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Drug discovery involves a crucial step of optimizing molecules with the desired structural groups. In the domain of computer-aided drug discovery, deep learning has emerged as a prominent technique in molecular modeling. Deep generative models, based on deep learning, play a crucial role in generating novel molecules when optimizing molecules. However, many existing molecular generative models have limitations as they solely process input information in a forward way. To overcome this limitation, we propose an improved generative model called BD-CycleGAN, which incorporates BiLSTM (bidirectional long short-term memory) and Mol-CycleGAN (molecular cycle generative adversarial network) to preserve the information of molecular input. To evaluate the proposed model, we assess its performance by analyzing the structural distribution and evaluation matrices of generated molecules in the process of structural transformation. The results demonstrate that the BD-CycleGAN model achieves a higher success rate and exhibits increased diversity in molecular generation. Furthermore, we demonstrate its application in molecular docking, where it successfully increases the docking score for the generated molecules. The proposed BD-CycleGAN architecture harnesses the power of deep learning to facilitate the generation of molecules with desired structural features, thus offering promising advancements in the field of drug discovery processes.

Using global magnetohydrodynamics simulations, we have developed a three-dimensional parametric model for the Venusian bow shock based on a generalized conic section function defined by six parameters, with the effects of the solar wind magnetosonic Mach number ( M _MS ) and the interplanetary magnetic field (IMF) involved. The parametric model’s results reveal the following findings: (1) The size of the Venusian bow shock is primarily determined by M _MS . An increase in M _MS results in the bow shock moving closer to Venus and a reduction in its flaring angle. (2) Both the subsolar standoff distance and the bow shock’s flaring angle increase with the strength of the IMF components that are perpendicular to the solar wind flow direction ( B _Y and B _Z in the Venus-centered solar orbital coordinate system), whereas the parallel IMF component ( B _X ) has a limited impact on the subsolar standoff distance but affects the flaring angle. (3) The cross section of the bow shock is elongated in the direction perpendicular to the IMF on the Y – Z plane, and the elongation degree is enhanced with increasing intensities of B _Y and B _Z . (4) The quasi-parallel bow shock locates closer to the planet as compared to the quasi-perpendicular bow shock. These findings are in alignment with prior empirical and theoretical models. The influences of M _MS and IMF on the bow shock’s position and geometry are attributed to the propagation of fast magnetosonic waves, showing the nature of the formation of a collisionless bow shock under the interaction of magnetized flow with an atmospheric object.

Traditional ytterbium-doped high-power fiber lasers generally use a unidirectional output structure. To reduce the cost and improve the efficiency of the fiber laser, we propose a bidirectional output fiber laser (BOFL). The BOFL has many advantages over that of the traditional unidirectional output fiber laser (UOFL) and has a wide application in the industrial field. In theory, the model of the BOFL is established, and a comparison of the nonlinear effect in the traditional UOFL and the BOFL is studied. Experimentally, high-power continuous wave (CW) and quasi-continuous wave (QCW) BOFLs are demonstrated. In the continuous laser, we first combine the BOFL with the oscillating amplifying integrated structure, and a near-single-mode bidirectional 2 × 4 kW output with a total power of above 8 kW is demonstrated. Then, with the simple BOFL, a CW bidirectional 2 × 5 kW output with a total power of above 10 kW is demonstrated. By means of pump source modulation, a QCW BOFL is developed, and the output of a near-single mode QCW laser with a peak output of 2 × 4.5 kW with a total peak power of more than 9 kW is realized. Both CW and QCW output BOFL are the highest powers reported at present.

Background: Selective reporting has important value in antibiotic management. The purpose of this study was to explore the impact of AST selective reporting on prescribing behavior, so as to provide evidence for the implementation and improvement of selective reporting policies in microbiology laboratories at home and abroad.Methods: A cross-sectional study was conducted in a teaching tertiary hospital in China in July 2021. We designed selective reports and routine reports for urinary tract infections caused by Escherichia coli and lower respiratory tract infections caused by Pseudomonas aeruginosa. Questionnaires were conducted among participants by case vignettes, and 116 valid questionnaires were collected. The appropriateness rate of antibiotic prescription and the prescription rate of drug-resistant antibiotics, cephalosporins, fluoroquinolones, and carbapenems were calculated and compared between the selective reporting group and the routine reporting group in each case.Results: In most cases, we found that AST selective reporting could increase the appropriateness rate of antibiotic prescription (p < 0.05) and reduce the drug-resistant antibiotic prescription rate (p < 0.01), cephalosporin drug prescription rate (p < 0.05) and fluoroquinolone drug prescription rate (p < 0.01). Although the difference in carbapenems prescription rate was not significant, selective reporting could reduce the number of its prescriptions to some extent.Conclusion: AST selective reporting can help promote the appropriate use of antibiotics and reduce the use of broad-spectrum antibiotics. It is suggested to develop scientific and effective selective reporting practices and strengthen the two-way communication between clinicians and microbiology laboratories, thereby enabling microbiology laboratories to play a more important role in clinical antimicrobial management.

Gait impairment is a common symptom of Parkinson's disease (PD), but its neural signature remains unclear due to the interindividual variability of gait performance. Identifying a robust gait-brain correlation at the individual level would provide insight into a generalizable neural basis of gait impairment. In this context, this study aimed to detect connectome that can predict individual gait function of PD, and follow-up analyses assess the molecular architecture underlying the connectome by relating it to the neurotransmitter-receptor/transporter density maps. Resting-state functional magnetic resonance imaging was used to detect the functional connectome, and gait function was assessed via a 10 m-walking test. The functional connectome was first detected within drug-naive patients (N = 48) by using connectome-based predictive modeling following cross-validation and then successfully validated within drug-managed patients (N = 30). The results showed that the motor, subcortical, and visual networks played an important role in predicting gait function. The connectome generated from patients failed to predict the gait function of 33 normal controls (NCs) and had distinct connection patterns compared to NCs. The negative connections (connection negatively correlated with 10 m-walking-time) pattern of the PD connectome was associated with the density of the D2 receptor and VAChT transporter. These findings suggested that gait-associated functional alteration induced by PD pathology differed from that induced by aging degeneration. The brain dysfunction related to gait impairment was more commonly found in regions expressing more dopaminergic and cholinergic neurotransmitters, which may aid in developing targeted treatments.

Forest soil CO2 flux measurements are important for studying global climate change. Current monitoring methods are based on closed gas chambers, which block the wind pumping effect of near-surface winds in the measurements, resulting in biased values. Therefore, in this study, the effects of near-surface winds on chamber-monitored fluxes were investigated. The CO2 flux was quantified using a designed flux reference system with different CO2 concentrations, and the monitoring performance of the closed chamber was studied. Wavelet coherence was used to analyze the response relationship between near-surface winds and soil gas, and was combined with a flux calculation model to explore the relevant factors influencing gas chamber measurement-produced bias. The data indicate that at near-surface wind speeds greater than 0.8 m·s−1, gas transport enhancement was significant and further increased the deviation of the gas chamber-monitored CO2 fluxes. The monitoring error of the flow chamber (NSF) increased from 7% to 30% in soils with low carbon content, but did not vary significantly (3–7%) in soils with high CO2 concentrations. The flux measurement bias of the non-flow chamber (NSNF) was positively correlated with the soil carbon content, with the measurement error expanding by 16–24% with increasing soil CO2 concentrations. The measurement errors of the exponential and linear models in a windless environment were 9.8% (Exp) and 18.7% (Lin), respectively. The estimation errors of both models were positively correlated with both the time of a single monitoring event and the wind-induced coefficient Dw. Therefore, flux calculation models should be improved by considering environments with wind disturbances to reduce the effect of wind on measured values, which will help improve the accuracy of ecosystem carbon budgets.

