOA. Relative to HS calves, CL calves tended to have higher hematocrit (27.4 vs. 24.7%). No differences were found between treatments in plasma concentrations of insulin and glucose, but HS calves had higher nonesterified fatty acids and β-hydroxybutyrate concentrations after 32 DOA. Compared with CL, HS calves had a faster glucose clearance after a glucose tolerance test and a slower insulin clearance after an insulin challenge. In conclusion, maternal HS during late gestation reduces calf starter intake and growth, alters blood metabolite profile, and increases noninsulin-dependent glucose uptake.
Refractory chronic GVHD (cGVHD) is an important complication after allogeneic hematopoietic SCT and is prognostic of poor outcome. MSCs are involved in tissue repair and modulating immune responses ...in vitro and in vivo. From April 2005 to October 2008, 19 patients with refractory cGVHD were treated with MSCs derived from the BM of volunteers. The median dose of MSCs was 0.6 × 10(6) cells per kg body weight. Fourteen of 19 patients (73.7%) responded well to MSCs, achieving a CR (n=4) or a PR (n=10). The immunosuppressive agent could be tapered to less than 50% of the starting dose in 5 of 14 surviving patients, and five patients could discontinue immunosuppressive agents. The median duration between MSC administration and immunosuppressive therapy discontinuation was 324 days (range, 200-550 days). No patients experienced adverse events during or immediately after MSC infusion. The 2-year survival rate was 77.7% in this study. Clinical improvement was accompanied by the increasing ratio of CD5+CD19+/CD5-CD19+ B cells and CD8+CD28-/CD8+CD28+ T cells. In conclusion, transfusion of MSCs expanded in vitro, irrespective of the donor, might be a safe and effective salvage therapy for patients with steroid-resistant, cGVHD.
Background and Aims
In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines ...survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF.
Approach and Results
Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole‐treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute‐on‐chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1–Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF‐β superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte‐derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow‐up study indicated that serum follistatin levels could predict the incidence and mortality of acute‐on‐chronic liver failure.
Conclusions
These results highlight a crucial role of the follistatin‐controlled activin‐HNF4α‐coagulation axis in determining the clinical outcome of massive hepatocyte loss‐induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.
The hematopoietic system produces a large number of highly specialized cell types that are derived through a hierarchical differentiation process from a common stem cell population. miRNAs are ...critical players in orchestrating this differentiation. Here, we report the development and application of a high-throughput microfluidic real-time quantitative PCR (RT-qPCR) approach for generating global miRNA profiles for 27 phenotypically distinct cell populations isolated from normal adult mouse hematopoietic tissues. A total of 80,000 RT-qPCR assays were used to map the landscape of miRNA expression across the hematopoietic hierarchy, including rare progenitor and stem cell populations. We show that miRNA profiles allow for the direct inference of cell lineage relations and functional similarity. Our analysis reveals a close relatedness of the miRNA expression patterns in multipotent progenitors and stem cells, followed by a major reprogramming upon restriction of differentiation potential to a single lineage. The analysis of miRNA expression in single hematopoietic cells further demonstrates that miRNA expression is very tightly regulated within highly purified populations, underscoring the potential of single-cell miRNA profiling for assessing compartment heterogeneity.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, and T-ALL patients are prone to early disease relapse and suffer from poor outcomes. The PTEN, PI3K/AKT and Notch ...pathways are frequently altered in T-ALL. PTEN is a tumor suppressor that inactivates the PI3K pathway. We profiled miRNAs in Pten-deficient mouse T-ALL and identified miR-26b as a potentially dysregulated gene. We validated decreased expression levels of miR-26b in mouse and human T-ALL cells. In addition, expression of exogenous miR-26b reduced proliferation and promoted apoptosis of T-ALL cells in vitro, and hindered progression of T-ALL in vivo. Furthermore, miR-26b inhibited the PI3K/AKT pathway by directly targeting PIK3CD, the gene encoding PI3Kδ, in human T-ALL cell lines. ShRNA for PIK3CD and CAL-101, a PIK3CD inhibitor, reduced the growth and increased apoptosis of T-ALL cells. Finally, we showed that PTEN induced miR-26b expression by regulating the differential expression of Ikaros isoforms that are transcriptional regulators of miR-26b. These results suggest that miR-26b functions as a tumor suppressor in the development of T-ALL. Further characterization of targets and regulators of miR-26b may be promising for the development of novel therapies.
Sex-determining region Y-box (SRY-box) containing gene 9 (SOX9) expression confers cancer stem cell features. However, SOX9 function in intrahepatic cholangiocarcinoma (iCCA) is unknown. This study ...investigated the effects and underlying mechanisms of SOX9 in iCCA.
SOX9 expression in 59 iCCA patients was examined by immunohistochemistry. The association between SOX9 expression and clinical outcome was evaluated. Gene signature and biological functions of SOX9 in iCCA were examined in vitro.
iCCA patients with high SOX9 expression had shorter survival time than those with low SOX9. In patients receiving chemotherapy, median survival time in patients with low and high levels of SOX9 were 62 and 22 months, respectively. In vitro, gemcitabine increased SOX9 expression in iCCA cells. When SOX9 was knocked down, gemcitabine-induced apoptosis was markedly increased. Silencing SOX9 significantly inhibited gemcitabine-induced phosphorylation of checkpoint kinase 1, a key cell cycle checkpoint protein that coordinates the DNA damage response and inhibited the expression of multidrug resistance genes. Microarray analyses showed that SOX9 knockdown in CCA cells altered gene signatures associated with multidrug resistance and p53 signalling.
SOX9 governs the response of CCA cells to chemotherapy. SOX9 is a biomarker to select iCCA patients eligible for efficient chemotherapy.
Maternal heat stress alters immune function of the offspring, as well as metabolism and future lactational performance, but its effect on the hormonal and metabolic responses of the neonate ...immediately after birth is still not clear. The objective of this study was to investigate the blood profiles of hormones and metabolites of calves born to cows that were cooled (CL) or heat-stressed (HS) during the dry period. Within 2 h after birth, but before colostrum feeding, blood samples were collected from calves 18 bulls (HS: n=10; CL: n=8) and 20 heifers (HS: n=10; CL: n=10) born to CL or HS dry cows, and hematocrit and plasma concentrations of total protein, prolactin, insulin-like growth factor-I, insulin, glucose, nonesterified fatty acid, and β-hydroxybutyrate were measured. Compared with CL, HS calves had lower hematocrit and tended to have lower plasma concentrations of insulin, prolactin, and insulin-like growth factor-I. However, maternal heat stress had no effect on plasma levels of total protein, glucose, fatty acid, and β-hydroxybutyrate immediately after birth. These results suggest that maternal heat stress desensitizes a calf’s stress response and alters the fetal development by reducing the secretion of insulin-like growth factor-I, prolactin, and insulin.
We report progress in the development of tunable room temperature triggered single photon sources based on single nitrogen-vacancy (NV) centres in nanodiamond coupled to open access optical ...micro-cavities. The feeding of fluorescence from an NV centre into the cavity mode increases the spectral density of the emission and results in an output stream of triggered single photons with spectral line width of order 1 nm, tunable in the range 640 - 700 nm. We record single photon purities exceeding 96% and estimated device efficiencies up to 3%. We compare performance using plano-concave microcavities with radii of curvature from 25 μm to 4 μm and show that up to 17% of the total emission is fed into the TEM
mode. Pulsed Hanbury-Brown Twiss (HBT) interferometry shows that an improvement in single photon purity is facilitated due to the increased spectral density.
PDF
