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Using data samples collected with the BESIII detector at the BEPCII collider at center-of-mass energies ranging from 3.80 to 4.95 GeV, corresponding to an integrated luminosity of 20 fb^{-1}, a measurement of Born cross sections for the e^{+}e^{-}→D^{0}D[over ¯]^{0} and D^{+}D^{-} processes is presented with unprecedented precision. Many clear peaks in the line shape of e^{+}e^{-}→D^{0}D[over ¯]^{0} and D^{+}D^{-} around the mass range of G(3900), ψ(4040), ψ(4160), Y(4260), and ψ(4415), etc., are foreseen. These results offer crucial experimental insights into the nature of hadron production in the open-charm region.

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OBJECTIVE: To explore the targets and pathways of Cynanchum wilfordii for treatment of ulcerative colitis (UC). METHODS: UPLC-QE-MS was used to identify the components of Cynanchum wilfordii ethanol extract, and their targets were screened using public databases for construction of the core protein-protein interaction (PPI) network and GO and KEGG enrichment analyses. Forty male C57 mice were randomized into normal control group, model group, mesalazine group and Cynanchum wilfordii group (n=10), and in the latter 3 groups, mouse UC models were established by treatment with 2.5% DSS and the latter 2 groups drug interventions by gavage. The therapeutic effect was evaluated by recording body weight changes and DAI score. Pathological changes of the colon tissue were observed with HE and AB-PAS staining, and JAK2 and STAT3 protein expressions were detected with Western blotting. The metabolites and metabolic pathways were identified by metabonomics analysis. RESULTS: We identified 240 chemical components in Cynanchum wilfordii alcoholic extracts, including 19 steroids. A total of 177 Cynanchum wilfordii targets, 5406 UC genes, and 117 intersection genes were obtained. JAK2 and STAT3 were the core targets and significantly enriched in lipid and atherosclerosis pathways. Cynanchum wilfordii treatment significantly increased the body weight and decreased DAI score of UC mice (P < 0.05), alleviated intestinal pathologies, and decreased JAK2 and STAT3 protein expressions in the colon tissues. Most of the 83 intersecting differential metabolites between the control, model and Cynanchum wilfordii groups were identified as glycerophospholipids, arachidonic acid, and amino acids involving glycerophospholipid metabolism and other pathways. Correlation analysis suggested that the core targets of Cynanchum wilfordii for UC participated in regulation of the metabolites. CONCLUSION: Cynanchum wilfordii alleviates lipid and amino acid metabolism disorders to lessen UC in mice by regulating the core targets including JAK2 and STAT3 and the levels of endogenous metabolites.

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The sum of nonspecific physiological responses exhibited by mammals in response to the disruption of thermal balance caused by high-temperature environments is referred to as heat stress (HS). HS affects the normal development of mammalian oocyte and embryos and leads to significant economic losses. Therefore, it is of great importance to gain a deep understanding of the mechanisms underlying the effects of HS on oocyte and embryonic development and to explore strategies for mitigating or preventing its detrimental impacts in the livestock industry. This article provides an overview of the negative effects of HS on mammalian oocyte growth, granulosa cell maturation and function, and embryonic development. It summarizes the mechanisms by which HS affects embryonic development, including generation of reactive oxygen species (ROS), endocrine disruption, the heat shock system, mitochondrial autophagy, and molecular-level alterations. Furthermore, it discusses various measures to ameliorate the effects of HS, such as antioxidant use, enhancement of mitochondrial function, gene editing, cultivating varieties possessing heat-resistant genes, and optimizing the animals'rearing environment. This article serves as a valuable reference for better understanding the relationship between HS and mammalian embryonic development as well as for improving the development of mammalian embryos and economic benefits under HS conditions in livestock production.