Although studies have estimated the associations of PM2.5 with total mortality or cardiopulmonary mortality, few have comprehensively examined cause-specific mortality risk and burden caused by ambient PM2.5. Thus, this study investigated the association of short-term exposure to PM2.5 with cause-specific mortality using a death-spectrum wide association study (DWAS). Individual information of 5,450,764 deaths during 2013–2018 were collected from six provinces in China. Daily PM2.5 concentration in the case and control days were estimated by a random forest model. A time-stratified case-crossover study design was applied to estimate the associations (access risk, ER) of PM2.5 with cause-specific mortality, which was then used to calculate the population-attributable fraction (PAF) of mortality and the corresponding mortality burden caused by PM2.5. Each 10 μg/m3 increase in PM2.5 concentration (lag03) was associated with a 0.80 % [95 % confidence interval (CI): 0.73 %, 0.86 %] rise in total mortality. We found greater mortality effect at PM2.5 concentrations

Abstract This study aimed to investigate the cortical microstructural/macrostructural degenerative patterns in Parkinson’s disease (PD) patients with mild cognitive impairment (MCI). Overall, 38 PD patients with normal cognition (PD-NC), 38 PD-MCI, and 32 healthy controls (HC) were included. PD-MCI was diagnosed according to the MDS Task Force level II criteria. Cortical microstructural alterations were evaluated with Neurite Orientation Dispersion and Density Imaging. Cortical thickness analyses were derived from T1-weighted imaging using the FreeSurfer software. For cortical microstructural analyses, compared with HC, PD-NC showed lower orientation dispersion index (ODI) in bilateral cingulate and paracingulate gyri, supplementary motor area, right paracentral lobule, and precuneus (P FWE 100 voxels) and the ODI values were associated with the Montreal Cognitive Assessment scores (r = 0.440, P

Abstract Spectrally determination of temperature based on the lanthanide-doped nanocrystals (NCs) is a vital strategy to noninvasively measure the temperature in practical applications. Here, we synthesized a series of SrF2:Yb3+/Ho3+ NCs and simultaneously observed the efficient visible upconversion luminescence (UCL) and near-infrared (NIR) downconversion luminescence (DCL) under 980, 940 and 915 nm excitations. Subsequently, these NCs were further utilized for thermometers based on the Boltzmann (thermally coupled levels, TCLs) and non-Boltzmann (non-thermally coupled levels, NTCLs) of Ho3+ ions in the first (~ 650 nm), second (~ 1012 nm) and third (~ 2020 nm) biological windows (BW-I, BW-II and BW-III) under tri-wavelength excitations. The thermometric parameters including the relative sensitivity ( $$S_{{\text{r}}}$$ S r ) and temperature uncertainty ( $$\delta T$$ δ T ) are quantitatively determined on the I 648/I 541 (BW-I), I 1186/I 1012 (BW-II), and I 1950/I 2020 (BW-III) transitions of Ho3+ ions in the temperature range of 303–573 K. Comparative experimental results demonstrated that the thermometer has superior performances.

Abstract Magnetosonic (MS) waves are dominant plasma waves causing severe Martian ionospheric erosion. They are generally considered to originate upstream of Martian bow shock with frequencies near the upstream proton gyrofrequency. However, whether MS waves can be locally excited lacks theoretical analysis. Here we present an event of MS waves with frequencies above and closely related to the local proton gyrofrequency in the Martian ionosphere. Concurrently, ring beam hot proton distributions are observed due to the penetration of magnetosheath protons. By employing the observed plasma and magnetic field data, the calculated linear growth rates for MS waves agree well with the observed wave power spectra, demonstrating that they can be locally excited by unstable ring beam hot protons at Mars. Our results could be of great help in understanding the excitation of MS waves in a heavy ion‐rich environment around unmagnetized planets.

BackgroundIn December 2022, there was a large Omicron epidemic in Hangzhou, China. Many people were diagnosed with Omicron pneumonia with variable symptom severity and outcome. Computed tomography (CT) imaging has been proven to be an important tool for COVID-19 pneumonia screening and quantification. We hypothesized that CT-based machine learning algorithms can predict disease severity and outcome in Omicron pneumonia, and we compared its performance with the pneumonia severity index (PSI)-related clinical and biological features.MethodsOur study included 238 patients with the Omicron variant who have been admitted to our hospital in China from 15 December 2022 to 16 January 2023 (the first wave after the dynamic zero-COVID strategy stopped). All patients had a positive real-time polymerase chain reaction (PCR) or lateral flow antigen test for SARS-CoV-2 after vaccination and no previous SARS-CoV-2 infections. We recorded patient baseline information pertaining to demographics, comorbid conditions, vital signs, and available laboratory data. All CT images were processed with a commercial artificial intelligence (AI) algorithm to obtain the volume and percentage of consolidation and infiltration related to Omicron pneumonia. The support vector machine (SVM) model was used to predict the disease severity and outcome.ResultsThe receiver operating characteristic (ROC) area under the curve (AUC) of the machine learning classifier using PSI-related features was 0.85 (accuracy = 87.40%, p

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) could develop preceding or come after motor symptoms during Parkinson's disease (PD). It remains unknown that whether PD with different timing of RBD onset relative to motor symptoms suggests different spatiotemporal sequence of neurodegeneration. This study aimed to explore the sequence of disease progression in crucially involved brain regions in PD with different timing of RBD onset. Method: We recruited 157 PD, 16 isolated RBD (iRBD), and 78 healthy controls. PD patients were identified as (1) PD with RBD preceding motor symptoms (PD-preRBD, n = 50), (2) PD with RBD posterior to motor symptoms (PD-postRBD, n = 31), (3) PD without RBD (PD-nonRBD, n = 75). The volumes of crucial brain regions, including the basal ganglia and limbic structures in T1-weighted imaging, and the contrast-noise-ratios of locus coeruleus (LC) and substantia nigra (SN) in neuromelanin-sensitive magnetic resonance imaging, were extracted. To simulate the sequence of disease progression for cross-sectional data, an event-based model was introduced to estimate the maximum likelihood sequence of regions' involvement for each group. Then, a statistical parameter, the Bhattacharya coefficient (BC), was used to evaluate the similarity of the sequence. Results: The model predicted that SN occupied the highest likelihood in the maximum likelihood sequence of disease progression in the all PD subgroups, while LC was specifically positioned earlier to SN in iRBD, a prodromal phase of PD. Subsequent early involvement of LC was observed in the both PD-preRBD and PD-postRBD. In contrast, atrophy in the para-hippocampal gyrus but relatively intact LC in the early stage was demonstrated in PD-nonRBD. Then, the similarity comparisons indicated higher BC between PD-postRBD and PD-preRBD (BC = 0.76) but lower BC between PD-postRBD and PD-nonRBD group (BC = 0.41). iRBD had higher BC against PD-preRBD (BC = 0.66) and PD-postRBD (BC = 0.63) but lower BC against PD- nonRBD (BC = 0.48). Conclusion: The spatiotemporal sequence of neurodegeneration between PD-pre and PD-post were similar but distinct from PD-nonRBD. The presence of RBD may be the essential factor for differentiating the degeneration patterns of PD, but the timing of RBD onset has currently proved to be not.

