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Abstract Background The aim of this study was to analyse the differences in the phenotypes of missing teeth between a pair of brothers with hypohidrotic ectodermal dysplasia (HED) and to investigate the underlying mechanism by comparing the mutated gene loci between the brothers with whole-exome sequencing. Methods The clinical data of the patients and their mother were collected, and genomic DNA was extracted from peripheral blood samples. By Whole-exome sequencing filtered for a minor allele frequency (MAF) ≤0.05 non-synonymous single-nucleotide variations and insertions/deletions variations in genes previously associated with tooth agenesis, and variations considered as potentially pathogenic were assessed by SIFT, Polyphen-2, CADD and ACMG. Sanger sequencing was performed to detect gene variations. The secondary and tertiary structures of the mutated proteins were predicted by PsiPred 4.0 and AlphaFold 2. Results Both brothers were clinically diagnosed with HED, but the younger brother had more teeth than the elder brother. An EDA variation (c.878 T > G) was identified in both brothers. Additionally, compound heterozygous variations of WNT10A (c.511C > T and c.637G > A) were identified in the elder brother. Digenic variations in EDA (c.878 T > G) and WNT10A (c.511C > T and c.637G > A) in the same patient have not been reported previously. The secondary structure of the variant WNT10A protein showed changes in the number and position of α-helices and β-folds compared to the wild-type protein. The tertiary structure of the WNT10A variant and molecular simulation docking showed that the site and direction where WNT10A binds to FZD5 was changed. Conclusions Compound heterozygous WNT10A missense variations may exacerbate the number of missing teeth in HED caused by EDA variation.

Abstract Background With the widespread use of antibiotics, antimicrobial resistance in Neisseria gonorrhoeae is worsening. The objective of this study was to evaluate the efficacy changes of seven antibiotics in the treatment of N. gonorrhoeae by using Monte Carlo simulation combined with pharmacokinetics/pharmacodynamics/ (PK/PD). Methods The minimum inhibitory concentration (MIC) of antibiotics against clinical isolates from 2013 to 2020 in Nanjing, China, was determined by agar dilution method. The probability of target attainment (PTA) was estimated at each MIC value and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. Results All dosage regimens of seven antibiotics achieved PTAs ≥ 90% for MIC ≤ 0.06 µg/ml. But when the MIC was increased to 1 µg/ml, PTAs at each MIC value exceeded 90% only for ceftriaxone 1,000 mg and 2,000 mg, zoliflodacin 2,000 mg and 3,000 mg. Among them, the CFR values of each dosing regimen against N. gonorrhoeae only for ceftriaxone, cefixime and zoliflodacin were ≥ 90% in Nanjing from 2013 to 2020. Conclusions Cephalosporins are still the first-line drugs in the treatment of gonorrhea. However, the elevated MIC values of cephalosporins can lead to decline in clinical efficacy of the conventional dose regimens, and increasing the dose of ceftriaxone to 1,000 mg-2,000 mg may improve the efficacy. In addition, zoliflodacin is possible to be a potential therapeutic agent in the future.

IntroductionAntihypertensive drugs are used preventatively to lower the risk of cardiovascular disease events. Comparative effectiveness studies on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and thiazides have yielded inconsistent results and given little consideration to patient adherence. Using a longitudinal cohort and considering time-varying adherence and confounding factors, we aimed to estimate the real-world effectiveness of five major antihypertensive drug monotherapies in the primary prevention of cardiovascular events.MethodsEligible patients for a retrospective inception cohort study were selected using information obtained from the University of Groningen IADB.nl pharmacy prescription database. Cohort 1 comprised adherent patients with a follow-up time exceeding 1 year, and cohort 2 comprised all patients independent of adherence. The exposures were ACEIs, ARBs, BBs, CCBs, and thiazides. The primary outcome was the time to the first prescription for an acute cardiac drug therapy (CDT) measured using valid drug proxies to identify the first major cardiovascular event. A per-protocol analytical approach was adopted with inverse probability of treatment weighted (IPTW), time-varying Cox regression analysis to obtain the hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsIn cohort 1 (n = 22,441), 1,294 patients (5.8%) were prescribed an acute CDT with an average follow-up time of 4.2 ± 2.8 years. Following IPTW, the hazard measures of ARBs and thiazides were lower than those of BBs (HRs: 0.79 and 0.80, respectively; 95% CIs: 0.64–0.97 and 0.69–0.94, respectively). Among drug-treated diabetic patients, the hazard measures were even lower, with HR point estimates of 0.43 (CI: 0.19–0.98) for ARBs and 0.32 (CI: 0.13–0.82) for thiazides. In cohort 2 (n = 33,427) and sensitivity analysis, the comparative effectiveness results for thiazides and BBs were similar to those for cohort 1.ConclusionThe findings of this real-world analysis suggest that the incidence of CDT associated with long-term thiazide or ARB monotherapy is lower than the incidence of CDT with BBs, notably among high-risk patients. Incidences of CDT associated with ACEIs and CCBs were comparable relative to those associated with BBs.

Mitochondrial diseases are a heterogeneous group of inherited disorders characterized by mitochondrial dysfunction, and these diseases are often severe or even fatal. Mitochondrial diseases are often caused by mitochondrial DNA mutations. Currently, there is no curative treatment for patients with pathogenic mitochondrial DNA mutations. With the rapid development of traditional gene editing technologies, such as zinc finger nucleases and transcription activator-like effector nucleases methods, there has been a search for a mitochondrial gene editing technology that can edit mutated mitochondrial DNA; however, there are still some problems hindering the application of these methods. The discovery of the DddA-derived cytosine base editor has provided hope for mitochondrial gene editing. In this paper, we will review the progress in the research on several mitochondrial gene editing technologies with the hope that this review will be useful for further research on mitochondrial gene editing technologies to optimize the treatment of mitochondrial diseases in the future.