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The incorporation of a counterion into an amorphous solid dispersion (ASD) has been proven to be an attractive strategy to improve the drug dissolution rate. In this work, the generality of enhancing the dissolution rates of free acid ASDs by incorporating sodium hydroxide (NaOH) was studied by surface-area-normalized dissolution. A set of diverse drug molecules, two common polymer carriers (copovidone or PVPVA and hydroxypropyl methylcellulose acetate succinate or HPMCAS), and two sample preparation methods (rotary evaporation and spray drying) were investigated. When PVPVA was used as the polymer carrier for the drugs in this study, enhancements of dissolution rates from 7 to 78 times were observed by the incorporation of NaOH into the ASDs at a 1:1 molar ratio with respect to the drug. The drugs having lower amorphous solubilities showed greater enhancement ratios, providing a promising path to improve the drug release performance from their ASDs. Samples generated by rotary evaporation and spray drying demonstrated comparable dissolution rates and enhancements when NaOH was added, establishing a theoretical foundation to bridge the ASD dissolution performance for samples prepared by different solvent-removal processes. In the comparison of polymer carriers, when HPMCAS was applied in the selected system (indomethacin ASD), a dissolution rate enhancement of 2.7 times by the incorporated NaOH was observed, significantly lower than the enhancement of 53 times from the PVPVA-based ASD. This was attributed to the combination of a lower dissolution rate of HPMCAS and the competition for NaOH between IMC and HPMCAS. By studying the generality of enhancing ASD dissolution rates by the incorporation of counterions, this study provides valuable insights into further improving drug release from ASD formulations of poorly water-soluble drugs.

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INTRODUCTION: The use of biological graft in laparoscopic inguinal hernia repair (LIHR) has been controversial, and there is a lack of high-level evidence to confirm the value of biological graft in LIHR. The purpose of this study is to evaluate the effectiveness of a novel composite biologics in LIHR. METHODS: A multicenter, single-blinded, randomized controlled clinical trial was designed. Fifty patients with unilateral primary inguinal hernia were randomly assigned to the experimental and control group (1:1). The experimental group was repaired with a non-crosslinked composite extracellular matrix from porcine urinary bladder matrix and small intestinal submucosa (UBM/SIS). The control group was repaired with a lightweight, large-pore, synthetic mesh. The primary endpoint was the effectiveness rate of hernia repair. RESULTS: The patients were followed up for four years. No significant difference was found between the experimental group and the control group in the effective rate of hernia repair (24/24[100%] vs 21/22[95.45%], RR, 0.4667; 95%CI, 0.3294-2.304; P = 0.4783). There was no fever, seroma, infection, groin pain, foreign body discomfort or recurrence in the experimental group during the follow-up. In the control group, there were 2 cases of seroma 14 days after operation, 1 case of groin discomfort 60 days after operation and one case of recurrence 410 days after surgery. CONCLUSION: Compared with the lightweight synthetic mesh, the novel UBM/SIS graft has comparable short-term and medium-term effectiveness in LIHR, and the incidence of postoperative complications such as seroma groin discomfort is lower. Trial registration Clinical Trials Registry: ChiCTR1800020173.

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Objective: To investigate syphilis infection and related factors among HIV-infected patients being followed up for more than one year in Zhejiang Province. Methods: Data were collected from the China Disease Control and Prevention Information System, and information such as demographic characteristics, viral load levels, and syphilis serologic test results was collected from HIV-infected persons who were diagnosed with HIV more than 1 year, aged ≥15 years with a current address in Zhejiang Province through December 31, 2022. The logistic regression model analyzed the prevalence of syphilis and the related factors. The SPSS 19.0 software was used for statistical analysis. Results: A total of 33 734 HIV-infected patients, with the prevalence of syphilis was 5.6% (1 879/33 734). Among the syphilis cases, the prevalence of syphilis was 6.4% (1 774/27 934) of males, 7.5% (640/8 543) of 25-34 years old age group, 7.6% (1 025/13 423) of unmarried, 8.3% (1 239/14 862) of homosexual transmission, 6.9% (214/3 080) with a non-local registered residence and 9.6% (602/6 267) with a history of STD before the HIV diagnosis. Multivariate Logistic regression analysis showed that participants who were male (aOR=2.19, 95%CI:1.77-2.72), 25-34 years old age group (aOR=1.80, 95%CI:1.47-2.20), homosexual transmission (aOR=1.67, 95%CI:1.49-1.88), with other provinces registered residence (aOR=1.26, 95%CI:1.09-1.47), and with a history of sexually transmitted disease (STD) before the HIV diagnosis (aOR=1.98, 95%CI:1.78-2.20) were associated with increased risk of syphilis. Being married (aOR=0.79, 95%CI:0.68-0.92) was associated with a decreased risk of syphilis. Conclusions: Syphilis infections were high in HIV-infected patients followed up more than one year in Zhejiang Province. It is recommended that syphilis surveillance and screening frequency should be strengthened among HIV-infected persons with characteristics such as male, homosexual transmission, and STD history.