Background: Urbanicity refers to the conditions that are particular to urban areas and is a growing environmental challenge that may affect hippocampus and neurocognition. This study aimed to investigate the effects of the average pre-adulthood urbanicity on hippocampal subfield volumes and neurocognitive abilities as well as the sensitive age windows of the urbanicity effects. Participants and methods: We included 5,390 CHIMGEN participants (3,538 females; age: 23.69 ± 2.26 years, range: 18–30 years). Pre-adulthood urbanicity of each participant was defined as the average value of annual night-time light (NL) or built-up% from age 0–18, which were extracted from remote-sensing satellite data based on annual residential coordinates of the participants. The hippocampal subfield volumes were calculated based on structural MRI and eight neurocognitive measures were assessed. The linear regression was applied to investigate the associations of pre-adulthood NL with hippocampal subfield volumes and neurocognitive abilities, mediation models were used to find the underlying pathways among urbanicity, hippocampus and neurocognition, and distributed lag models were used to identify sensitive age windows of urbanicity effect. Results: Higher pre-adulthood NL was associated with greater volumes in the left (β = 0.100, 95%CI: [0.075, 0.125]) and right (0.078, [0.052, 0.103]) fimbria and left subiculum body (0.045, [0.020, 0.070]) and better neurocognitive abilities in information processing speed (-0.212, [-0.240, −0.183]), working memory (0.085, [0.057, 0.114]), episodic memory (0.107, [0.080, 0.135]), and immediate (0.094, [0.065, 0.123]) and delayed (0.087, [0.058, 0.116]) visuospatial recall, and hippocampal subfield volumes and visuospatial memory showed bilateral mediations for the urbanicity effects. Urbanicity effects were greatest on the fimbria in preschool and adolescence, on visuospatial memory and information processing from childhood to adolescence and on working memory after 14 years. Conclusion: These findings improve our understanding of the impact of urbanicity on hippocampus and neurocognitive abilities and will benefit for designing more targeted intervention for neurocognitive improvement.

Properly analyzing and reporting data remains a challenging task in epidemiologic research, as underreporting of data is often overlooked. The evaluation on the effect of underreporting remains understudied. In this study, we examined the effect of different scenarios of mortality underreporting on the relationship between PM10, temperature, and mortality. Mortality data, PM10, and temperature data in seven cities were obtained from Provincial Center for Disease Control and Prevention (CDC), China Meteorological Data Sharing Service System, and China National Environmental Monitoring Center, respectively. A time-series design with a distributed lag nonlinear model (DLNM) was used to examine the effects of five mortality underreporting scenarios: 1) Random underreporting of mortality; 2) Underreporting is monotonically increasing (MI) or monotonically decreasing (MD); 3) Underreporting due to holiday and weekends; 4) Underreporting occurs before the 20th day of each month, and these underreporting will be added after the 20th day of the month; and 5) Underreporting due to holiday, weekends, MI, and MD. We observed that underreporting at random (UAR) scenario had little effect on the association between PM10, temperature, and daily mortality. However, other four underreporting not at random (UNAR) scenarios mentioned above had varying degrees of influence on the association between PM10, temperature, and daily mortality. Additionally, in addition to imputation under UAR, the variation of minimum mortality temperature (MMT) and attributable fraction (AF) of mortality attributed to temperature in the same imputation scenarios is inconsistent in different cities. Finally, we observed that the pooled excess risk (ER) below MMT was negatively associated with mortality and the pooled ER above MMT was positively associated with mortality. This study showed that UNAR impacted the association between PM10, temperature, and mortality, and potential underreporting should be dealt with before analyzing data to avoid drawing invalid conclusions.

Persistent organic pollutants (POPs) are ubiquitous and bioaccumulative, posing potential and long-term threats to human health and the ecological environment. Quantitative structure–activity relationship (QSAR) studies play a guiding role in analyzing the toxicity and environmental fate of different organic pollutants. In the current work, five molecular descriptors are utilized to construct QSAR models for predicting the mean and maximum air half-lives of POPs, including specifically the energy of the highest occupied molecular orbital (HOMO_Energy_DMol3), a component of the dipole moment along the z-axis (Dipole_Z), fragment contribution to SAscore (SAscore_Fragments), subgraph counts (SC_3_P), and structural information content (SIC). The QSAR models were achieved through the application of three machine learning methods: partial least squares (PLS), multiple linear regression (MLR), and genetic function approximation (GFA). The determination coefficients (R2) and relative errors (RE) for the mean air half-life of each model are 0.916 and 3.489% (PLS), 0.939 and 5.048% (MLR), 0.938 and 5.131% (GFA), respectively. Similarly, the determination coefficients (R2) and RE for the maximum air half-life of each model are 0.915 and 5.629% (PLS), 0.940 and 10.090% (MLR), 0.939 and 11.172% (GFA), respectively. Furthermore, the mechanisms that elucidate the significant factors impacting the air half-lives of POPs have been explored. The three regression models show good predictive and extrapolation abilities for POPs within the application domain.

Objective To investigate the main causes of blood donor deferral in domestic blood center. Methods The causes of donor deferral were classified into 12 categories as previous medical history, drug use, alcohol consumption, menstrual period, underweight, abnormal blood pressure, abnormal body temperature, abnormal hemoglobin (Hb), lipemic blood, positive hepatitis B surface antigen (HBsAg), elevated alanine aminotransferase (ALT) and others according to the comparison indicators of Asia-Pacific Blood Network (APBN) and the national standard Blood Donor Health Examination Requirements. The relevant data of the top 3 causes of donor deferral, voluntarily reported by the members of Practice Comparison Working Group of China’s Mainland Blood Collection and Supply Institutions from 2014 to 2019, were collected and a histogram was generated. Results The median donor deferral rate of 20 domestic blood centers from 2014 to 2019 was 12.14%, with the lowest at 0.18% and highest at 32.32%, respectively. The top three causes for donor deferral were elevated ALT, abnormal Hb and abnormal blood pressure in year 2014, 2015, 2018 and 2019; elevated ALT, lipemic blood and abnormal blood pressure in 2016; elevated ALT, abnormal Hb, and lipemic blood in 2017. Conclusion The main causes of donor deferral were elevated ALT, abnormal Hb, abnormal blood pressure and lipemic blood.

In most acute promyelocytic leukemia (APL) cells, promyelocytic leukemia (PML) fuses to retinoic acid receptor α (RARα) due to chromosomal translocation, thus generating PML/RARα oncoprotein, which is a relatively stable oncoprotein for degradation in APL. Elucidating the mechanism regulating the stability of PML/RARα may help to degrade PML/RARα and eradicate APL cells. Here, we describe a deubiquitinase (DUB)-involved regulatory mechanism for the maintenance of PML/RARα stability and develop a novel pharmacological approach to degrading PML/RARα by inhibiting DUB. We utilized a DUB siRNA library to identify the ovarian tumor protease (OTU) family member deubiquitinase YOD1 as a critical DUB of PML/RARα. Suppression of YOD1 promoted the degradation of PML/RARα, thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice. Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I (G5) as the first YOD1 pharmacological inhibitor. As expected, G5 notably degraded PML/RARα protein and eradicated APL, particularly drug-resistant APL cells. Importantly, G5 also showed a strong killing effect on primary patient-derived APL blasts. Overall, our study not only reveals the DUB-involved regulatory mechanism on PML/RARα stability and validates YOD1 as a potential therapeutic target for APL, but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL, particularly drug-resistant APL treatment.

IntroductionThis study aimed to investigate the feasibility of predicting progression-free survival (PFS) in breast cancer patients using pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) radiomics signature and clinical parameters.MethodsBreast cancer patients who underwent 18F-FDG PET/CT imaging before treatment from January 2012 to December 2020 were eligible for study inclusion. Eighty-seven patients were randomly divided into training (n = 61) and internal test sets (n = 26) and an additional 25 patients were used as the external validation set. Clinical parameters, including age, tumor size, molecularsubtype, clinical TNM stage, and laboratory findings were collected. Radiomics features were extracted from preoperative PET/CT images. Least absolute shrinkage and selection operators were applied to shrink feature size and build a predictive radiomics signature. Univariate and multivariate Cox proportional hazards models and Kaplan-Meier analysis were used to assess the association of rad-score and clinical parameter with PFS. Nomograms were constructed to visualize survival prediction. C-index and calibration curve were used to evaluate nomogram performance.ResultsEleven radiomics features were selected to generate rad-score. The clinical model comprised three parameters: clinical M stage, CA125, and pathological N stage. Rad-score and clinical-model were significantly associated with PFS in the training set (P< 0.01) but not the test set. The integrated clinical-radiomics (ICR) model was significantly associated with PFS in both the training and test sets (P< 0.01). The ICR model nomogram had a significantly higher C-index than the clinical model and rad-score in the training and test sets. The C-index of the ICR model in the external validation set was 0.754 (95% confidence interval, 0.726–0.812). PFS significantly differed between the low- and high-risk groups stratified by the nomogram (P = 0.009). The calibration curve indicated the ICR model provided the greatest clinical benefit.ConclusionThe ICR model, which combined clinical parameters and preoperative 18F-FDG PET/CT imaging, was able to independently predict PFS in breast cancer patients and was superior to the clinical model alone and rad-score alone.

