PegIFN alpha-2a reduces relapse in HBeAg-negative patients after nucleo(s)tide analogue cessation: A randomized-controlled trial.

BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) cessation can lead to hepatitis B surface antigen (HBsAg) clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-α-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse up to week 96. METHODS: In this multicenter randomized-controlled clinical trial, 180 non-cirrhotic patients with HBeAg-negative chronic hepatitis B on continuous NUC therapy for ≥2.5 years, with HBV DNA levels <60 IU/ml, were randomized to discontinue NUC therapy (n = 90) or receive 48 weeks of PegIFN-α-2a treatment (n = 90). Patients were followed up for up to 96 weeks. The primary endpoint was the virological relapse rate up to week 96. RESULTS: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, p <0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, p = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, p = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, p = 0.03) than the NUC cessation group. CONCLUSIONS: Switching from NUC to PegIFN-α-2a treatment for 48 weeks significantly reduces virological relapse rates and leads to higher HBsAg loss rates than NUC treatment cessation alone in patients with HBeAg-negative chronic hepatitis B. IMPACT AND IMPLICATIONS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse, but an optimized scheme to reduce the virological relapse rate after NUC withdrawal is yet to be reported. This randomized-controlled trial investigated the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse up to week 96 in patients with HBeAg-negative chronic hepatitis B. The interferon monotherapy group had a significantly lower cumulative virological relapse rate (20.8% vs. 53.6%, p <0.0001) and higher HBsAg loss rate (21.5% vs. 9.0%, p = 0.03) than the NUC cessation group up to week 96. This provides an optimized strategy for NUC cessation in HBeAg-negative patients. TRIAL REGISTRATION NUMBER: NCT02594293.

Exceptional Hole-Selective Properties of Ta2O5 Films via Sn4+ Doping for High Performance Silicon Heterojunction Solar Cells.

Carrier-selective passivating contacts using transition metal oxides (TMOs) have attracted great attention for crystalline silicon (c-Si) heterojunction solar cells recently. Among them, tantalum oxide (Ta2O5) exhibits outstanding advantages, such as a wide bandgap, good surface passivation, and a small conduction band offset with c-Si, which is typically used as an electron-selective contact layer. Interestingly, it is first demonstrated that solution-processed Ta2O5 films exhibit a high hole selectivity, which blocks electrons and promotes hole transport simultaneously. Through the ozone pre-treatment of Ta2O5/p-Si interface and optimization of the film thickness (≈9 nm), the interfacial recombination is suppressed and the contact resistivity is reduced from 178.0 to 29.3 mΩ cm2. Moreover, the Sn4+ doping increases both the work function and oxygen vacancies of the film, contributing to the improved hole-selective contact performance. As a result, the photoelectric conversion efficiencies of Ta2O5/p-Si heterojunction solar cells are significantly improved from 14.84% to 18.47%, with a high thermal stability up to 300 °C. The work has provided a feasible strategy to explore new features of TMOs for carrier-selective contact applications, that is, bipolar carrier transport properties.

Parallel-transmission spatial spectral pulse design with local specific absorption rate control: Demonstration for robust uniform water-selective excitation in the human brain at 7 T.

PURPOSE: To propose a novel method for parallel-transmission (pTx) spatial-spectral pulse design and demonstrate its utility for robust uniform water-selective excitation (water excitation) across the entire brain. THEORY AND METHODS: Our design problem is formulated as a magnitude-least-squares minimization with joint RF and k-space optimization under explicit specific-absorption-rate constraints. For improved robustness against off-resonance effects, the spectral component of the excitation target is prescribed to have a water passband and a fat stopband. A two-step algorithm was devised to solve our design problem, with Step 1 aiming to solve a reduced problem to find a sensible start point for Step 2 to solve the original problem. The efficacy of our pulse design was evaluated in simulation, phantom, and human experiments using the commercial Nova head coil. Universal pulses were also designed based on a 10-subject training data set to demonstrate the utility of our method for plug-and-play pTx. RESULTS: For kT-points and spiral nonselective parameterizations, our design method outperformed the pTx interleaved binomial approach, reducing RMS error by up to about 35% for water excitation and about 97% for fat suppression (over a 200-Hz bandwidth) while decreasing local specific absorption rate by about 30%. Both our subject-specific and universal pulses improved water excitation, restoring signal loss in the cerebellum while suppressing fat signal even in regions of large susceptibility-induced off-resonances. CONCLUSION: Demonstrated useful for 4D (3D spatial, one-dimensional spectral) pTx spatial-spectral pulse design, our proposed method provides an effective solution for robust volumetric uniform water excitation, holding a promise to many ultrahigh-field applications.