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We report the measurement of the inclusive cross sections for e^{+}e^{-}→nOCH (where nOCH denotes non-open charm hadrons) with improved precision at center-of-mass (c.m.) energies from 3.645 to 3.871 GeV. We observe three resonances: R(3760), R(3780), and R(3810) with significances of 8.1σ, 13.7σ, and 8.8σ, respectively. The R(3810) state is observed for the first time, while the R(3760) and R(3780) states are observed for the first time in the nOCH cross sections. Two sets of resonance parameters describe the energy-dependent line shape of the cross sections well. In set I [set II], the R(3810) state has mass (3805.7±1.1±2.7) [(3805.7±1.1±2.7)] MeV/c^{2}, total width (11.6±2.9±1.9) [(11.5±2.8±1.9)] MeV, and an electronic width multiplied by the nOCH decay branching fraction of (10.9±3.8±2.5) [(11.0±3.4±2.5)] eV. In addition, we measure the branching fractions B[R(3760)→nOCH]=(25.2±16.1±30.4)%[(6.4±4.8±7.7)%] and B[R(3780)→nOCH]=(12.3±6.6±8.3)%[(10.4±4.8±7.0)%] for the first time. The R(3760) state can be interpreted as an open-charm (OC) molecular state, but containing a simple four-quark state component. The R(3810) state can be interpreted as a hadrocharmonium state.

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We perform a study of the χ_{c1}(3872) line shape using the data samples of e^{+}e^{-}→γχ_{c1}(3872), χ_{c1}(3872)→D^{0}D[over ¯]^{0}π^{0}, and π^{+}π^{-}J/ψ collected with the BESIII detector. The effects of the coupled channels and the off-shell D^{*0} are included in the parametrization of the line shape. The line shape mass parameter is obtained to be M_{X}=(3871.63±0.13_{-0.05}^{+0.06}) MeV. Two poles are found on the first and second Riemann sheets corresponding to the D^{*0}D[over ¯]^{0} branch cut. The pole location on the first sheet is much closer to the D^{*0}D[over ¯]^{0} threshold than the other, and is determined to be 7.04±0.15_{-0.08}^{+0.07} MeV above the D^{0}D[over ¯]^{0}π^{0} threshold with an imaginary part -0.19±0.08_{-0.19}^{+0.14} MeV.

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Using a sample of (10087±44)×10^{6} J/ψ events, which is about 45 times larger than that was previously analyzed, a further investigation on the J/ψ→γ3(π^{+}π^{-}) decay is performed. A significant distortion at 1.84 GeV/c^{2} in the line shape of the 3(π^{+}π^{-}) invariant mass spectrum is observed for the first time, which could be resolved by two overlapping resonant structures, X(1840) and X(1880). The new state X(1880) is observed with a statistical significance larger than 10σ. The mass and width of X(1880) are determined to be 1882.1±1.7±0.7 MeV/c^{2} and 30.7±5.5±2.4 MeV, respectively, which indicates the existence of a pp[over ¯] bound state.

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Using e^{+}e^{-} collision data corresponding to an integrated luminosity of 7.33 fb^{-1} recorded by the BESIII detector at center-of-mass energies between 4.128 and 4.226 GeV, we present an analysis of the decay D_{s}^{+}→π^{+}π^{-}e^{+}ν_{e}, where the D_{s}^{+} is produced via the process e^{+}e^{-}→D_{s}^{*±}D_{s}^{∓}. We observe the f_{0}(980) in the π^{+}π^{-} system and the branching fraction of the decay D_{s}^{+}→f_{0}(980)e^{+}ν_{e} with f_{0}(980)→π^{+}π^{-} measured to be (1.72±0.13_{stat}±0.10_{syst})×10^{-3}, where the uncertainties are statistical and systematic, respectively. The dynamics of the D_{s}^{+}→f_{0}(980)e^{+}ν_{e} decay are studied with the simple pole parametrization of the hadronic form factor and the Flatté formula describing the f_{0}(980) in the differential decay rate, and the product of the form factor f_{+}^{f_{0}}(0) and the c→s Cabibbo-Kobayashi-Maskawa matrix element |V_{cs}| is determined for the first time to be f_{+}^{f_{0}}(0)|V_{cs}|=0.504±0.017_{stat}±0.035_{syst}. Furthermore, the decay D_{s}^{+}→f_{0}(500)e^{+}ν_{e} is searched for the first time but no signal is found. The upper limit on the branching fraction of D_{s}^{+}→f_{0}(500)e^{+}ν_{e}, f_{0}(500)→π^{+}π^{-} decay is set to be 3.3×10^{-4} at 90% confidence level.