Abstract Using the 8.5‐year Venus Express measurements, we demonstrate the asymmetric plasma distributions in the Venusian magnetosheath. An escaping plume is formed by pickup oxygen ions in the hemisphere where the motional electric field points outward from Venus, while the velocity of solar wind protons is faster in the opposite hemisphere. The pickup O+ escape rate is estimated to be (3.6 ± 1.4) × 1024 s−1 at solar maximum, which is comparable to the ion loss rate through the magnetotail, and (1.3 ± 0.4) × 1024 s−1 at solar minimum. The increase of O+ fluxes with extreme ultraviolet (EUV) intensity is significant upstream of the bow shock, partially attributed to the increase of exospheric neutral oxygen density. However, the solar wind velocity just has a slight effect on the pickup O+ escape rate in the magnetosheath, while the effect of solar wind density is not observed. Our results suggest the pickup O+ escape rate is mainly controlled by EUV radiation.

ABSTRACT The capsid protein (CA), an essential component of human immunodeficiency virus type 1 (HIV-1), represents an appealing target for antivirals. Small molecules targeting the CAI-binding cavity in the C-terminal domain of HIV-1 CA (CA CTD) confer potent antiviral activities. In this study, we report that a small molecule, protoporphyrin IX (PPIX), targets the HIV-1 CA by binding to this pocket. PPIX was identified via in vitro drug screening, using a homogeneous and time-resolved fluorescence-based assay. CA multimerization and a biolayer interferometry (BLI) assay showed that PPIX promoted CA multimerization and bound directly to CA. The binding model of PPIX to CA CTD revealed that PPIX forms hydrogen bonds with the L211and E212 residues in the CA CTD. Moreover, the BLI assay demonstrated that this compound preferentially binds to the CA hexamer versus the monomer. The superposition of the CAI CTD-PPIX complex and the hexameric CA structure suggests that PPIX binds to the interface formed by the NTD and the CTD between adjacent protomers in the CA hexamer via the T72 and E212 residues, serving as a glue to enhance the multimerization of CA. Taken together, our studies demonstrate that PPIX, a hexamer-targeted CA assembly enhancer, should be a new chemical probe for the discovery of modulators of the HIV-1 capsid assembly. IMPORTANCE CA and its assembled viral core play essential roles in distinct steps during HIV-1 replication, including reverse transcription, integration, nuclear entry, virus assembly, and maturation through CA–CA or CA–host factor interactions. These functions of CA are fundamental for HIV-1 pathogenesis, making it an appealing target for antiviral therapy. In the present study, we identified protoporphyrin IX (PPIX) as a candidate CA modulator that can promote CA assembly and prefers binding the CA hexamer versus the monomer. PPIX, like a glue, bound at the interfaces between CA subunits to accelerate CA multimerization. Therefore, PPIX could be used as a new lead for a CA modulator, and it holds potential research applications.

Diode-pumped rare gas lasers are potential candidates for high-energy and high-beam quality laser systems. Currently, most investigations are focused on metastable Ar lasers. The Kr system has the unique advantages of higher quantum efficiency and lower discharge requirements for comparison. In this paper, a diode-pumped metastable Kr laser was demonstrated for the first time. Using a repetitively pulsed discharge at a Kr/He pressure of up to approximately 1500 Torr, metastable Kr atoms of more than 1013 cm–3 were generated. Under diode pumping, the laser realized a dual-wavelength output with an average output power of approximately 100 mW and an optical conversion efficiency of approximately 10% with respect to the absorbed pump power. A kinetics study involving population distribution and evolution was conducted to analyze the laser performance.

Magnetic reconnection is a process that can rapidly convert magnetic field energy into plasma thermal energy and kinetic energy, and it is also an important energy conversion mechanism in space physics, astrophysics and plasma physics. Research related to analytical solutions for time-dependent three-dimensional magnetic reconnection is extremely difficult. For decades, several mathematical descriptions have been developed regarding different reconnection mechanisms, in which the equations based on magnetohydrodynamics theory outside the reconnection diffusion region are widely accepted. However, the equation set cannot be analytically solved unless specified constraints are imposed or the equations are reduced. Based on previous analytical methods for kinematic stationary reconnection, here the analytical solutions for time-dependent kinematic three-dimensional magnetic reconnection are discussed. In contrast to the counter-rotating plasma flows that existed in steady-state reconnection, it is found that spiral plasma flows, which have never been reported before, can be generated if the magnetic field changes exponentially with time. These analyses reveal new scenarios for time-dependent kinematic three-dimensional magnetic reconnection, and the deduced analytical solutions could improve our understanding of the dynamics involved in reconnection processes, as well as the interactions between the magnetic field and plasma flows during magnetic reconnection.

Background: Although many studies have reported the mortality effect of temperature, there were few studies on the mortality risk of humidity, let alone the joint effect of temperature and humidity. This study aimed to investigate the joint and interaction effect of high temperature and relative humidity on mortality in China, which will deepen understanding the health risk of mixture climate exposure. Methods: The mortality and meteorological data were collected from 353 locations in China (2013–2017 in Jilin, Hunan, Guangdong and Yunnan provinces, 2009–2017 in Zhejiang province, and 2006–2011 in other Provinces). We defined location-specific daily mean temperature ≥ 75th percentile of distribution as high temperature, while minimum mortality relative humidity as the threshold of high relative humidity. A time-series model with a distributed lag non-linear model was first employed to estimate the location-specific associations between humid-hot events and mortality, then we conducted meta-analysis to pool the mortality effect of humid-hot events. Finally, an additive interaction model was used to examine the interactive effect between high temperature and relative humidity. Results: The excess rate (ER) of non-accidental mortality attributed to dry-hot events was 10.18% (95% confidence interval (CI): 8.93%, 11.45%), which was higher than that of wet-hot events (ER = 3.21%, 95% CI: 0.59%, 5.89%). The attributable fraction (AF) of mortality attributed to dry-hot events was 10.00% (95% CI: 9.50%, 10.72%) with higher burden for females, older people, central China, cardiovascular diseases and urban city. While for wet-hot events, AF was much lower (3.31%, 95% CI: 2.60%, 4.30%). We also found that high temperature and low relative humidity had synergistic additive interaction on mortality risk. Conclusion: Dry-hot events may have a higher risk of mortality than wet-hot events, and the joint effect of high temperature and low relative humidity may be greater than the sum of their individual effects.

