Shallow groundwater table fluctuations promote the accumulation and loss of phosphorus from surface soil to deeper soil in croplands around plateau lakes in Southwest China.

The continuous excessive application of phosphorus (P) fertilizers in intensive agricultural production leads to a large accumulation of P in surface soils, increasing the risk of soil P loss by runoff and leaching. However, there are few studies on the accumulation and loss of P from surface soil to deep soil profiles driven by shallow groundwater table (SGT) fluctuations. This study used the intensive cropland around 7 plateau lakes in Yunnan Province as an example and conducted in situ monitoring of P storage in the soil profile and SGT during the rainy season (RS) and dry season (DS) as well as simulation experiments on soil P loss. The aim was to study the spatiotemporal variation in P accumulation in the soil profile of cropland driven by SGT fluctuations in the RS and DS and estimate the P loss in the soil profile driven by SGT fluctuations. The results showed that fluctuations in the SGT promoted P accumulation from the surface soil to deeper soil. The proportions of P stored in various forms in the 30-60 cm and 60-100 cm soil layers in the RS were greater than those in the DS, while the average proportion in the 0-30 cm soil layer in the DS was as high as 48%. Compared with those in the DS, the maximum decreases in the proportion of P stored as TP and Olsen-P in the 0-100 cm soil layer in the RS were 16% and 58%, respectively, due to the rise in the SGT (SGT <30 cm), while the soil TP storage decreased by only 1% when the SGT was maintained at 60-100 cm. The critical thresholds for soil Olsen-P and TP gradually decreased with increasing soil depth, and the risk of P loss in deeper soil increased. The loss of soil P was increased by fluctuations in the SGT. Based on the cropland area around the 7 plateau lakes, P storage, and SGT fluctuations, the average loss intensity and loss amount of TP in the 0-100 cm soil layer around the 7 plateau lakes were estimated to be 25 kg/ha and 56 t, respectively. Therefore, reducing exogenous P inputs, improving soil endogenous P utilization efficiency and maintaining deep soil P retention are the basic strategies for preventing and controlling P accumulation and loss in deep soil caused by SGT fluctuations.

Design, synthesis and evaluation of carbamate-bridged amino acid prodrugs of cycloicaritin with improved antitumor activity, aqueous solubility and phase II metabolic stability.

Cycloicaritin (CICT), a bioactive flavonoid derived from the genus Epimedium, exhibits a variety of beneficial biological activities, including promising anticancer effects. However, its poor oral bioavailability is attributed to its extremely low aqueous solubility and rapid elimination via phase II conjugative metabolism. To overcome these limitations, we designed and synthesized a series of carbamate-bridged prodrugs, protecting the hydroxyl group at the 3-position of cycloicaritin by binding with the N-terminus of a natural amino acid. The optimal prodrug 4b demonstrated a significant increase in aqueous solubility as compared to CICT, as well as improved stability in phase II metabolism, while allowing for a rapid release of CICT in the blood upon gastrointestinal absorption. The prodrug 4b also facilitated oral absorption through organic anion-transporting polypeptide 2B1-mediated transport and exhibited moderate cytotoxicity. Importantly, the prodrug enhanced the oral bioavailability of CICT and displayed dose-dependent antitumor activity with superior safety. In summary, the prodrug 4b is a novel potential antitumor drug candidate, and the carbamate-bridged amino acid prodrug approach is a promising strategy for the oral delivery of CICT.

Optimization of Cohesive Parameters in the Interfacial Transition Zone of Rubberized Concrete Based on the Response Surface Method.

Rubber concrete has been applied to a certain extent in fatigue-resistant structures due to its good durability. Based on a cohesive model of rubber composed of a five-phase material containing mortar, aggregate, rubber, aggregate-mortar interfacial transition zone (ITZ), and rubber-mortar ITZ, this paper studies the influence of the cohesive parameters in the rubber-mortar ITZ on the fatigue problem of rubber concrete on the mesoscopic scale. As the weak part of cement-based composite materials, the ITZ has a great influence on the mechanical properties and durability of concrete, but the performance of the ITZ is difficult to test in macro experiments, resulting in difficulties in determining its simulation parameters. Based on the cohesive model with a rubber content of 5%, this study uses Monofactor analysis and the Plackett-Burman test to quickly and effectively determine the primary and secondary influences of the cohesive model parameters in the rubber-mortar ITZ; further, the response surface method is used to optimize the cohesive parameters in the rubber-mortar ITZ, and the numerical simulation results after optimizing the cohesive parameters are compared and analyzed with the simulation results before optimization. The results show that, under the setting of the optimized parameters, the simulation results of each item of the optimal cohesive model parameters in the rubber-mortar ITZ are in line with the reality and closer to the experimental data, and they are also applicable to rubber concrete models with different rubber dosing.