Abstract Objective Drug non-adherence in primary preventive cardiovascular therapy is one of the most important modifiable drivers of cardiovascular events. The effect of deductibles in healthcare cost-sharing plans (the amount that has to be paid for healthcare services before the insurance company starts to pay) on such non-adherence in a European setting is unknown. Therefore, we estimated the association between deductibles and the adherence to primary preventive antihypertensive and antihyperlipidemic medication. Methods Using the claims database of Menzis Health Insurer in the Netherlands, we applied ordered beta regression mixed modelling to estimate the association between deductibles and adherence taking several demographic and social-economic factors, repeated measurements and within-patient variation into account. Results All in all, 106,316 patients starting primary preventive antihypertensive or antihyperlipidemic monotherapy were eligible for analysis. At index date, mean age of the study population was 58 years and 52% were male. Reaching the deductible limit and no need to pay for medication anymore increased the adherence [relative adherence ratio (RAR) 1.03, 95% confidence interval (95% CI): 1.00–1.05] for antihyperlipidemic therapy and 1.02 (95% CI: 1.00–1.04) for antihypertensive therapy. A larger deductible amount decreases the adherence of antihyperlipidemic and antihypertensive therapy (RAR 0.83; 95% CI: 0.69–1.00 and RAR 0.85, 95% CI: 0.74–0.98, respectively). Conclusion Independent of other risk factors for non-adherence, presence of deductibles in health insurance is associated with a small negative effect on the adherence to both primary preventive antihypertensive as well as antihyperlipidemic therapy. Further study is needed on the potential health-economic consequences.

Over the past few decades, the construction industry has been suffering from project delays. It remains a recognized challenge to accurately predict the actual project’s progress, despite the vast amount of field data and scheduling methods available. In this paper, four different machine learning (ML) models including K-nearest neighbor (KNN), support vector regression (SVR), gradient boosting trees (GBT), and artificial neural network (ANN) were used for forecasting the construction duration of work areas. Field data were collected, including progress, workload, labor, weather, planned days, and location, as inputs and construction days as output for each work area to develop the models. A simple and widely used baseline model was used to confirm the accuracy and generalization capability of ML models. The comparison of the results revealed that ANN and GBT models produced significantly superior results. Additionally, the GBT model is substantially more computationally efficient. In conclusion, the GBT model could be successfully and effectively applied to improve the prediction of construction duration. The proposed ML models could be utilized as a decision support tool for construction project managers to adjust construction site resource allocation.

Scientific and effective urban waterlogging risk prediction can help improve urban waterlogging disaster prevention capabilities. Combining the numerical simulation model with the data-driven model, the construction of the urban waterlogging risk predictive model can satisfy the prediction accuracy and improve the prediction timeliness. Thus, this paper established an urban waterlogging risk predictive model based on the coupling of the BP neural network and SWMM model, and set five input patterns, finally selected the accumulative precipitation process and precipitation characteristics as input to predict the regional waterlogging risks under different urban rainstorm scenarios. The results show that the overall performance of the pipe drainage system in the study area is lower, and it cannot resist the rainstorm with a higher return period. Moreover, the total waterlogging risk of the southern old city is higher than that of the northern new city in the study area. The calculation speed of the prediction model constructed in this paper is thousands of times higher than that of the numerical model, so the calculation speed is very fast, which meets the requirements of the forecast timeliness. HIGHLIGHTS Using fine data to build the SWMM model and various methods to verify the SWMM model.; Using web crawler technology to extract ponding points.; Using entropy weight method for risk quantization.; Using set pair analysis to evaluate the accuracy of the BP neural network.; Coupling SWMM model with BP neural network for risk prediction.;

The accurate estimation of the infiltration boundary of a buried point source is required in the hydraulic design of a subsurface drip irrigation (SDI) system, as well as in the numerical simulation of soil water movement. In this study, an experiment was conducted to measure the variation in emitter flow rate and soil back pressure in silty loam soil. The infiltration cavity was observed, and the radius was estimated by matching the measured emitter flow rate and soil back pressure using HYDRUS-2D simulations. The relationship between the cavity radius, emitter flow rate, and soil back pressure, as affected by the soil bulk density, working pressure, and nominal emitter flow rate, are discussed. The results indicate that the infiltration cavity formed rapidly during irrigation with an irregular shape. The surface area increased as nominal emitter flow rate increased and soil bulk density increased. The variation of flow rate as a function of time had no necessary relationship with that of soil back pressure, due to the formation of the cavity. When the infiltration process became stable, higher soil bulk density resulted in increase in soil back pressure and decrease in emitter flow rate. However, the effects of working pressure and nominal emitter flow rate on soil back pressure were unclear. The emitter flow rate and back pressure, solved by an existing analytical model using estimated radius, demonstrated satisfactory agreement with the measured data, with the minimum root-mean-square error (RMSE), compared with those using a constant radius. When the infiltration boundary was taken as a constant head, the soil back pressure and cavity both significantly affected the simulated soil wetting patterns. The effect of cavity radius on the wetting front could be neglected for the constant flux boundary.

Falling from height (FFH) is a significant safety concern in the construction industry. It requires construction safety managers to identify and prevent FFH from occurring as early as possible. However, due to insufficient expertise and the shortage of relevant personnel, it is often challenging to accurately and promptly identify FFH risks, especially those more dangerous ones. To address this issue, we proposed a new identification method for FFH risk points by incorporating BIM, path simulation, and machine learning techniques. Our approach, based on the likelihood exposure consequence criterion, efficiently identified and prioritized hazardous FFH risk points. Unlike prior studies, we emphasized the spatial distribution of workers by incorporating site layout and construction schedule considerations. The algorithm generated a safe routing plan, which was validated in experiments, emphasizing its effectiveness in early detection and mitigation of FFH risks. This research provided a comprehensive approach to FFH risk management that integrates building information modeling, path simulation, and machine learning to comprehensively address FFH risks in construction and generate safe route plans for effective safety management. The proposed method significantly contributes to the early detection and elimination of potential FFH risks in construction projects.