BackgroundStroke has become a main cause of death in China. With global warming, the studies on temperature and stroke have attracted much attention.ObjectiveTo analyze he relationships between heatwave and the years of life lost (YLL) by different subtypes of stroke by controlling temporal and spatial effects with Bayesian spatio-temporal model, and to study the modifiers of the health effect of heatwave.MethodsThe daily information of stroke deaths, meteorological data, and air pollutant data in 40 districts and counties of Guangdong Province were collected during the warm seasons (from May to October) in the years from 2014 to 2017. The individual YLL was first calculated by matching age and gender according to the life table, and then the daily YLL rate (person-years/100 000 people) was obtained by summarizing the daily YLL and correcting it with the population of each district or county. Bayesian spatio-temporal model was used to fit a proposed exposure-response relationship between heatwave and the YLL rates of different subtypes of stroke. Finally, stratified analyses were conducted by age (

BackgroundIn recent years, the incidence of metabolic syndrome (MS) is increasing significantly in China. Some studies have found that temperature is related to single metabolic index, but there is a lack of research on associated mechanism and identifying path of the influence of temperature on MS.ObjectiveBased on the data of Guangdong Province, to investigate the effect of temperature on MS and its pathway.MethodsA total of 8524 residents were enrolled by multi-stage random sampling from October 2015 to January 2016 in Guangdong. Basic characteristics, behavioral characteristics, health status, and physical activity level were obtained through questionnaires and physical examinations, and meteorological data were obtained from meteorological monitoring sites. We matched individual data both with the temperature data of the physical examination day and of a lag of 14 d. A generalized additive model was used to explore the exposure-effect relationship between temperature and MS and its indexes, calculate effect values, and explore the effects of single-day lag temperature. Based on the literature and the results of generalized additive model analysis, a path analysis was conducted to explore the pathways of temperature influencing MS.ResultsThe association between daily average temperature on the current day or lag 14 day and MS risk was not statistically significant. When daily average temperature increased by 1 ℃, the change values of fasting blood-glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), and high density lipoprotein cholesterol (HDL-C) were −0.033 (95%CI: −0.040-−0.026) mmol·L−1, −0.662 (95%CI: −0.741-−0.583) mmHg, −0.277 (95%CI: −0.323-−0.230) mmHg, and −0.005 (95%CI: −0.007-−0.004) mmol·L−1 respectively. The effects of average daily temperature on FBG, blood pressure, HDL-C, and waist circumference lasted until lag 14 day. The effects of daily average temperature on SBP and DBP were the largest on the current day. Daily average temperature of current day had direct and indirect effects on FBG and SBP. Temperature had an indirect effect on TG, and the intermediate variables were waist circumference and FBG, with an indirect effect value of −0.011 (95%CI: −0.020-−0.002). The indirect effects of daily average temperature on SBP, FBG, and TG were weak.ConclusionThere is no significant correlation between temperature and risk of MS, and daily average temperature of current day could significantly affected blood pressure and FBG with a lag effect. Daily average temperature of current day has indirect effects on FBG and TG.

BackgroundIt is projected that the frequency, density, and duration of compound hot extreme may increase in the 21st century in the context of global warming.ObjectiveTo explore the association between compound hot extreme and blood pressure, and identify sensitive populations.MethodsThis was a cross-sectional study. The study subjects were from six Guangdong Province Chronic Disease and Nutrition Surveys during 2002 through 2015. A questionnaire was administered to the participants with questions about demographic information, drinking and smoking status, and measurements on their height, weight, and blood pressure were also collected. We chose the data of May, September, and October to explore the association between compound hot extreme and blood pressure. Compound hot extreme means a hot day with a proceeding hot night. Daily meteorological data were obtained from China Meteorological Data Service Centre. We employed inverse distance weighting to interpolate the temperature and relative humidity values for each participant. A distributed lag non-linear model was used to estimate the association between compound hot extreme and blood pressure. Stratified analyses by sex, age, area, body mass index (BMI), smoking status, and drinking status were also performed to identify sensitive populations. A sensitivity analysis was conducted by adjusting the degrees of freedom for lag spline and removing relative humidity.ResultA total of 10967 participants without history of hypertension were included in this study. The average systolic blood pressure (SBP) was 120.8 mmHg and the average diastolic blood pressure (DBP) was 74.5 mmHg. The proportion of participants who experienced hot day, hot night, or compound hot extreme were 9.34%, 17.95% and 2.90%, respectively. Compared to hot day, hot night and compound hot extreme were related with decreased blood pressure, and the effect of compound hot extreme was stronger: the changes and 95%CI for SBP was −6.2 (−10.3-−2.1) mmHg, and for DBP was −2.7 (−5.2-−0.2) mmHg. Compound hot extreme induced decreased SBP among male, population ≥ 65 years, and those whose BMI < 24 kg·m-2, and their ORs (95%CIs) were −6.2 (−10.7-−1.6). −19.1 (−33.0-−5.1), and −6.7 (−11.8~−1.6) mmHg, respectively, and also decreased DBP among population ≥ 65 years, and its OR (95%CI) was −8.4 (−15.6-−1.1) mmHg. During compound hot extremes, participants living in rural areas showed decreased SBP and DBP, and the ORs (95%CIs) were −10.5 (−16.6-−4.5) and −4.4 (−7.7-−1.1) mmHg respectively, while those living in urban areas showed increased SBP, and the OR (95%CI) was 9.7 (2.9-16.5) mmHg. A significant decrease in blood pressure [OR (95%CI)] was also found in non-smokers [DBP, −3.7 (−6.6-−0.8) mmHg] and non-drinkers [SBP, −4.8 (−9.4-−0.2) mmHg; DBP, −3.4 (−6.0-−0.9) mmHg].ConclusionCompound hot extreme is negatively associated with SBP, and being male, aged 65 years and over, and having BMI < 24 kg·m−2 may be more sensitive to compound hot extreme.

Abstract Controlling the upconversion luminescence (UCL) intensity ratio, especially pumped at 808 nm, is of fundamental importance in biological applications due to the water molecules exhibiting low absorption at this excitation wavelength. In this work, a series of β-NaYbF4:Er microrods were synthesized by a simple one-pot hydrothermal method and their intense green (545 nm) and red (650 nm) UCL were experimentally investigated based on the single-particle level under the excitation of 808 nm continuous-wave (CW) laser. Interestingly, the competition between the green and red UCL can be observed in highly Yb3+-doped microcrystals as the excitation intensity gradually increases, which leads to the UCL color changing from green to orange. However, the microcrystals doped with low Yb3+ concentration keep green color which is independent of the excitation power. Further investigations demonstrate that the cross-relaxation (CR) processes between Yb3+ and Er3+ ions result in the UCL competition. Graphical Abstract

Abstract Background CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan‐cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real‐world clinical‐grade sequencing. Methods This was a single‐center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described. Results In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12‐altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow‐up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11–5.74). Ten patients with CDK12‐altered tumors received at least one immune checkpoint inhibitor‐containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression‐free survival for patients who had metastatic disease and received a checkpoint inhibitor‐containing regimen was 1.16 years (95% CI: 0.32–2.00). Conclusion CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12‐altered tumors.

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic B lymphocytes with high levels of Wnt5a in the plasma. Currently, the cell source of Wnt5a remains controversial. The receptor of Wnt5a is ROR1, whose expression is associated with disease progression and resistance to venetoclax, a BCL-2 inhibitor approved for the treatment of CLL. In this study, we found that the levels of Wnt5a in the plasma of CLL patients were positively correlated with absolute monocyte counts, but not lymphocyte counts. We cultured monocyte-derived nurse-like cells (NLCs) from patients with CLL, and detected Wnt5a expressed in NLCs. Flow cytometry and transwell assays showed that the antibody neutralizing Wnt5a inhibited the enhanced survival and migration in CLL cells co-cultured with NLCs. Furthermore, we performed a drug screening with CLL cells cultured with or without NLCs with a library containing 133 FDA-approved oncology drugs by using high-throughput flow cytometry. We observed a significant resistance to venetoclax in CLL cells co-cultured with NLCs. Immunoblot revealed the activation of NF-κB with enhanced expression of MCL-1 and BCL-XL in CLL cells co-cultured with NLCs. Neutralizing Wnt5a or blocking NF-κB pathway significantly decreased the expression of MCL-1 and BCL-XL, which leads to enhanced sensitivity to venetoclax in CLL cells co-cultured with NLCs. In conclusion, our data showed that NLCs could be one of the sources of Wnt5a detected in patients with CLL, and Wnt5a-induced NF-κB activation in the CLL microenvironment results in resistance to venetoclax in CLL cells.