RF coil design strategies for improving SNR at the ultrahigh magnetic field of 10.5T.

PURPOSE: Toward pushing the boundaries of ultrahigh fields for human brain imaging, we wish to evaluate experimentally achievable SNR relative to ultimate intrinsic SNR (uiSNR) at 10.5T, develop design strategies toward approaching the latter, quantify magnetic field-dependent SNR gains, and demonstrate the feasibility of whole-brain, high-resolution human brain imaging at this uniquely high field strength. METHODS: A dual row 16-channel self-decoupled transmit (Tx) and receive (Rx) array was developed for 10.5T using custom Tx/Rx switches. A 64-channel receive-only array was built to fit into the 16-channel Tx/Rx array. Electromagnetic modeling and experiments were used to define safe operational power limits. Experimental SNR was evaluated relative to uiSNR at 10.5T and 7T. RESULTS: The 64-channel Rx array alone captured approximately 50% of the central uiSNR at 10.5T, while an identical array developed for 7T captured about 76% of uiSNR at 7T. The 16-channel Tx/80-channel Rx configuration brought the fraction of uiSNR captured at 10.5T to levels comparable to the 64-channel Rx array at 7T. SNR data displayed an approximate B 0 2 $$ {\mathrm{B}}_0^2 $$ dependence over a large central region when evaluated in the context of uiSNR. Whole-brain, high-resolution T 2 * $$ {\mathrm{T}}_2^{\ast } $$ -weighted and T1-weighted anatomical and gradient-recalled-echo BOLD-EPI functional MRI images were obtained at 10.5T for the first time with such an advanced array. CONCLUSION: We demonstrated the ability to approach the uiSNR at 10.5T over the human brain, achieving large SNR gains over 7T, currently the most commonly used ultrahigh-field platform. Whole-brain, high-resolution anatomical and EPI-based functional MRI data were obtained at 10.5T, illustrating the promise of greater than 10T fields in studying the human brain.

Application of metagenomic next-generation sequencing in optimizing the diagnosis of ascitic infection in patients with liver cirrhosis.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) is an emerging technique for the clinical diagnosis of infectious disease that has rarely been used for the diagnosis of ascites infection in patients with cirrhosis. This study compared mNGS detection with conventional culture methods for the on etiological diagnosis of cirrhotic ascites and evaluated the clinical effect of mNGS. METHODS: A total of 109 patients with ascites due to cirrhosis were included in the study. We compared mNGS with conventional culture detection by analyzing the diagnostic results, pathogen species and clinical effects. The influence of mNGS on the diagnosis and management of ascites infection in patients with cirrhosis was also evaluated. RESULTS: Ascites cases were classified into three types: spontaneous bacterial peritonitis (SBP) (16/109, 14.7%), bacterascites (21/109, 19.3%) and sterile ascites (72/109, 66.1%). In addition, 109 patients were assigned to the ascites mNGS-positive group (80/109, 73.4%) or ascites mNGS-negative group (29/109, 26.6%). The percentage of positive mNGS results was significantly greater than that of traditional methods (73.4% vs. 28.4%, P < 0.001). mNGS detected 43 strains of bacteria, 9 strains of fungi and 8 strains of viruses. Fourteen bacterial strains and 3 fungal strains were detected via culture methods. Mycobacteria, viruses, and pneumocystis were detected only by the mNGS method. The mNGS assay produced a greater polymicrobial infection rate than the culture method (55% vs. 16%). Considering the polymorphonuclear neutrophil (PMN) counts, the overall percentage of pathogens detected by the two methods was comparable, with 87.5% (14/16) in the PMN ≥ 250/mm3 group and 72.0% (67/93) in the PMN < 250/mm3 group (P > 0.05). Based on the ascites PMN counts combined with the mNGS assay, 72 patients (66.1%) were diagnosed with ascitic fluid infection (AFI) (including SBP and bacterascites), whereas based on the ascites PMN counts combined with the culture assay, 37 patients (33.9%) were diagnosed with AFI (P < 0.05). In 60 (55.0%) patients, the mNGS assay produced positive clinical effects; 40 (85.7%) patients had their treatment regimen adjusted, and 48 patients were improved. The coincidence rate of the mNGS results and clinical findings was 75.0% (60/80). CONCLUSIONS: Compared with conventional culture methods, mNGS can improve the detection rate of ascites pathogens, including bacteria, viruses, and fungi, and has significant advantages in the diagnosis of rare pathogens and pathogens that are difficult to culture; moreover, mNGS may be an effective method for improving the diagnosis of ascites infection in patients with cirrhosis, guiding early antibiotic therapy, and for reducing complications related to abdominal infection. In addition, explaining mNGS results will be challenging, especially for guiding the treatment of infectious diseases.