Objective To determine the long-term effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events.Design Retrospective inception cohort study covering a 25-year study period.Setting University Groningen IADB.nl pharmacy prescription database with data from 1996 to 2020.Participants Patients aged 18 years or older, free of any cardiovascular disease (CVD) drug therapies prior to initiation of a preventive antihypertensive monotherapy (ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs) and thiazides).Outcome measures Primary outcome was the time to first prescription of acute cardiac drug therapy (CDT) measured by valid drug proxies to identify a first major CVD event in patients without a history of CVD.Results Among 33 427 initiators, 5770 (17.3%) patients experienced an acute CDT. The average follow-up time was 7.8±5.4 years. The 25-year incidence rate per 1000 person-years were 28.4, 25.2, 20.1, 28.4 and 25.2 for ACEI, ARB, BB, CCB and thiazide starters, respectively. Inverse probability weighted Cox regression showed that thiazide starters had lower hazards than the reference BB starters (HR: 0.88, 95%CI: 0.82 to 0.96). Among patients on diabetes drugs, risks were lower (HR: 0.58, 95%CI: 0.34 to 0.96). CCB starters had higher hazards than reference BB (HR: 1.26, 95% CI: 1.13 to 1.41). The overall estimated number needed to treat for thiazides compared with BBs to prevent one acute CDT in 25 years was 26, and five among patients on diabetes drugs.Conclusions After adjustments for confounders, patients starting on monotherapy with thiazides had a lower incidence of CDT compared with those starting on BBs, notably among patients on diabetes drugs. Conversely, patients who began CCB monotherapy had a higher incidence of CDT compared with those starting on BBs. Other monotherapies had comparable incidence of cardiovascular disease compared with BBs.

Abstract Background There is increasing evidence that mesenchymal stem cells (MSCs) help shape the tumor microenvironment and promote tumor progression, and ion channels might play a critical role in this process. The objective of the present study was to explore the function and mechanism of MT-CAFs on progression of colon cancer. Methods Here, a gene chip was used for a general analysis of gene expression changes in MSC-transformed CAF cells (MT-CAFs). Bioinformatic tool and western blot screened out the ion channel protein TRPC3 with significantly increased expression, and identify the function through two-photon microscope. The progression of cancer was detected via MTS, transwell and Wound Healing. ELISA deected the secretion of inflammation factors. TRPC3/NF-KB axis was identified by western blot and immunofluorescence. Results TRPC3 can caused calcium influx, which further activated the NF-KB signaling pathway. Knockdown or inhibition of TRPC3 in MSCs significantly reduced the activation of NF-KB, and decreased the growth, migration, and invasion of MT-CAFs. After TRPC3 knockdown, the ability of MT- CAFs to promote tumor migration and invasion was impaired. Conversely, the upregulation of TRPC3 expression in MT-CAFs had the opposite effect. In vivo, TRPC3 expressed on MSCs also contributed to the tumorigenesis and progression of cancer cells. In addition, the Oncomine and GEPIA databases showed that TRPC3 expression is higher in colon cancer tissues compared with normal colon tissues, and was positively correlated with the expression of the CAF genes alpha-smooth muscle (α-SMA/ACTA2) and fibroblast activation protein Alpha. The disease-free survival of patients with positive TRPC3 expression in MSCs was significantly shorter than those with negative expression. Conclusions These results indicate that TRPC3 expressed on MT-CAFs plays a critical role in tumor progression via the NF-KB signaling pathway, and is correlated with poor prognosis in colon cancer patients. Therefore, TRPC3 may be a novel therapeutic target for the treatment of colon cancer.

We propose a seawater salinity sensor array based on a micro/nanofiber Bragg grating structures, which allows for the simultaneous measurement of temperature and salinity. The proposed sensing structure is fabricated through a process involving optical fiber tapering, femtosecond laser inscription, and chemical etching. The equivalent refractive index (RI) of this sensor structure is influenced by the surrounding RI, resulting in a Bragg characteristic wavelength shift that can be used for salinity sensing. The experimental results show that the salinity sensitivity for two cascaded sensor arrays is 8.39 pm/‰ and 7.71 pm/‰, while the temperature sensitivity is 8.28 pm/°C and 8.03 pm/°C, respectively. This sensor structure is compact, exhibits excellent linearity, and offers good repeatability. It holds great potential for applications in seawater environmental monitoring and quantitative studies of seawater dispersion characteristics.

The double-skin roof has been applied in the design of modern granaries for energy saving. Compared with the ordinary parallel double plate, the double skin composed of an inclined upper plate can effectively improve the situation of a “hot roof” through an air exhaust, thus having better thermal performance. To study the advantages of a double-skin roof with an inclined upper plate and the effects of physical parameters on convective heat transfer, an experimental and numerical study was carried out in this work. According to the actual size of the grain depot in the application, an experimental setup was established based on the similarity theory with a scale of 1:28 to the real one. The double-skin roof consists of two plates: the lower one was used as the original surface of the depot, and the other was suspended above. For comparison, the two flat plates were arranged to be parallel or inclined. Changeable parameters included the flow rate through the air gap between the double plates, the thickness of the air gap, and the reducing ratio. Other parameters, such as the air temperature, were the same, and the influence of the above factors on the performance of the double-skin roof was studied. The results showed that both the flow rate and the air gap’s thickness can affect the roof’s thermal performance. Under the optimal working conditions in the parallel mode (with an air gap of 0.07 m and a flow rate of 60 m3/h), the temperature increment at the surface of the grain bulk was 1.88 °C, which was lower than the mode without a suspended upper plate. Moreover, the inclined design of the upper plate increased the air velocity along the flowing direction, which strengthened the convection at the outlet and, thus, improved the average thermal performance of the opened roof. The inclined mode controlled the temperature at the grain bulk surface within 24 °C, which dropped by 1 °C compared with the parallel mode under the same working conditions. In addition, a geometric model of the experimental setup was created, and the grid was divided through the software ANSYS ICEM 15.0 The convection term in the conservation equation was discretized with the QUICK scheme, and the solution for the flow field was obtained using the SIMPLE algorithm. The experimental data were used as the input profile for the model, and the numerical results were compared with the experimental results to verify the accuracy of the model. The average and the maximum errors were between 3% and 8.9%, respectively. The simulation results indicated the effects of the reducing ratio on the roof thermal performance with the analysis of the Rayleigh number and the Nusselt number. In the inclined mode, a smaller reducing ratio was beneficial to air convection. With a reducing ratio of about 0.5, the outlet velocity of the roof was higher by 30.6%, resulting in a larger local Nu number and better thermal performance. When the dimensionless length was in a range of 0.34~0.37, the Nu number was increasing. Near the inlet of the double-skin roof, the Nu number increased with the Ra number, given a dimensionless length of below 0.15. Therefore, the ventilated double-skin roof with an inclined upper plate is recommended for roof reconstruction design because of its advanced air convection.