This phase III, randomized, placebo-controlled study conducted in three stages (6-week, randomized, placebo-controlled stage 1; 24-week, open-label stage 2; and continuous extension stage 3) assessed the long-term efficacy and safety of eltrombopag use in Chinese patients with chronic immune thrombocytopenia (ITP). This article presents the results from stage 2. Overall, 150 patients (placebo-eltrombopag [P-E], 50; eltrombopag-eltrombopag [E-E], 100) received open-label eltrombopag. The median platelet count was maintained between 41 × 109/L and 80 × 109/L. Most patients in both groups (P-E, 90.0%; E-E, 81.8%) achieved platelet counts ≥30 × 109/L and ≥2 times the baseline platelet count at least once with eltrombopag treatment. Overall, 32% of patients achieved platelet counts ≥50 × 109/L in ≥75% of platelet count assessments. Both groups showed a decreased tendency to infrequent bleeding and clinically significant bleeding events during stage 2 compared with baseline. Among patients who received ≥1 ITP medication at baseline, 70.4% in the P-E group and 40.8% in the E-E group reduced or permanently stopped ≥1 of their ITP medications. The stage 2 results further demonstrated a sustainable long-term efficacy and good tolerability of eltrombopag with a favorable benefit–risk ratio in Chinese chronic ITP patients. Trial registration: Clinicaltrials.gov NCT01762761. Registered 8 January 2013, https://clinicaltrials.gov/ct2/show/NCT01762761

AbstractHierarchical brain organization, in which rich-club and diverse-club situates in core position, is critical for global information integration in human brain network. Parkinson’s disease (PD), a common movement disorder, has been conceptualized as a network disorder. Levodopa is an effective treatment for PD. Whether a functional divergence between hierarchical brain system under PD pathology, and how this divergence is regulated by immediate levodopa therapy, remains unknown. We constructed functional network in 61 PD patients and 89 normal controls, and graph theoretical analyses were applied to examine the neural mechanism of levodopa short response from the perspective of brain hierarchical configuration. The results revealed that: (1) PD patients exhibited disrupted function within rich-club organization, while the diverse-club remained preserved function, indicating a differentiated brain topology organization in PD; (2) along the rich-club derivate hierarchical system, PD patients showed impaired network properties within rich-club and feeder subnetwork, and decreased nodal degree centrality in rich-club and feeder nodes, along with increased nodal degree in peripheral nodes, suggesting the distinct functional patterns in different types of nodes; and (3) levodopa could normalize the abnormal network architecture of rich-club system. This study provides evidence for levodopa effects on hierarchical brain system with divergent function.

We present an investigation of the effect of pumping wavelength on the threshold of transverse mode instability (TMI) in high-power ytterbium-doped fiber laser. By using a fiber laser amplifier with a bi-directional pumping structure, we obtain the TMI thresholds under wavelength-stabilized and non-wavelength-stabilized 976 nm laser diodes (LDs) pumping scheme. The results show that the non-wavelength-stabilized LD pump has a higher TMI threshold compared to the wavelength-stabilized LD pump. By optimizing the operating current of the non-wavelength-stabilized 976 nm LD, a ∼4kW output laser with near single-mode beam quality (M2∼1.3) is achieved, with a slope efficiency of ∼84.4%. The analysis yields that when the pumping wavelength deviates from the 976 nm peak, the TMI threshold can be increased. This reveals that optimizing pump source wavelength has great potential for suppressing TMI effect in the power scaling of fiber lasers.

The main factors limiting the power scaling of high-peak-power high-brightness quasi-continuous wave (QCW) fiber laser oscillator and a possible solution are analyzed in this paper. The impacts of fiber length and grating parameters on the output power are studied by rate equations. Under the optimized parameters, a high-brightness QCW fiber laser oscillator with a peak power of 7.3 kW is presented experimentally by using a 24 meter long spindle-shaped Yb-doped fiber with a constant core cladding ratio, and that is the best performance of peak power and brightness in near-single-mode QCW fiber lasers at present to the best of our knowledge. The corresponding pulse energy is 0.57 J and the beam quality M2 factor is about 1.43 under the condition of repetition frequency of 1 kHz and pulse width of 100 μs. The details are analyzed, and also the limiting factors of further power scaling, strategies of suppressing nonlinear effects and the principle of optical device parameter optimization.

Intestinal bacterial communities play an important role in the growth and health of aquatic animal hosts and have drawn increasing attention. However, the role of the intestinal microbiota in the growth of freshwater prawns remains unclear. Here, the intestinal microbiota of freshwater prawns (Macrobrachium rosenbergii) at different life stages (one, two, and three months old) were investigated using 16S rRNA sequencing. The results showed that community richness and diversity increased with growth, which might be one of the reasons that the prawns maintained a fast growth rate before sexual maturation. Three core phyla were identified in the one-month-old group, namely, Firmicutes (79.24%), Proteobacteria (17.09%) and Actinobacteriota (2.01%). Five core phyla were identified in the two-month-old group, including Firmicutes (47.84%), Proteobacteria (44.22%), Actinobacteriota (1.83%), Acidobacteriota (1.66%) and Bacteroidota (1.24%), and the core phyla in the three-month-old group were similar, except for Acidobacterota, which was not identified. A total of 12 core genera were identified in all samples, and significant differences were observed in the relative abundance of gut microbiota between the three groups (p < 0.05). Exiguobacterium, Lactococcus and Shewanella were the three most significantly differentially abundant genera between stages. In addition, Candidatus Hepatoplasma was detected only in the two- and three-month-old prawn groups. This study provides information on the differences in the intestinal microbiota in different developmental stages, which contribute to adaptation to salinity in the early developmental stage and digestive ability to meet the growth needs of Macrobrachium rosenbergii.

Brain iron deposition is a promising marker for human brain health, providing insightful information for understanding aging as well as neurodegenerations, e.g., Parkinson's disease (PD) and Alzheimer's disease (AD). To comprehensively evaluate brain iron deposition along with aging, PD-related neurodegeneration, from prodromal PD (pPD) to clinical PD (cPD), and AD-related neurodegeneration, from mild cognitive impairment (MCI) to AD, a total of 726 participants from July 2013 to December 2020, including 100 young adults, 189 old adults, 184 pPD, 171 cPD, 31 MCI and 51 AD patients, were included. Quantitative susceptibility mapping data were acquired and used to quantify regional magnetic susceptibility, and the resulting spatial standard deviations were recorded. A general linear model was applied to perform the inter-group comparison. As a result, relative to young adults, old adults showed significantly higher iron deposition with higher spatial variation in all of the subcortical nuclei (p

Breast cancer remains the most common malignancy in women and constantly threatens the lives of patients worldwide. State-of-the-art renewal has indicated the involvement of RUNX-associated transcription factor 2 (RUNX2) in tumorigenesis and cancer progression, yet the detailed information during breast cancer is largely obscure. Herein, we took advantage of breast cancer cell lines and in vivo tumorigenicity test as well as multifaceted phenotypic analyses (e.g., RNA-sequencing, ChIP and qRT-PCR assay) to verify the pathogenic mechanism of RUNX2 in triple negative breast cancer aggressiveness and chemoresistance. Strikingly, the proliferation, migration, invasion and chemoresistance of resistant cell lines in triple negative breast cancer was effectively suppressed by RUNX2 silencing, and the in vivo tumorigenicity was significantly weakened as well. Furthermore, with the aid of transcriptomic and bioinformatic analyses, we found MMP1 was highly expressed in triple negative breast cancer (TNBC) and showed a strong correlation with the poor prognosis of the patients, which was consistent with the expression pattern of RUNX2. Finally, by conducting ChIP and qRT-PCR assessment, we verified that RUNX2 functioned via directly binding to the specific motifs in the promoter of MMP1 and thus activating the transcriptional process. Collectively, our data demonstrated the facilitating effect of RUNX2 during triple negative breast cancer progression by directly orchestrating the expression of MMP1, which supplied overwhelming new references for RUNX2-MMP1 axis serving as a novel candidate for breast cancer diagnosis and treatment.