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Based on data samples collected with the BESIII detector at the BEPCII collider, the process e^{+}e^{-}→Σ^{+}Σ[over ¯]^{-} is studied at center-of-mass energies sqrt[s]=2.3960, 2.6454, and 2.9000 GeV. Using a fully differential angular description of the final state particles, both the relative magnitude and phase information of the Σ^{+} electromagnetic form factors in the timelike region are extracted. The relative phase between the electric and magnetic form factors is determined to be sinΔΦ=-0.67±0.29(stat)±0.18(syst) at sqrt[s]=2.3960 GeV, ΔΦ=55°±19°(stat)±14°(syst) at sqrt[s]=2.6454 GeV, and 78°±22°(stat)±9°(syst) at sqrt[s]=2.9000 GeV. For the first time, the phase of the hyperon electromagnetic form factors is explored in a wide range of four-momentum transfer. The evolution of the phase along with four-momentum transfer is an important input for understanding its asymptotic behavior and the dynamics of baryons.

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By analyzing 7.33 fb^{-1} of e^{+}e^{-} annihilation data collected at center-of-mass energies between 4.128 and 4.226 GeV with the BESIII detector, we report the observation of the semileptonic decay D_{s}^{+}→η^{'}µ^{+}ν_{µ}, with a statistical significance larger than 10σ, and the measurements of the D_{s}^{+}→ηµ^{+}ν_{µ} and D_{s}^{+}→η^{'}µ^{+}ν_{µ} decay dynamics for the first time. The branching fractions of D_{s}^{+}→ηµ^{+}ν_{µ} and D_{s}^{+}→η^{'}µ^{+}ν_{µ} are determined to be (2.235±0.051_{stat}±0.052_{syst})% and (0.801±0.055_{stat}±0.028_{syst})%, respectively, with precision improved by factors of 6.0 and 6.6 compared to the previous best measurements. Combined with the results for the decays D_{s}^{+}→ηe^{+}ν_{e} and D_{s}^{+}→η^{'}e^{+}ν_{e}, the ratios of the decay widths are examined both inclusively and in several ℓ^{+}ν_{ℓ} four-momentum transfer ranges. No evidence for lepton flavor universality violation is found within the current statistics. The products of the hadronic form factors f_{+,0}^{η^{(')}}(0) and the c→s Cabibbo-Kobayashi-Maskawa matrix element |V_{cs}| are determined. The results based on the two-parameter series expansion are f_{+,0}^{η}(0)|V_{cs}|=0.452±0.010_{stat}±0.007_{syst} and f_{+,0}^{η^{'}}(0)|V_{cs}|=0.504±0.037_{stat}±0.012_{syst}, which help to constrain present models on f_{+,0}^{η^{(')}}(0). The forward-backward asymmetries are determined to be ⟨A_{FB}^{η}⟩=-0.059±0.031_{stat}±0.005_{syst} and ⟨A_{FB}^{η^{'}}⟩=-0.064±0.079_{stat}±0.006_{syst} for the first time, which are consistent with the theoretical calculation.

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Using (10087±44)×10^{6} J/ψ events collected with the BESIII detector, numerous Ξ^{-} and Λ decay asymmetry parameters are simultaneously determined from the process J/ψ→Ξ^{-}Ξ[over ¯]^{+}→Λ(pπ^{-})π^{-}Λ[over ¯](n[over ¯]π^{0})π^{+} and its charge-conjugate channel. The precisions of α_{Λ0} for Λ→nπ^{0} and α[over ¯]_{Λ0} for Λ[over ¯]→n[over ¯]π^{0} compared to world averages are improved by factors of 4 and 1.7, respectively. The ratio of decay asymmetry parameters of Λ→nπ^{0} to that of Λ→pπ^{-}, ⟨α_{Λ0}⟩/⟨α_{Λ-}⟩, is determined to be 0.873±0.012_{-0.010}^{+0.011}, where the first and the second uncertainties are statistical and systematic, respectively. The ratio is smaller than unity more than 5σ, which signifies the existence of the ΔI=3/2 transition in Λ for the first time. Besides, we test for CP symmetry in Ξ^{-}→Λπ^{-} and in Λ→nπ^{0} with the best precision to date.