Abstract Background Endothelial cells are located in the inner lumen of blood and lymphatic vessels and exhibit the capacity to form new vessel branches from existing vessels through a process called angiogenesis. This process is energy intensive and tightly regulated. Glycolysis is the main energy source for angiogenesis. Retinoic acid (RA) is an active metabolite of vitamin A and exerts biological effects through its receptor retinoic acid receptor (RAR). In the clinic, RA is used to treat acne vulgaris and acute promyelocytic leukemia. Emerging evidence suggests that RA is involved in the formation of the vasculature; however, its effect on endothelial cell angiogenesis and metabolism is unclear. Methods Our study was designed to clarify the abovementioned effect with human embryonic stem cell-derived endothelial cells (hESC-ECs) employed as a cell model. Results We found that RA inhibits angiogenesis, as manifested by decreased proliferation, migration and sprouting activity. RNA sequencing revealed general suppression of glycometabolism in hESC-ECs in response to RA, consistent with the decreased glycolytic activity and glucose uptake. After screening glycometabolism-related genes, we found that fructose-1,6-bisphosphatase 1 (FBP1), a key rate-limiting enzyme in gluconeogenesis, was significantly upregulated after RA treatment. After silencing or pharmacological inhibition of FBP1 in hESC-ECs, the capacity for angiogenesis was enhanced, and the inhibitory effect of RA was reversed. ChIP-PCR demonstrated that FBP1 is a target gene of RAR. When hESC-ECs were treated with the RAR inhibitor BMS493, FBP1 expression was decreased and the effect of RA on angiogenesis was partially blocked. Conclusions The inhibitory role of RA in glycometabolism and angiogenesis is RAR/FBP1 dependent, and FBP1 may be a novel therapeutic target for pathological angiogenesis.

Abstract Background Beiging of white fat plays an important role in energy metabolism. Beige adipocytes contribute to the regulation of body weight and body temperature through expenditure of chemical energy to produce heat, and they have therefore recently attracted considerable attention as potential targets for therapeutic approaches in metabolic disorders, including obesity. All adipocytes, including beige adipocytes, differentiate from mesenchymal stem cells (MSCs), which may provide an important path for clinical intervention; however, the mechanism of beiging of human adipose cell-derived MSCs is not fully understood. Here, we provide insights on the role of IRISIN, which is known to be secreted by skeletal muscle and promote beiging of white fat. Results We established an IRISIN-induced mesenchymal stem cell beiging model and found that IRISIN protein interacts with the MSC membrane protein TRPC3. This interaction results in calcium influx and consequential activation of Erk and Akt signaling pathways, which causes phosphorylation of PPARγ. The phosphorylated PPARγ enters the nucleus and binds the UCP1 promoter region. Furthermore, the role of TRPC3 in the beiging of MSCs was largely abolished in Trpc3−/− mice. We additionally demonstrate that the calcium concentration in the brain of mice increases upon IRISIN stimulation, followed by an increase in the content of excitatory amino acids and norepinephrine, while Trpc3−/− mice exhibit the reverse effect. Conclusions We found that TRPC3 is a key factor in irisin-induced beiging of MSCs, which may provide a new target pathway in addressing metabolic disorders. Our results additionally suggest that the interaction of irisin with TRPC3 may affect multiple tissues, including the brain. Graphical abstract

In order to explore the evolvement mechanism of hydrometeorological elements, spatial–temporal distribution of precipitation in the Huai river basin is studied by statistical drawing and empirical orthogonal function decomposition. How to make an objective combination for the predictive results of precipitation? Information fusion in data assimilation is introduced to merge the improved National Centers for Environmental Prediction coupled forecast system model version 2 (CFSv2) with the multilinear regression model. Firstly, in terms of time, the annual precipitation is apt to decline at most stations within 30 years, and precipitation mainly concentrates in the flood season. The characteristics of spatial distribution are similar to topographic features. It can also be found that precipitation gradually decreases from south to north. Secondly, from statistical forecasting, the relationship between precipitation and global sea surface temperature (SST) is explored. Prediction equation is established with SST and the average precipitation. Thirdly, from dynamic model forecasting, the CFSv2 original model and the CFSv2 statistical downscaling model are used to analyze the influence of model deviation on fusion prediction. The optimum interpolation assimilation method is applied for realizing the optimal integration of statistical and dynamic model prediction. Finally, the standardized precipitation index (SPI) is calculated by the combined forecasting of annual precipitation to evaluate drought conditions. The results show that SST is an important factor affecting precipitation, which may be applied as a forecasting direction with other factors. The merged precipitation prediction skill by the CFSv2 original model and the statistical model do not have the great promotion, which is still lower than the prediction skill only by the statistical model. However, the merged precipitation prediction skill by the CFSv2 statistical downscaling model and the statistical model is better than the prediction skills by the two models mentioned above, respectively. These indicate that when the prediction difference between the models is large, the merged prediction error cannot be minimized. When the prediction skill levels are equal, there is an improvement in the merged result. So, it is necessary to revise the climate dynamic model by downscaling. What is more, the obtained drought levels match the actual disaster conditions, providing theoretical support of hydrology and meteorology for the prevention of natural disasters. HIGHLIGHTS Information fusion in data assimilation is introduced to merge precipitation forecasting from an improved CFSv2 model and a regression model.; SST is an important factor that may be applied as a precipitation forecasting direction with other factors.; When prediction skill levels between two models are equal, there is an improvement in the merged result. So, it is necessary to revise the climate dynamic model by statistical downscaling.;

Overactive bladder (OAB) is the most bothersome symptom in lower urinary tract symptoms (LUTS). Current pharmacologic treatment aims to inhibit detrusor contraction; however, shows unsatisfied efficacy and high discontinuation rate. LIM kinases (LIMKs) promote smooth muscle contraction in the prostate; however, their function in the bladder smooth muscle remains unclear. Here, we studied effects of the LIMK inhibitors on bladder smooth muscle contraction and proliferation both in vitro and in vivo experiments. Bladder expressions of LIMKs are elevated in OAB rat detrusor tissues. Two LIMK inhibitors, SR7826 and LIMKi3, inhibit contraction of human detrusor strip, and cause actin filament breakdown, as well as cell proliferation reduction in cultured human bladder smooth muscle cells (HBSMCs), paralleled by reduced cofilin phosphorylation. Silencing of LIMK1 and LIMK2 in HBSMCs resulted in breakdown of actin filaments and decreased cell proliferation. Treatment with SR7826 or LIMKi3 decreased micturition frequency and bladder detrusor hypertrophy in rats with bladder outlet obstruction. Our study suggests that LIMKs may promote contraction and proliferation in the bladder smooth muscle, which could be inhibited by small molecule LIMK inhibitors. LIMK inhibitors could be a potential therapeutic strategy for OAB- related LUTS.