BackgroundChimeric antigen receptor T (CAR-T) cell therapy has made significant advances for hematological malignancies but encounters obstacles in the treatment of solid tumors mainly due to tumor immunosuppressive microenvironment.MethodsImmunohistochemistry analysis was performed to examine the cellular expression of nectin cell adhesion molecule-4 (Nectin4) and fibroblast activation protein (FAP) in a variety of malignant solid tumors. Then, we engineered the fourth-generation Nectin4-targeted CAR-T (Nectin4-7.19 CAR-T) and FAP-targeted CAR-T (FAP-12 CAR-T) cells to evaluate their safety and efficacy in vitro and in vivo.ResultsIn our study, we firstly demonstrated the aberrant overexpression of Nectin4 on both primary and metastatic solid tumors and FAP on cancer-associated fibroblasts. Then, we found that our fourth-generation Nectin4-7.19 CAR-T cells expressed IL-7 and CCL19 efficiently and exhibited superior proliferation, migration, and cytotoxicity compared to the second-generation Nectin4 CAR-T cells, while FAP-12 CAR-T cells exerted their ability of targeting both murine and human FAP effectively in vitro. In a fully immune-competent mouse model of metastatic colorectal cancer, lymphodepletion pretreated mice achieved complete remission with human Nectin4-targeted murine CAR-T (Nectin4 mCAR-T) cells. In the NSG mouse model of lung metastases, Nectin4-7.19 CAR-T cells eradicated metastatic tumors and prolonged survival in combination with FAP-12 CAR-T cells.ConclusionsThese findings showed that Nectin4-7.19 CAR-T cells had potential therapeutic efficacy and exerted a synergistic role with FAP-12 CAR-T cells, further demonstrating that Nectin4 and FAP were able to serve as promising targets for safe and effective CAR-T therapy of malignant solid tumors.

BackgroundUnderstanding genetic influences on Alzheimer’s disease (AD) may improve early identification. Polygenic hazard score (PHS) is associated with the age of AD onset and cognitive decline. It interacts with other risk factors, but the nature of such combined effects remains poorly understood.Materials and methodsWe examined the effect of genetic risk and hippocampal atrophy pattern on episodic memory in a sample of older adults ranging from cognitively normal to those diagnosed with AD using structural MRI. Participants included 51 memory unimpaired normal control (NC), 69 mild cognitive impairment (MCI), and 43 AD adults enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Hierarchical linear regression analyses examined the main and interaction effects of hippocampal subfield volumes and PHS, indicating genetic risk for AD, on a validated episodic memory composite score. Diagnosis-stratified models further assessed the role of PHS.ResultsPolygenic hazard score moderated the relationship between right fimbria/hippocampus volume ratio and episodic memory, such that patients with high PHS and lower volume ratio had lower episodic memory composite scores [ΔF = 6.730, p = 0.011, ΔR2 = 0.059]. This effect was also found among individuals with MCI [ΔF = 4.519, p = 0.038, ΔR2 = 0.050]. In contrast, no interaction effects were present for those NC or AD individuals. A follow-up mediation analysis also indicated that the right fimbria/hippocampus volume ratio might mediate the link between PHS and episodic memory performance in the MCI group, whereas no mediation effects were present for those NC or AD individuals.ConclusionThese findings suggest that the interaction between AD genetic risk and hippocampal subfield volume ratio increases memory impairment among older adults. Also, the results highlighted a potential pathway in which genetic risk affects memory by degrading hippocampal subfield volume ratio in cognitive decline subjects.

BackgroundCell metabolic reprogramming is a hallmark of tumor prognosis, and fatty acid metabolism (FAM) plays a crucial role in the tumor microenvironment (TME). However, the relationship between FAM, TME, and prognosis of acute myeloid leukemia (AML) patients remains elusive.MethodsWe extracted the single-cell RNA sequencing (scRNA-Seq) and bulk transcriptome data of AML patients from the TCGA and GEO databases and assessed the relationship between FAM, TME, and AML patient prognosis. We also performed functional enrichment (FE) assay to evaluate the significance of FAM in anti-AML immunosurveillance.ResultsOur scRNA-Seq analysis revealed that the leukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. Using these FAM-related genes, we developed a prognostic model that accurately estimated AML patient outcome. FE analysis showed that FAM was strongly related to alterations of TME-based immunosurveillance in AML patients. More importantly, we demonstrated that FAM inhibition via pharmaceutical targeting of PLA2G4A, a highly expressed FAM gene in AML patients with poor prognosis, enhanced the NK cell-mediated immunosurveillance in leukemia cells.ConclusionsLeukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. We have successfully established the FAM formula that predicts AML patient prognosis and alterations in the TME-based immunosurveillance. We also found that PLA2G4A was a highly expressed FAM gene in AML patients with poor prognoses. Pharmaceutical targeting of PLA2G4A increased the expression of NKG2DL in leukemia cells in vitro and thus enhanced the NK cell-mediated immunosurveillance.

Opsariichthys bidens (Chinese hooksnout carp) is a small stream fish with high economic value. As the males of this species grow faster than females, it follows that mono-sex breeding has significant potential for commercial production. However, little is known about the sex determination system in O. bidens, this is the key process that is used to develop mono-sex breeding in fish. In the present study, we induced gynogenesis by fertilizing O.bidens eggs with ultra-violet (UV)- inactivated Cyprinus carpio haematopterus (Koi carp) sperm followed by cold shock treatment. Results showed that the optimal induction conditions was 25 min duration of cold shock treatment at 2 min post fertilization (mpf), the highest fertilization rate and hatching rate for gynogenic embryos were 68.24 ± 3.75% and 12.54 ± 1.59%, respectively. Embryos derived from gynogenesis developed normally, but the hybrid embryos failed (created with non-UV-inactivated Koi carp sperm and O.bidens eggs). Genetic analysis demonstrated only maternal inheritance in the gynogenetic offspring. Histological analysis further showed that the gonads of all gynogenetic fish were ovaries, thus suggesting that the sex-determining system of O. bidens is male heterogametic (XX-XY). The present study is the first to establish a procedure for inducing gynogenesis, we also identified the sex determination system (SD) of O. bidens, that will be possible to produce only male.

Abstract Background There existed evidence that type 2 diabetes mellitus (T2DM) prevalence and control rate have seasonal variation. Our study aimed to examine the ambient temperature and fasting plasma glucose (FPG) association and estimate temperature-adjusted T2DM prevalence and control rate. Methods Four cross-sectional health surveys with 26,350 respondents were conducted in Guangdong Province from 2007 to 2015. Multistage cluster sampling was used to recruit study participants. The data of demographic characteristics, lifestyle factors, diet and use of hypoglycemic medicine, height, weight, FPG and meteorological information were collected. And an inverse distance-weighted method was employed to estimate daily temperature exposures at the individual’ s residential district/county. Base on World Health Organization 2006 criteria, participants were divided into normal fasting glucose (NFG) participants (n = 23,877), known T2DM patients (n = 916) and newly detected T2DM patients (n = 1557). Generalized additive mixed model was employed to evaluate the nonlinear associations between temperature and FPG among different T2DM subgroups. The T2DM prevalence and control rate were estimated based on temperature-FPG association. Results The curves of temperature and FPG were downward parabola for total, NFG and known T2DM groups, while it was “U”-shaped for newly detected T2DM patients. When temperature decreased from 30 °C to 4 °C, the FPG significantly increased 0.24 (95%CI: 0.15, 0.33) mmol/L, 0.10 (95%CI: 0.06, 0.14) mmol/L and 1.34 (95%CI: 0.56, 2.12) mmol/L in total, NFG and known T2DM groups, respectively. Compared to 19 °C, newly detected T2DM patients’ FPGs were increased 0.73 (95%CI: 0.13, 1.30) mmol/L at 4 °C and 0.53 (0.00, 1.07) mmol/L at 30 °C. The model-estimated temperature-adjusted T2DM prevalence had a down and up trend, with 9.7% at 5 °C, 8.9% at 20 °C and 9.4% at 30 °C, respectively. At 5, 10, 15, 20, 25 and 30 °C, the model-estimated temperature-adjusted T2DM control rates were 33.2, 35.4, 38.2, 43.6, 49.1 and 55.2%. Conclusion Temperature was negatively associated with FPG for NFG and known T2DM subgroups, while their association was U-shape for newly detected T2DM patients. Hence, the temperature-adjusted T2DM prevalence show a dip/peak pattern and T2DM control rate display a rising trend when temperature increase. Our findings suggest temperature should be considered in T2DM clinic management and epidemiological survey.