Intrinsic edge states and strain-tunable spin textures in the Janus 1T-VTeCl monolayer.

Using first-principles calculations and micro-magnetic simulations, we investigate the electronic structures, the effect of biaxial strain on the topological characteristics, magnetic anisotropy energy (MAE), Dzyaloshinskii-Moriya interaction (DMI) and spin textures in the Janus 1T phase VTeCl (1T-VTeCl) monolayer. Our results show that 1T-VTeCl has an intrinsic edge state, and a topological phase transition with a sizeable band gap is achieved by applying biaxial strain. Interestingly, the MAE can be switched from the in-plane to the off-plane with a compressive strain of -5%. Microscopically, the origin of MAE is mainly associated with the large spin-orbit coupling (SOC) from the heavy nonmagnetic Te atoms rather than that from the V atoms. Furthermore, the induced DMI (0.09 meV) can occur stabilizing magnetic merons without applying temperatures and magnetic fields. Then, the skyrmions, frustrated antiferromagnetism and vortex are induced after applying a suitable compressive strain. Our study provides compelling evidence that the 1T-VTeCl monolayer with topological properties holds great potential for application in spintronic devices, as well as information storage devices based on different magnetic phases achievable through strain engineering.

The possible influence of third-order shim coils on gradient-magnet interactions: an inter-field and inter-site study.

OBJECTIVE: To assess the possible influence of third-order shim coils on the behavior of the gradient field and in gradient-magnet interactions at 7 T and above. MATERIALS AND METHODS: Gradient impulse response function measurements were performed at 5 sites spanning field strengths from 7 to 11.7 T, all of them sharing the same exact whole-body gradient coil design. Mechanical fixation and boundary conditions of the gradient coil were altered in several ways at one site to study the impact of mechanical coupling with the magnet on the field perturbations. Vibrations, power deposition in the He bath, and field dynamics were characterized at 11.7 T with the third-order shim coils connected and disconnected inside the Faraday cage. RESULTS: For the same whole-body gradient coil design, all measurements differed greatly based on the third-order shim coil configuration (connected or not). Vibrations and gradient transfer function peaks could be affected by a factor of 2 or more, depending on the resonances. Disconnecting the third-order shim coils at 11.7 T also suppressed almost completely power deposition peaks at some frequencies. DISCUSSION: Third-order shim coil configurations can have major impact in gradient-magnet interactions with consequences on potential hardware damage, magnet heating, and image quality going beyond EPI acquisitions.

A Fluorescent Probe Containing Triphenylamine-Benzofuranone Moiety for Detecting Cysteine and Imaging in Living Pulmonary Cells Under Hypercapnia.

In this work, a fluorescent probe TPB-Cys derived from triphenylamine-benzofuranone was developed for monitoring the cysteine (Cys) level and imaging in living pulmonary cells under hypercapnia condition. A systematic hypoxia module was tried to cover both the in-solution test and pulmonary cellular imaging. The hypoxia condition did not obviously affect the fluorescence response signal during the in-solution test. The fluorescence signal at 540 enhanced in a dose-dependent enhancement along with the increase of the Cys concentration. The probe showed the advantages including relatively long linear range, high sensitivity, high stability, and high selectivity. With low cyto-toxicity, TPB-Cys achieved the monitoring of the endogenous Cys level in living pulmonary cells. Furthermore, it also realized the visualization of the affection of the hypoxia and hypoxia recovered conditions. This work was informative for both the accurate diagnosis and potential medical techniques.