Previous studies have shown that the risk of colon cancer is greatly increased in people with obesity, and fat content in colorectal cancer tissue is increased in people with obesity. As an important part of tumor microenvironment, adipose-derived mesenchymal stem cells (MSCs) are also another important source of cancer-associated fibroblasts (CAFs), which may be one of the important mechanisms of affecting tumor progression. However, the mechanism is poorly defined. In the present study, CAFs were transformed from MSCs [MSC-transformed CAFs (MTCAFs)] by co-culturing with HCT116 cells. Bioinformatics and Western blotting analysis indicated a positive correlation between intercellular adhesion molecule-1(ICAM-1) and the progression of colon cancer. In clinical colon cancer specimens, we found that ICAM-1 was highly expressed and related to shorter disease-free survival, which might act as an indication for the progression of clinical colon cancer. Our data showed that ICAM-1 secreted from MTCAFs could positively promote the proliferation, migration, and invasion of colon cancer cells by activating signal transducer and activator of transcription 3 (STAT3) and Serine/threonine-protein kinase (AKT) signaling and that blocking ICAM-1 in MTCAFs reversed these effects. We further verified that ICAM-1 secreted from MTCAFs promoted tumor progression in vivo. Taken together, ICAM-1 plays a critical role in regulating tumor growth and metastasis, which could be a potential therapeutic target in colon cancer.

Abstract Cancer-associated fibroblasts (CAFs) play critical roles in cancer progression by regulating tumor cell proliferation, angiogenesis, and metastasis. Recent studies demonstrated that CAFs induce inhibitory immune cell infiltration and chemotherapy resistance in gastric cancer by activating the NF-κB signaling pathway to secrete IL6, IL8, and other inflammatory factors. Inhibition of the NF-κB signaling pathway in CAFs might be a potential therapeutic strategy in gastric cancer. However, how the NF-κB pathway is activated in CAFs remains unclear. We showed that mesenchymal stem cells (MSCs) differentiated into CAFs, induced by the exosomes derived from gastric cancer cells. During the process of differentiation from MSCs into CAFs, we showed that nuclear PKM2 expression was continuously upregulated and associated with NF-κB P65 acetylation, contributing to P65 nuclear retention in CAFs and constant transcription of IL-6, IL-8, and other inflammatory factors, thus promoting gastric cancer cell proliferation. We showed that NF-κB P65 acetylation was induced by P300. We showed that nuclear PKM2 was derived from exosomes of gastric cancer cell lines and the positive feedback loop induced by PKM2-P65 combination. It is also proved that P300 inhibitors can inhibit tumor proliferation in an AGS subcutaneous xenograft tumor model. Our study showed that gastric cancer cells influence the continuous activation of the NF-κB signaling pathway in CAFs by secreting gastric cancer exosomes containing PKM2, thus inducing abnormal metabolism and inflammation activation. This study provides a new therapeutic target for CAF normalization or deactivation strategies.

The TRIpartite Motif (TRIM) proteins play key roles in cell differentiation, apoptosis, development, autophagy, and innate immunity in vertebrates. In the present study, a novel TRIM9 homolog (designated as LvTRIM9-1) specifically expressed in the lymphoid organ of shrimp was identified from the Pacific whiteleg shrimp Litopenaeus vannamei. Its deduced amino acid sequence possesses the typical features of TRIM proteins, including a RING domain, two B-boxes, a coiled-coil domain, a FN3 domain, and a SPRY domain. The transcripts of LvTRIM9-1 were mainly located in the lymphoid tubules of the lymphoid organ. Knockdown of LvTRIM9-1 could apparently inhibit the transcriptions of some genes from white spot syndrome virus (WSSV) and reduce the viral propagation in the lymphoid organ. Overexpression of LvTRIM9-1 in mammalian cells could activate the promoter activity of NF-κB, and an in vivo experiment in shrimp showed that knockdown of LvTRIM9-1 reduced the expression of LvRelish in the lymphoid organ. Yeast two-hybridization and co-immunoprecipitation (Co-IP) assays confirmed that LvTRIM9-1 could directly interact with LvIMD, a key component of the IMD pathway, through its SPRY domain. These data suggest that LvTRIM9-1 could activate the IMD pathway in shrimp via interaction with LvIMD. This is the first evidence to show the regulation of a TRIM9 protein on the IMD pathway through its direct interaction with IMD, which will enrich our knowledge on the role of TRIM proteins in innate immunity of invertebrates.

Upregulation of immune checkpoint proteins is one of the main mechanisms for tumor immune escape. The expression of programmed death ligand-1 (PD-L1) in colorectal cancer (CRC) is higher than in normal colorectal epithelial tissue, and patients with higher PD-L1 expression have a poorer prognosis. Additionally, PD-L1 expression in CRC is affected by the tumor microenvironment (TME). As a major component of the TME, cancer-associated fibroblasts (CAFs) can act as immune regulators and generate an immunosuppressive tumor microenvironment. Therefore, we speculated that CAFs may be related to the upregulation of PD-L1 in CRC, which leads to tumor immune escape. We found that CAFs upregulate PD-L1 expression in CRC cells through AKT phosphorylation, thereby reducing the killing of CRC cells by peripheral blood mononuclear cells. The ratio of CAFs to CRC cells was positively correlated with AKT phosphorylation and the expression of PD-L1 in CRC in vitro. Consistent with the in vitro results, high CAF content and high expression of PD-L1 were negatively correlated with disease-free survival (DFS) of CRC patients. These results indicate that the upregulation of PD-L1 expression in CRC by CAFs through the activation of Akt is one of the molecular mechanisms of tumor immune escape. Thus, targeted anti-CAF therapy may help improve the efficacy of immunotherapy.