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Based on 4.4 fb^{-1} of e^{+}e^{-} annihilation data collected at the center-of-mass energies between 4.60 and 4.70 GeV with the BESIII detector at the BEPCII collider, the pure W-boson-exchange decay Λ_{c}^{+}→Ξ^{0}K^{+} is studied with a full angular analysis. The corresponding decay asymmetry is measured for the first time to be α_{Ξ^{0}K^{+}}=0.01±0.16(stat)±0.03(syst). This result reflects the noninterference effect between the S- and P-wave amplitudes. The phase shift between S- and P-wave amplitudes has two solutions, which are δ_{p}-δ_{s}=-1.55±0.25(stat)±0.05(syst) rad or 1.59±0.25(stat)±0.05(syst) rad.

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Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study. In this work, an EP suspension formulation for a development drug candidate GDC-6599 was successfully developed. The formulation spanned a wide concentration range from 0.1 to 2.0 mg/mL. A non-solubilizing vehicle, 0.6 % (w/v) methylcellulose solution was used to suspend GDC-6599. An aversive agent denatonium benzoate at an extremely low level (6 ppm) was applied as a taste masking agent. This enabled a simple matrix for the analysis of related substances from GDC-6599 during all stability studies. Microcrystalline cellulose at 10 mg/mL concentration was added to the EP formulation to generate a suspension appearance, leading to the success of using a single placebo for matching active formulation at all concentrations. The developed formulation demonstrated excellent homogeneity, sufficient stability and passed microbiological enumeration test. Rinsing performance test demonstrated that greater than 99.8 % amount of drug was successfully recovered by rinsing with water twice, providing guidance for clinical dosing. Biopharmaceutical assessment was conducted by both in silico simulation and in vitro tests. Greater than 90 % bioaccessibility of the EP suspension formulation was obtained via an in vitro system mimicking the human gastrointestinal absorption, consistent with the result from the in silico modeling. The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies.

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Objective: To investigate the clinical and prognostic characteristics of newly diagnosed multiple myeloma (NDMM) patients with myelofibrosis (MF). Methods: The clinical data of 160 NDMM patients admitted to Henan Provincial People's Hospital from January 2012 to July 2022 were analyzed retrospectively. They were divided into MF group(n=74) and non-MF group(n=86) according to whether combined with MF. Patients in MF group were further splited into MF-1 group (n=47) and MF-2/3 group (n=27). All patients were treated with bortezomib and immunomodulatory-based combination therapy. The efficacy was evaluated after 4 courses, and the clinical features and prognosis between the two groups were compared. The deadline for follow-up was December 30, 2022 and the median follow-up period [M (Q1, Q3)] was 23.5 (14.4, 40.5) months. Kaplan-Meier method was used for survival analysis, and Cox regression model was used to analyze the influencing factors of survival. Results: Among 160 patients with NDMM, 91 were males and 69 were females, with a median age [M (Q1, Q3)] of 59 (54, 69) years. In MF group, the bone marrow immature plasma cell percentage, total plasma cell percentage were 9.6% (3.2%, 28.5%) and 36.4% (18.5%, 51.1%), respectively, which were higher than 6.0% (1.2%, 17.2%) and 24.0% (12.0%, 46.0%) of the non-MF group (both P<0.05). Hb level was 84.0(74.5, 100.5)g/L and PLT was (151.99±90.68) ×109/L in the MF group, which were lower than 96.0 (81.0, 112.0)g/L and (180.38±85.32) ×109/L of non-MF group (both P<0.05). But there were no significant differences in ISS stage, karyotypic and fluorescence in situ hybridization (FISH) high-risk genetic abnormalities between the two groups (all P>0.05). Objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) were not significantly different between the two groups (all P>0.05). The rate of 17p- was 25.9% (7/27) in MF-2/3 group, which was higher than 8.1% (7/86) of non-MF group (P=0.049). The median OS of the MF-2/3 group was 25.0 (95%CI: 23.6-26.4) months, which was shorter than that of the non-MF group (54.0 months, P=0.031). Multivariate Cox regression analysis showed that grade MF-2/3 was not a risk factor for OS in NDMM patients (HR=1.507, 95%CI: 0.624-3.993, P=0.425). Conclusions: The ratio of bone marrow immature plasma cells and total plasma cells in NDMM patients with MF are higher than that in patients without MF, and the Hb and PLT are lower than that in patients without MF. NDMM patients with grade 2/3 MF have shorter survival than those without MF.

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Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.