Cordycepin Enhances the Therapeutic Efficacy of Doxorubicin in Treating Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high mortality and poor prognosis. Meanwhile, doxorubicin, a chemotherapeutic agent for triple-negative breast cancer, has poor sensitivity. The objective of this study was to examine the effect of cordycepin on doxorubicin sensitivity and efficacy in the TNBC xenograft model and explore the relevant molecular pathways. The combination of the drugs in nude mice carrying MDA-MB-231 xenografts significantly reduced the volume, size, and weight of xenografts and improved the tumor inhibition rate. The drug combination was significantly more effective than cordycepin or doxorubicin alone, reflecting the fact that cordycepin enhanced the anti-tumor effects of doxorubicin in MDA-MB-231 xenografts. At the same time, the monitoring of several biological parameters failed to detect any obvious side effects associated with this treatment. After predicting the importance of the TNF pathway in inhibiting tumor growth using network pharmacology methods, we verified the expression of TNF pathway targets via immunohistochemistry and quantitative PCR. Furthermore, a TNF-α inhibitor was able to abrogate the beneficial effects of cordycepin and doxorubicin treatment in MDA-MB-231 cells. This clearly indicates the role of TNF-α, or related molecules, in mediating the therapeutic benefits of the combined treatment in animals carrying TNBC xenografts. The observations reported here may present a new direction for the clinical treatment of TNBC.

Avicularin alleviates acute liver failure by regulation of the TLR4/MyD88/NF-κB and Nrf2/HO-1/GPX4 pathways to reduce inflammation and ferroptosis.

Acute liver failure (ALF) is an inflammation-mediated hepatocyte death process associated with ferroptosis. Avicularin (AL), a Chinese herbal medicine, exerts anti-inflammatory and antioxidative effects. However, the protective effect of AL and the mechanism on ALF have not been reported. Our in vivo results suggest that AL significantly alleviated lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced hepatic pathological injury, liver enzymes, inflammatory cytokines, reactive oxygen species and iron levels and increased the antioxidant enzyme activities (malondialdehyde and glutathione). Our further in vitro experiments demonstrated that AL suppressed inflammatory response in LPS-stimulated RAW 264.7 cells via blocking the toll-like receptor 4 (TLR4)/myeloid differentiation protein-88 (MyD88)/nuclear factor kappa B (NF-κB) pathway. Moreover, AL attenuated ferroptosis in D-GalN-induced HepG2 cells by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) pathway. Therefore, AL can alleviate inflammatory response and ferroptosis in LPS/D-GalN-induced ALF, and its protective effects are associated with blocking TLR4/MyD88/NF-κB pathway and activating Nrf2/HO-1/GPX4 pathway. Moreover, AL is a promising therapeutic option for ALF and should be clinically explored.

AMIGO2 attenuates innate cisplatin sensitivity by suppression of GSDME-conferred pyroptosis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. Cisplatin is commonly used in the treatment of many malignant tumours including NSCLC. The innate drug sensitivity greatly affects the clinical efficacy of cisplatin-based chemotherapy. As a plasma membrane adhesion molecule, amphoterin-induced gene and ORF-2 (AMIGO2) initially identified as a neurite outgrowth factor has been recently found to play a crucial role in cancer occurrence and progression. However, it is still unclear whether AMIGO2 is involved in innate cisplatin sensitivity. In the present study, we provided the in vitro and in vivo evidences indicating that the alteration of AMIGO2 expression triggered changes of innate cisplatin sensitivity as well as cisplatin-induced pyroptosis in NSCLC. Further results revealed that AMIGO2 might inhibit cisplatin-induced activation of (caspase-8 and caspase-9)/caspase-3 via stimulating PDK1/Akt (T308) signalling axis, resulting in suppression of GSDME cleavage and the subsequent cell pyroptosis, thereby decreasing the sensitivity of NSCLC cells to cisplatin treatment. The results provided a new insight that AMIGO2 regulated the innate cisplatin sensitivity of NSCLC through GSDME-mediated pyroptosis.

Reconstruction for 7T high-resolution whole-brain diffusion MRI using two-stage N/2 ghost correction and L1-SPIRiT without single-band reference.