ABSTRACT This study was conducted to determine the in vitro activities of gentamicin alone and in combination with ceftriaxone, ertapenem, and azithromycin against multidrug-resistant (MDR) Neisseria gonorrhoeae isolates. A total of 407 clinical isolates from Nanjing, China, obtained in 2016 to 2017, had MICs determined for gentamicin using the agar dilution method. MDR status was ascribed to 97 strains that displayed decreased susceptibility or resistance to extended-spectrum cephalosporins (ESCs) (ceftriaxone [MIC, ≥0.125 mg/liter] and cefixime [MIC, ≥0.25 mg/liter]), plus resistance to at least two of the following antimicrobials: penicillin (MIC, ≥2 mg/liter), ciprofloxacin (MIC, ≥1 mg/liter), and azithromycin (MIC, ≥1 mg/liter). MDR strains underwent MIC determinations for antimicrobial combinations using the antimicrobial gradient epsilometer test (Etest). Results that ranged from synergy to antagonism were interpreted using the fractional inhibitory concentration (FICI). All 407 gonococcal isolates were susceptible to gentamicin; MICs ranged from 2 mg/liter to 16 mg/liter. Synergy was demonstrated in 16.5% (16/97), 27.8% (27/97), and 8.2% (8/97) of MDR strains when gentamicin was combined with ceftriaxone (geometric mean [GM] FICI, 0.747), ertapenem (GM FICI, 0.662), and azithromycin (GM FICI, 1.021), respectively. No antimicrobial antagonism was observed with any combination tested against MDR strains; overall, antimicrobial combinations were indifferent. The GM MICs of gentamicin were reduced by 2.63-, 3.80-, and 1.98-fold when tested in combination with ceftriaxone, ertapenem, and azithromycin, respectively. The GM MICs of the three additional antimicrobials individually were reduced by 3-, 2.57-, and 1.98-fold, respectively, when each was tested in combination with gentamicin. Gentamicin alone was effective in vitro against N. gonorrhoeae, including MDR isolates. Combination testing of MDR strains showed lower MICs against gentamicin and each of three antimicrobials (ceftriaxone, ertapenem, and azithromycin) when used in combination. IMPORTANCE Antimicrobial-resistant Neisseria gonorrhoeae is a major global public health concern. New treatment options are urgently needed to successfully treat multidrug-resistant (MDR) Neisseria gonorrhoeae infections. This study showed that gentamicin maintained excellent in vitro susceptibility against clinical gonococcal isolates collected in 2016 and 2017, including MDR isolates. Combinations of gentamicin plus ertapenem, ceftriaxone, and azithromycin produced synergistic effects against certain MDR isolates. No antagonism was observed in any of the antimicrobial combinations, which may prove useful to guide clinical testing of combination therapies.

Urothelial cancer (UC) is one of the common refractory tumors and chemotherapy is the primary treatment for it. The advent of immune checkpoint inhibitors (ICI) has facilitated the development of treatment strategies for UC patients. To screen out UC patients sensitive to ICI, researchers have proposed that PD-L1, tumor mutation burden and TCGA molecular subtypes can be used as predictors of ICI efficacy. However, the performance of these predictors needs further validation. We need to identify novel biomarkers to screen out UC patients sensitive to ICI. In our study, we collected the data of two clinical cohorts: the ICI cohort and the TCGA cohort. The result of the multivariate Cox regression analysis showed that glycogen metabolism score (GMS) (HR = 1.26, p = 0.017) was the negative predictor of prognosis for UC patients receiving ICI treatment. Low-GMS patients had a higher proportion of patients achieving complete response or partial response to ICI. After the comparison of gene mutation status between high-GMS and low-GMS patients, we identified six genes with significant differences in mutation frequencies, which may provide new directions for potential drug targets. Moreover, we analyzed the immune infiltration status and immune-related genes expression between high-GMS and low-GMS patients. A reduced proportion of tumor-associated fibroblasts and elevated proportion of CD8+ T cells can be observed in low-GMS patients while several immunosuppressive molecules were elevated in the high-GMS patients. Using the sequencing data of the GSE164042 dataset, we also found that myeloid-derived suppressor cell and neutrophil related signature scores were lower in α-glucosidase knockout bladder carcinoma cells when compared to the control group. In addition, angiogenesis, classic carcinogenic pathways, immunosuppressive cells related pathways and immunosuppressive cytokine secretion were mainly enriched in high-GMS patients and cell samples from the control group. Finally, we suspected that the combination treatment of ICI and histone deacetylase inhibitors may achieve better clinical responses in UC patients based on the analysis of drug sensitivity data. In conclusion, our study revealed the predictive value of GMS for ICI efficacy of UC patients, providing a novel perspective for the exploration of new drug targets and potential treatment strategies.

Background: Discrete choice experiment (DCE) as a tool that can measure medical stakeholders' preferences especially patients recently has been increasingly applied in health care.Objective: The aim of this study was to examine the hotspots and trends of the application of DCE in health care and to provide reference and direction for further development of DCE in the future.Method: A bibliometric method was implemented using the Web of Science (WoS) Core Collection for the period from the database established to December 8, 2020. The data files are imported into CiteSpace and Excel to analyze and visualize the annual volume of productive, authors, countries, cited journals, cited articles, and keywords.Results: A total of 1,811 articles were retrieved, then we read the abstract of each paper one by one, and 1,562 articles were included after screening, with an exponential increase in publication volume. John F. P. Bridges contributed to 40 publications and ranked first, followed by F. Reed Johnson (n = 37), Julie Ratcliffe (n = 36). The majority of the papers were conducted in the United States (n = 513) and the United Kingdom (n = 433). The top three cited journals were “Health Economics” (n = 981), “Value in Health” (n = 893), and “Pharmaceutical Economics” (n = 774), and the top three articles were “Constructing experimental designs for discrete-choice experiments: report of the ISPOR Conjoint Analysis Experimental Design Good Research Practices Task Force,” “Conjoint analysis applications in health-a checklist: a report of the ISPOR Good Research Practices for Conjoint Analysis Task Force,” and “Discrete choice experiments in health economics: a review of the literature.” The research hotspots and trends included “health technology assessment,” “survival,” “preference based measure,” and “health state valuation.”Conclusion: The size of the literature about DCE studies in health care showed a noticeable increase in the past decade. The application of DCE in health care remains in an early growth phase, and “health technology assessment,” “survival,” “preference based measure,” and “health state valuation” reflected the latest research hotpots and future trends.