Abstract Neutrophils are significant compositions of solid tumors and exert distinct functions in different types of tumors. However, the precise role of neutrophils in the progression of breast cancer (BC) is presently unclear. In this study, by investigating the single-cell RNA sequencing data, we identify a new neutrophil subset, C5aR1-positive neutrophils, that correlates with tumor progression and poor survival for BC patients. Furthermore, it is discovered that C5aR1-positive neutrophils enhance BC cell glycolysis via upregulating ENO1 expression. Mechanically, C5aR1-positive neutrophil-secreted IL1β and TNFα cooperatively activate ERK1/2 signaling, which phosphorylates WTAP at serine341 and thereby stabilizes WTAP protein. The stabilization of WTAP further promotes RNA m6A methylation of ENO1, impacting the glycolytic activity of BC cells. Importantly, C5aR1-positive neutrophils also promote breast cancer growth in vivo, and this effect is abolished by WTAP silencing. In clinical BC samples, increased C5aR1-positive neutrophils correlate with elevated IL1β, TNFα, and ENO1 expression. A high co-expression of C5aR1-positive neutrophil gene signature and ENO1 predicts worse prognosis of BC patients compared with a low co-expression. Collectively, our study reveals a novel subset of C5aR1-positive neutrophils that induces breast cancer glycolysis via increasing ERK1/2-WTAP-dependent m6A methylation of ENO1. These findings support the potential for exploration of C5aR1-positive neutrophils as a therapeutic target in breast cancer.

Abstract Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. We screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early-onset MPC of stomach and colorectum were further evaluated for variants in cancer related genes using both normal and tumor whole exome sequencing. Among 71 patients with MPCs, variants classified to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n = 10), MSH6 (n = 2), PMS2 (n = 2), and MSH2 (n = 1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5 were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR = 31.6, 2.73–1700.6, p = 0.001). Additionally, there were high-confidence LoF variants at FANCG and CASP8 in two patients accompanied by somatic loss of heterozygosity in tumor, respectively. The results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.

The aims of this study were to investigate the activation of T lymphocytes in peripheral blood from children with Hodgkin's lymphoma (HL) and explore their roles for prognosis in HL. A cohort of 52 newly diagnosed children with HL during the past 10 years was enrolled for analysis in this study. Peripheral blood samples of the patients were acquired before treatment in our hospital, and T-cell subsets were detected by a four-color flow cytometer. CD4+ T cells and CD4+/CD8+ T-cell ratio decreased significantly in patients with HL vs. healthy controls. CD8+ T cells, CD3+CD4+HLA-DR+ T cells, and CD3+CD8+HLA-DR+ T cells increased markedly in patients with HL vs. healthy controls. Receiver-operating characteristic (ROC) curve analysis showed that CD3+CD4+HLA-DR+ T cells and CD3+CD8+HLA-DR+ T cells each distinguished the high-risk group from the low- and intermediate-risk group. The area under the ROC curve for predicting high-risk patients was 0.795 for CD3+CD4+HLA-DR+ T cell and 0.784 for CD3+CD8+HLA-DR+ T cell. A comparison of peripheral blood T-cell subsets that responded differently to therapy showed significantly higher percentages of CD3+CD4+HLA-DR+ T cells and CD3+CD8+HLA-DR+ T cells in patients who achieved complete remission compared to those who did not achieve complete remission. In addition, high percentages of both CD3+CD4+HLA-DR+ T cells and CD3+CD8+HLA-DR+ T cells were associated with inferior event-free survival. Peripheral immune status may be related to disease severity in HL. CD3+CD4+HLA-DR+ T cells and CD3+CD8+HLA-DR+ T cells may be a novel indicator for risk stratification of HL and may be an independent risk factor for inferior outcome in childhood HL.

Chimeric antigen receptor (CAR)-T cell therapy has been shown to have considerable therapeutic effects in hematological malignancies, and NKG2D(z) CAR-T cell therapy has been verified to be safe based on clinical trials. However, due to the poor persistence of NKG2D(z) CAR-T cells, their therapeutic effect is not obvious. Here, we constructed NKG2D(bbz) CAR-T cells that can simultaneously activate 4-1BB and DAP10 costimulatory signaling. They were found to be cytotoxic to the target cells in vitro and in vivo. They exhibited low differentiation, low exhaustion, and good proliferation. Importantly, the proportions of central memory T (Tcm) and stem cell-like memory T (Tscm) cell subsets were strikingly increased. After long-term incubation with the target cells, they displayed reduced exhaustion compared to NKG2D(z) CAR-T cells. Further, in the presence of the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, they exhibited reduced exhaustion and apoptosis, upregulated Bcl2 expression, and an increased proportion of Tcm cell subsets. Finally, NKG2D(bbz) CAR-T cells had better antitumor effects in vivo. In summary, the results showed that NKG2D(bbz) CAR-T cells may be valuable for cellular immunotherapy of cancer.

Up to now, transverse mode instability (TMI) and stimulated Raman scattering (SRS) have become the main factors limiting the power scaling of conventional ytterbium-doped fiber laser. Many technologies are proposed to suppress the SRS or TMI individually, but most of them are contradictions in practical application. In this article, we focus on the technologies that can balance the suppression of both SRS and TMI, including fiber coiling optimization, pump wavelength optimization, pump configuration optimization, and novel vary core diameter active fiber. Firstly, we validate the effectiveness of these technologies in both theoretical and relatively low-power experiments, and introduce the abnormal TMI threshold increasing in a few-mode fiber amplifier with fiber coiling. Then, we scale up the power through various types of fiber lasers, including wide linewidth and narrow linewidth fiber lasers, as well as quasi-continuous wave (QCW) fiber lasers. As a result, we achieve 5~8 kW fiber laser oscillators, 10~20 kW wide linewidth fiber laser amplifiers, 4 kW narrow linewidth fiber amplifiers, and 10 kW peak power QCW fiber oscillators. The demonstration of these new technical schemes is of great significance for the development of high-power fiber lasers.

Abstract Background Typhoons greatly threaten human life and property, especially in China. Therefore, it is important to make effective policy decisions to minimize losses associated with typhoons. Methods In this study, the GeoDetector method was used to quantify the determinant powers of natural and socioeconomic factors, and their interactions, on the population casualty rate of super typhoon Lekima. The local indicator of spatial association (LISA) method was followed to explore the spatial pattern of the population casualty rate under the influence of the identified dominant factors. Results Both natural and socioeconomic factors were found to have significantly impacted the population casualty rate due to super typhoon Lekima. Among the selected factors, maximum precipitation was dominant factor (q = 0.56), followed by maximum wind speed (q = 0.45). In addition, number of health technicians (q = 0.35) and number of health beds (q = 0.27) have a strong influence on the population casualty rate. Among the interactive effects of 12 influencing factors, the combined effects of maximum precipitation and ratio of brick-wood houses, the maximum precipitation and ratio of steel-concrete houses, maximum precipitation and number of health technicians were highest (q = 0.72). Furthermore, high-risk areas with very high casualty rates were concentrated in the southeastern part of Zhejiang and northern Shandong Provinces, while lower-risk areas were mainly distributed in northern Liaoning and eastern Jiangsu provinces. Conclusions These results contribute to the development of more specific policies aimed at safety and successful property protection according to the regional differences during typhoons.