PURPOSE: To combine a new two-stage N/2 ghost correction and an adapted L1-SPIRiT method for reconstruction of 7T highly accelerated whole-brain diffusion MRI (dMRI) using only autocalibration scans (ACS) without the need of additional single-band reference (SBref) scans. METHODS: The proposed ghost correction consisted of a 3-line reference approach in stage 1 and the reference-free entropy method in stage 2. The adapted L1-SPIRiT method was formulated within the 3D k-space framework. Its efficacy was examined by acquiring two dMRI data sets at 1.05-mm isotropic resolutions with a total acceleration of 6 or 9 (i.e., 2-fold or 3-fold slice and 3-fold in-plane acceleration). Diffusion analysis was performed to derive DTI metrics and estimate fiber orientation distribution functions (fODFs). The results were compared with those of 3D k-space GRAPPA using only ACS, all in reference to 3D k-space GRAPPA using both ACS and SBref (serving as a reference). RESULTS: The proposed ghost correction eliminated artifacts more robustly than conventional approaches. Our adapted L1-SPIRiT method outperformed 3D k-space GRAPPA when using only ACS, improving image quality to what was achievable with 3D k-space GRAPPA using both ACS and SBref scans. The improvement in image quality further resulted in an improvement in estimation performances for DTI and fODFs. CONCLUSION: The combination of our new ghost correction and adapted L1-SPIRiT method can reliably reconstruct 7T highly accelerated whole-brain dMRI without the need of SBref scans, increasing acquisition efficiency and reducing motion sensitivity.

Anticoagulation targeting membrane-bound anionic phospholipids improves outcomes of traumatic brain injury in mice.

Severe traumatic brain injury (TBI) often causes an acute systemic hypercoagulable state that rapidly develops into consumptive coagulopathy. We have recently demonstrated that TBI-induced coagulopathy (TBI-IC) is initiated and disseminated by brain-derived extracellular vesicles (BDEVs) and propagated by extracellular vesicles (EVs) from endothelial cells and platelets. Here, we present results from a study designed to test the hypothesis that anticoagulation targeting anionic phospholipid-expressing EVs prevents TBI-IC and improves the outcomes of mice subjected to severe TBI. We evaluated the effects of a fusion protein (ANV-6L15) for improving the outcomes of TBI in mouse models combined with in vitro experiments. ANV-6L15 combines the phosphatidylserine (PS)-binding annexin V (ANV) with a peptide anticoagulant modified to preferentially target extrinsic coagulation. We found that ANV-6L15 reduced intracranial hematoma by 70.2%, improved neurological function, and reduced death by 56.8% in mice subjected to fluid percussion injury at 1.9 atm. It protected the TBI mice by preventing vascular leakage, tissue edema, and the TBI-induced hypercoagulable state. We further showed that the extrinsic tenase complex was formed on the surfaces of circulating EVs, with the highest level found on BDEVs. The phospholipidomic analysis detected the highest levels of PS on BDEVs, as compared with EVs from endothelial cells and platelets (79.1, 15.2, and 3.5 nM/mg of protein, respectively). These findings demonstrate that TBI-IC results from a trauma-induced hypercoagulable state and may be treated by anticoagulation targeting on the anionic phospholipid-expressing membrane of EVs from the brain and other cells.

Conformation-dependent blockage of activated VWF improves outcomes of traumatic brain injury in mice.

Traumatic brain injury-induced coagulopathy (TBI-IC) causes life-threatening secondary intracranial bleeding. Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood. We report results of a study designed to test the hypothesis that von Willebrand factor (VWF) released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy. This hyperadhesive VWF can be selectively blocked by a VWF A2-domain protein to prevent TBI-IC and to improve neurological function with a minimal risk of bleeding. We demonstrated that A2 given through intraperitoneal injection or IV infusion reduced TBI-induced death by >50% and significantly improved the neurological function of C57BL/6J male mice subjected to severe lateral fluid percussion injury. A2 protected the endothelium from extracellular vesicle-induced injury, reducing TBI-induced platelet activation and microvesiculation, and preventing a TBI-induced hypercoagulable state. A2 achieved this therapeutic efficacy by specifically blocking the A1 domain exposed on the hyperadhesive VWF released during acute TBI. These results suggest that VWF plays a causal role in the development of TBI-IC and is a therapeutic target for this life-threatening complication of TBI.

Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis.

FGFR3 kinase mutations are associated with a variety of malignancies, but FGFR3 mutant inhibitors have rarely been studied. Furthermore, the mechanism of pan-FGFR inhibitors resistance caused by kinase domain mutations is still unclear. In this study, we try to explain the mechanism of drug resistance to FGFR3 mutation through global analysis and local analysis based on molecular dynamics simulation, binding free energy analysis, umbrella sampling and community network analysis. The results showed that FGFR3 mutations caused a decrease in the affinity between drugs and FGFR3 kinase, which was consistent with the reported experimental results. Possible mechanisms are that mutations affect drug-protein affinity by altering the environment of residues near the hinge region where the protein binds to the drug, or by affecting the A-loop and interfering with the allosteric communication networks. In conclusion, we systematically elucidated the underlying mechanism of pan-FGFR inhibitor resistance caused by FGFR3 mutation based on molecular dynamics simulation strategy, which provided theoretical guidance for the development of FGFR3 mutant kinase inhibitors.