The noise and gain characteristics of pulsed double-pass (DP) amplifiers operating at low repetition rates are analyzed theoretically and experimentally. The Frantz-Nodvik equations are extended to realize rapid calculation of signal gain in DP fiber amplifiers. At the same time, the rate equations are used to compute the evolution of amplified spontaneous emission (ASE) noise. The effects of the pump scheme, the input energy, and the insertion loss on the gain and noise characteristics are discussed. Based on the simulation results, a new structure Yb-doped DP amplifier is proposed. The experimental results show that the small-signal gain of the DP amplifier can exceed 50 dB. In particular, the average ASE background of the DP amplifier at high-energy output is lower than that of the single-pass amplifier at the same output. This result is quite different from continuous-wave fiber amplifiers.

Although the study on the regulatory mechanism of endothelial differentiation from the perspective of development provides references for endothelial cell (EC) derivation from pluripotent stem cells, incomplete reprogramming and donor-specific epigenetic memory are still thought to be the obstacles of iPSCs for clinical application. Thus, it is necessary to establish a stable iPSC-EC induction system and investigate the regulatory mechanism of endothelial differentiation. Based on a single-layer culture system, we successfully obtained ECs from porcine iPSCs (piPSCs). In vitro, the derived piPSC-ECs formed microvessel-like structures along 3D gelatin scaffolds. Under pathological conditions, the piPSC-ECs functioned on hindlimb ischemia repair by promoting blood vessel formation. To elucidate the molecular events essential for endothelial differentiation in our model, genome-wide transcriptional profile analysis was conducted, and we found that during piPSC-EC derivation, the synthesis and secretion level of TGF-β as well as the phosphorylation level of Smad2/3 changed dynamically. TGF-β-Smad2/3 signaling activation promoted mesoderm formation and prevented endothelial differentiation. Understanding the regulatory mechanism of iPSC-EC derivation not only paves the way for further optimization, but also provides reference for establishing a cardiovascular drug screening platform and revealing the molecular mechanism of endothelial dysfunction.

Floodplain wetlands in the China side of the Amur River Basin (CARB) undergone consistent decreases because of both natural and anthropogenic drivers. Monitoring floodplain wetlands dynamics and conversions over long-time periods is thus fundamental to sustainable management and protection. Due to complexity and heterogeneity of floodplain environments, however, it is difficult to map wetlands accurately over a large area as the CARB. To address this issue, we developed a novel and robust classification approach integrating image compositing algorithm, objected-based image analysis, and hierarchical random forest classification, named COHRF, to delineate floodplain wetlands and surrounding land covers. Based on the COHRF classification approach, 4622 Landsat images were applied to produce a 30-m resolution dataset characterizing dynamics and conversions of floodplain wetlands in the CARB during 1990–2018. Results show that (1) all floodplain land cover maps in 1990, 2000, 2010, and 2018 had high mapping accuracies (ranging from 90 %±0.001–97%±0.005), suggesting that COHRF is a robust classification approach; (2) CARB experienced an approximately 25 % net loss of floodplain wetlands with an area declined from 8867 km2 to 6630 km2 during 1990–2018; (3) the lost floodplain wetlands were mostly converted into croplands, while, there were 111 km2 and 256 km2 of wetlands rehabilitated from croplands during periods of 2000–2010 and 2010–2018, respectively. To our knowledge, this study is the first attempt that focus on delineating floodplain wetlands at a large-scale and produce the first 30-m spatial resolution dataset demonstrating long-term dynamics of floodplain wetlands in the CARB. The COHRF classification approach could be used to classify other ecosystems readily and robustly. The resultant dataset will contribute to sustainable use and conservation of wetlands in the Amur River Basin and provide essential information for related researches.

Crustin are a family of antimicrobial peptides that play an important role in protecting against pathogens infection in the innate immune system of crustaceans. Previously, we identified several novel types of crustins, including type VI and type VII crustins. However, their immune functions were still unclear. In the present study, the immune function of type VII crustin LvCrustinVII were investigated in Litopenaeus vannamei. LvCrustinVII was wildly expressed in all tested tissues, with relatively high expression levels in hepatopancreas, epidermis and lymphoid organ. Upon Vibrio parahaemolyticus infection, LvCrustinVII was significantly upregulated in hepatopancreas. Recombinant LvCrustinVII (rLvCrustinVII) showed strong inhibitory activities against Gram-negative bacteria Vibrio harveyi and V. parahaemolyticus, while weak activities against the Gram-positive bacteria Staphylococcus aureus. Binding assay showed that rLvCrustinVII could bind strongly to V. harveyi and V. parahaemolyticus, as well as the cell wall components Glu, LPS and PGN. In the presence of Ca2+, rLvCrustinVII could agglutinate V. parahaemolyticus and enhance hemocyte phagocytosis. The present data partially illustrate the immune function of LvCrustinVII, which enrich our understanding on the functional mechanisms of crustins and provide useful information for application of this kind of antimicrobial peptides.

Abstract Background Lactobacillus casei (L. casei) is well known for its probiotic property in human and animals. Lactoferricin (Lfcin) polypeptide can effectively modulate host immune responses and have antimicrobial activity in vivo and in vitro. In order to develop a food-grade L. casei system constitutively expressing bovine Lfcin, this study constructed a thymidine auxotrophy (ΔthyA) recombinant L. casei. Results Based on the thymidylate synthase gene (thyA) insert site, LFEC(Lfcin expression cassette)was inserted into L. casei genome through homologous recombination, successfully expressed and could be stably inherited. The recombinant L. casei, ΔthyA L. casei-LFEC, is sensitive to chloramphenicol and limited when cultured without thymine. Meanwhile, ΔthyA L. casei-LFEC has both good antibacterial activity against Escherichia coli and Staphylococcus aureus and antiviral activity against porcine epidemic diarrhea virus (PEDV). Conclusions We successfully constructed a recombinant L. casei strain expressing Lfcin, ΔthyA L. casei-LFEC, which could only survive in the presence of thymine, and had excellent antimicrobial and antiviral activity with good genetic stability and sensitivity. This research provides a cost-effective alternative to the antibiotics with additional biological functions and wider applicability prospect. Using ΔthyA as the selectable mark instead of antibiotic to construct genetic engineering L.casei provides a safe and effective approach of feed additives in livestock raising.