Single unit analysis and wide-field imaging reveal alterations in excitatory and inhibitory neurons in glioma.

While several studies have attributed the development of tumour-associated seizures to an excitatory-inhibitory imbalance, we have yet to resolve the spatiotemporal interplay between different types of neuron in glioma-infiltrated cortex. Herein, we combined methods for single unit analysis of microelectrode array recordings with wide-field optical mapping of Thy1-GCaMP pyramidal cells in an ex vivo acute slice model of diffusely infiltrating glioma. This enabled simultaneous tracking of individual neurons from both excitatory and inhibitory populations throughout seizure-like events. Moreover, our approach allowed for observation of how the crosstalk between these neurons varied spatially, as we recorded across an extended region of glioma-infiltrated cortex. In tumour-bearing slices, we observed marked alterations in single units classified as putative fast-spiking interneurons, including reduced firing, activity concentrated within excitatory bursts and deficits in local inhibition. These results were correlated with increases in overall excitability. Mechanistic perturbation of this system with the mTOR inhibitor AZD8055 revealed increased firing of putative fast-spiking interneurons and restoration of local inhibition, with concomitant decreases in overall excitability. Altogether, our findings suggest that diffusely infiltrating glioma affect the interplay between excitatory and inhibitory neuronal populations in a reversible manner, highlighting a prominent role for functional mechanisms linked to mTOR activation.

Electronic properties, skyrmions and bimerons in Janus CrXY (X, Y = S, Se, Te, Cl, Br, I, and X ≠ Y) monolayers.

Using first-principles calculations, we systematically investigate the electronic properties, chiral skyrmions and bimerons in two-dimensional (2D) Janus CrXY (X, Y = S, Se, Te, Cl, Br, I, and X ≠ Y) monolayers. We found that the categories of nonmagnetic atoms (X and Y in CrXY) determine whether CrXY is a ferromagnetic metal or a semiconductor. Unexpectedly, the CrBrS monolayer of these CrXY materials is a room temperature ferromagnetic semiconductor with a Curie temperature of 303 K, and it possesses an off-plane magnetic anisotropy energy of 0.06 meV. Besides, a strong Dzyaloshinskii-Moriya interaction (DMI) of 3.10 meV is found in CrTeI and is mainly induced by the strong spin-orbit coupling of the nonmagnetic atoms Te(I) rather than that of the magnetic Cr atoms. Furthermore, using micromagnetic simulations, skyrmions can be stabilized in CrSeBr without external magnetic fields. More importantly, the bimerons in CrSeCl with in-plane magnetic anisotropy can be transformed into skyrmions or a ferromagnetic state by controlling the direction of external magnetic fields. Our work investigates fourteen kinds of Janus monolayers, serving as guidelines for materials research on DMI, skyrmions and bimerons.

Evaluating stored platelet shape change using imaging flow cytometry.

Platelets are routinely stored at room temperature for 5-7 days before transfusion. Stored platelet quality is traditionally assessed by Kunicki's morphology score. This method requires extensive training, experience, and is highly subjective. Moreover, the number of laboratories familiar with this technique is decreasing. Cold storage of platelets has recently regained interest because of potential advantages such as reduced bacterial growth and preserved function. However, platelets exposed to cold temperatures change uniformly from a discoid to a spherical shape, reducing the morphology score outcomes to spheroid versus discoid during cooling. We developed a simpler, unbiased screening tool to measure temperature-induced platelet shape change using imaging flow cytometry. When reduced to two dimensions, spheres appear circular, while discs are detected on a spectrum from fusiform to circular. We defined circular events as having a transverse axis of >0.8 of the longitudinal axis and fusiform events ≤0.8 of the longitudinal axis. Using this assay, mouse and human platelets show a temperature and time-dependent, two-dimensional shape change from fusiform to circular, consistent with their three-dimensional change from discs to spheres. The method we describe here is a valuable tool for detecting shape change differences in response to agonists or temperature and will help screening for therapeutic measures to mitigate the cold-induced storage lesion.

What is the context? Platelets for transfusion are currently stored for 5­7 days at room temperature, increasing the risk for bacterial growthCold storage reduces the risk for bacterial growth but reduces circulation timeStored platelet quality can be assessed by the light microscopy-based Morphology Score, first described in the 1970sDownsides of the Morphology Score include subjectivity, extensive training, and reduced availability in platelet laboratories.What is new? In this study, we provide data showing that the Morphology score is reduced to a binary spheres versus discs response in cold-exposed plateletsWe developed an imaging flow cytometry-based approach to quantify platelets' response to cold based on the two-dimensional projection of the three-dimensional shapes, i.e., fusiform (discoid) versus circular (discoid and spherical)We provide validation of this approach in mouse and human plateletsWhat is the impact?This study provides an easy and unbiased tool for laboratories working on circumventing the cold-induced storage lesion or documenting spherical shape change in general.

Genome-wide association study identifies functional genomic variants associated with young stock survival in Nordic Red Dairy Cattle.

Identifying quantitative trait loci (QTL) associated with calf survival is essential for both reducing economic loss in cattle industry and understanding the genetic basis of the trait. To identify mutations and genes underlying young stock survival (YSS), we performed GWAS using de-regressed estimated breeding values of a YSS index and its component traits defined by sex and age in 3,077 Nordic Red Dairy Cattle (RDC) bulls and 2 stillbirth traits (first lactation and later lactations) in 5,141 RDC bulls. Two associated QTL regions on Bos taurus autosome (BTA) 4 and 6 were identified for the YSS index. The results of 4 YSS component traits indicate that same QTL regions were associated with bull and heifer calf mortality, but the effects were different over the growing period and suggested an additional QTL on BTA23. The GWAS on stillbirth identified 3 additional QTL regions on BTA5, 14, and 24 compared with YSS and its component traits. The conditional test of BTA6 showed at least 2 closely located QTL segregating for YSS component traits and stillbirth. We found 2 independent QTL for stillbirth on BTA23. The post-GWAS revealed LCORL, PPM1K, SSP1, MED28, and LAP3 are putative causal genes on BTA6, and a frame shift variant within LCORL, BTA6:37401770 (rs384548488) could be the putative causal variant. On BTA4, the GRB10 gene is the putative causal gene and BTA4:5296018 is the putative causal variant. In addition, NDUFA9 and FGF23 on BTA5, LYN on BTA14, and KCNK5 on BTA23 are putative causal genes for QTL for stillbirth. The gene analysis also proposed several candidate genes. Our findings shed new light on the candidate genes affecting calf survival, and the knowledge could be utilized to reduce calf mortality and thereby enhance welfare of dairy cattle.

Cadmium facilitates the formation of large lipid droplets via PLCß2-DAG-DGKε-PA signal pathway in Leydig cells.

Cadmium (Cd) exposure damages the reproductive system. Lipid droplets (LDs) play an important role in steroid-producing cells to provide raw material for steroid hormone. We have found that the LDs of Leydig cells exposed to Cd are bigger than those of normal cells, but the effects on steroidogenesis and its underlying mechanism remains unclear. Using Isobaric tag for relative and absolute quantitation (iTARQ) proteomics, phosphodiesterase beta-2 (PLCß2) was identified as the most significantly up-regulated protein in immature Leydig cells (ILCs) and adult Leydig cells (ALCs) derived from male rats exposed to maternal Cd. Consistent with high expression of PLCß2, the size of LDs was increased in Leydig cells exposed to Cd, accompanied by reduction in cholesterol and progesterone (P4) levels. However, the high PLCß2 did not result in high diacylglycerol (DAG) level, because Cd exposure up-regulated diacylglycerol kinases ε (DGKε) to promote the conversion from DAG to phosphatidic acid (PA). Exogenous PA, which was consistent with the intracellular PA concentration induced by Cd, facilitated the formation of large LDs in R2C cells, followed by reduced P4 level in the culture medium. When PLCß2 expression was knocked down, the increased DGKε caused by Cd was reversed, and then the PA level was decreased to normal. As results, large LDs returned to normal size, and the level of total cholesterol was improved to restore steroidogenesis. The accumulation of PA regulated by PLCß2-DAG-DGKε signal pathway is responsible for the formation of large LDs and insufficient steroid hormone synthesis in Leydig cells exposed to Cd. These data highlight that LD is an important target organelle for Cd-induced steroid hormone deficiency in males.