In the recent decades, development of agricultural and human settlements have severely affected wetlands on the China-side of the Amur River Basin (CARB). A long-term holistic view of spatio-temporal variations of the wetlands on the CARB is essential for supporting sustainable conservation of wetlands in this region. In this study, a training sample migration method along with Random Forest classifier were adopted to map wetland and other land covers from two key seasons image collections. The proposed classification method was applied to Landsat images, and a 30-m resolution dataset was obtained, which reflected the dynamic changes of historical wetland distribution on the CARB region from 1990 to 2010. As the accuracy assessments showed, land cover maps of the CARB had high accuracies. The classification results indicated that the wetland area decreased from 89,432 km2 to 75,061 km2 between 1990 and 2010, with a net loss of 16%, which was mainly converted to paddy field and dry farmland, and the changes were most obvious in Sanjiang Plain and Songnen Plain. This suggests that agricultural activities are the main cause of wetland loss. The results can provide reliable information for the research on wetland management and sustainable development of the society and economy in the CARB.

A gain slab configuration with a low thermally induced wavefront distortion, which is based on heating the edge by the cladding layer, is proposed. The gain slab will be applied to a helium-cooled Nd: glass multislab laser amplifier with an output of 100 J at a repetition rate of 10 Hz. Additionally, a 3D numerical simulation model is developed to analyze the thermo-optic effects in the gain slab. Some parameters, including the absorption coefficient (α) of the cladding layer, the shape of the pump beam, and the gap between the pump area and absorbing cladding layer, are optimized to eliminate the thermo-optic effects. The results indicate that the peak-to-valley (P-V) of the thermally induced wavefront distortion of the specific gain slab can be reduced by 61% if other parameters remain constant.

This paper reports on a Joule-level multi-pass laser amplification device with diode end-pumped square-rod neodymium glass (Nd:glass) bonded to K9 glass. The device generated 1.17 J pulse energy at 1 Hz and 1053 nm. The optical-to-optical efficiency was 13.01%, and the effective energy extraction efficiency was 44.23%. Comparing Nd:glass of the same specification without K9 glass under the same conditions, the thermal wave aberration of the former was 85.71% of that of the latter, which is 0.78 um. The near-field modulation degree at the highest energy output was 1.42 within 90% of the spot, and the far-field energy concentration was 81.88% within the 2.5-fold diffraction limit. The Nd:glass bonding method of the square rod is relatively novel in laser amplification systems pumped by the diode end face and can be further studied in future works.

In this paper, a model to predict the thermal effects in a flashlamp-pumped direct-liquid-cooled split-disk Nd:LuAG ceramic laser amplifier has been presented. In addition to pumping distribution, the model calculates thermal-induced wavefront aberration as a function of temperature, thermal stress and thermal deformation in the gain medium. Experimental measurements are carried out to assess the accuracy of the model. We expect that this study will assist in the design and optimization of high-energy lasers operated at repetition rate.

The characterization of a laser diode (LD)-pumped neodymium-doped silica glass (NDSG) laser is here described. The gain performance and wavefront distortion were measured, and the thermal toughness and uniformity distribution of the material were experimentally observed. At a pumping frequency of 1 Hz and energy 7.79 J, a small-signal gain of 1.16 was measured, and the wavefront distortion reached 2.67 λ (wavelength λ = 1053 nm). At a pumping frequency of 25 Hz with 194 W power, the NDSG was still not cracked, which is consistent with its high thermal shock parameter. However, the material uniformity was relatively poor. These results indicate good prospects for the application of NDSG lasers at high energy and high repetition frequency, but the gain performance, uniformity, and other aspects affected by the manufacturing process need to be improved.

The influence of driving conditions on the phase-modulation ability of an optically addressable spatial-light modulator (OASLM) is investigated using an equivalent circuit method and a system for measuring wave-front modulation that uses a phase-unwrapping data-processing method, and is constructed with a charge-coupled device and wave-front sensor. 1λ peak-to-valley phase change for a 1053 nm laser beam is acquired with the home-made OASLM at the optimal driving voltage of 14 V at 200 Hz. The detection system for wave-front modulation has a spatial resolution of 200 µm for binary images and a minimum distinguishable contrast of 1 mm. On-line phase modulation with feedback control can be acquired with the OASLM and the corresponding measuring system.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy. [ABSTRACT FROM AUTHOR]

Abstract Background Currently, treatment regimens for visceral leishmaniasis (VL) are limited because of the presence of numerous adverse effects. Nicotinamide, a readily available and cost-effective vitamin, has been widely acknowledged for its safety profile. Several studies have demonstrated the anti-leishmanial effects of nicotinamide in vitro. However, the potential role of nicotinamide in Leishmania infection in vivo remains elusive. Methods In this study, we assessed the efficacy of nicotinamide as a therapeutic intervention for VL caused by Leishmania infantum in an experimental mouse model and investigated its underlying molecular mechanisms. The potential molecular mechanism was explored through cytokine analysis, examination of spleen lymphocyte subsets, liver RNA-seq analysis, and pathway validation. Results Compared to the infection group, the group treated with nicotinamide demonstrated significant amelioration of hepatosplenomegaly and recovery from liver pathological damage. The NAM group exhibited parasite reduction rates of 79.7% in the liver and 86.7% in the spleen, respectively. Nicotinamide treatment significantly reduced the activation of excessive immune response in infected mice, thereby mitigating hepatosplenomegaly and injury. Furthermore, nicotinamide treatment enhanced fatty acid β-oxidation by upregulating key enzymes to maintain lipid homeostasis. Conclusions Our findings provide initial evidence supporting the safety and therapeutic efficacy of nicotinamide in the treatment of Leishmania infection in BALB/c mice, suggesting its potential as a viable drug for VL. Graphical Abstract