The First Report of Tritrichomonas Foetus and Tetratrichomonas Buttreyi in Raccoon Dogs (Nyctereutes Procyonoides) in China.

BACKGROUND: In recent years, the trichomonosis in raccoon dogs in China had occurred frequently. Pentatrichomonas hominis had been described in raccoon dogs in China in some previous studies. PURPOSE TO REVEAL: whether raccoon dogs can be infected by other trichomonad species besides P. hominis, and clarify the prevalence and species distribution of trichomonad in raccoon dogs. METHODS: Herein, the 389 fecal samples were collected from farm-raised raccoon dogs in Hebei Province, all the samples were detected using the microscopic examination and several fecal samples containing trichomonad-like organisms were processed, cultured, stained, and photographed. Meanwhile, all the samples were screened by the species-specific nested PCR based on the small subunit rRNA (SSU rRNA) gene of P. hominis,Tritrichomonas foetus and Tetratrichomonas buttreyi, respectively, and all positive secondary PCR amplications obtained in this study were sequenced, aligned and analysed. RESULTS: 62 fecal samples (15.9%,62/389) were trichomonad-positive under light microscopy, and the trichomonad-like cells were clearly observed in the culture contents. The PCR results showed that 100 samples were trichomonad-positive, including 45 P. hominis-positive samples (11.6%,45/389), 32 T. foetus-positive samples (8.2%,32/389), and 33 T. buttreyi-positive samples (8.5%,33/389), respectively. Double mixed infections were observed in 10 samples. The prevalence of T. foetus and P. hominis were both significantly higher in raccoon dogs with diarrhea (13.9%, and 25.0%) than that in raccoon dogs without diarrhea (7.6%, and 9.3%) (p < 0.05).All samples confirmed as trichomonad-positive under microscopy were also found to be trichomonad-positive by PCR analysis. The sequencing and phylogenetic analysis demonstrated the sequences obtained in this study belonged to P. hominis, T. foetus and T. buttreyi SSU rRNA, respectively. Among them, the T. buttreyi SSU rRNA sequences obtained in this study harbored the new sequence polymorphisms. Based on preliminary morphological and molecular analyses, raccoon dogs are considered as the new host of T. foetus and T. buttreyi. CONCLUSION: This is the first report about the identifcation and prevalence of T. foetus and T. buttreyi in raccoon dogs in China, and the results increase our knowledge about the host range and prevalence of trichomonad species.

[Comparsion of bone setting technique combined with percutaneous vertebroplasty and percutaneous kyphoplasty for the treatment of osteoporotic vertebral compression fractures].

OBJECTIVE: To explore clinical efficacy of osteoplasty combined with percutaneous vertebroplasty(PVP) and percutaneous kyphoplasty (PKP) alone in treating osteoporosis vertebral compression fractures (OVCFs). METHODS: The clinical data of 80 patients with single-level OVCFs treated from January 2021 to June 2022 were retrospectively analyzed, and were divided into treatment group and control group according to different surgical methods, 40 patients in each group. In treatment group, there were 24 males and 16 females, aged from 60 to 83 years old with an average of (70.43±7.31) years old;bone mineral density ranged from -3.30 to -2.50 SD with an average of(-2.84±0.24) SD;1 patient with T10, 4 patients with T11, 11 patients with T12, 7 patients with L1, 7 patients with L2, 5 patients with L3, 3 patients with L4, 2 patients with L5;bone setting technique combined with PVP were performed. In control group, there were 27 males and 13 females, aged from 60 to 82 years old with an average of (68.98±6.94) years old;bone mineral density ranged from -3.40 to -2.50 SD with an average of (-2.76±0.23) SD;2 patients with T10, 3 patients with T11, 13 patients with T12, 11 patients with L1, 5 patients with L2, 3 patients with L3, 2 patients with L4, 1 patient with L5;simple PKP were peformed. Visual analogue scale (VAS) and lumbar Oswestry disability index (ODI) were compared between two groups before operation, 3 days, 3 and 12 months after operation. The changes of local kyphotic angle, vertebral wedge angle and vertebral anterior margin height ratio were compared between two groups before operation, 3 days and 12 months after operation. RESULTS: All patients were successfully completed operation. Treatment group were followed up from 13 to 22 months with an average of (16.82±2.14) months, and control group were followed up from 13 to 23 months with an average of (16.45±2.56) months. Three patients were occurred bone cement leakage in treatment group, while 1 patient were occurred bone cement leakage and 1 patient occurred sensory disturbance of lower limb skin in control group;there were no significant difference in complications between two groups (P>0.05). There were no significant difference in preoperative VAS and ODI between two groups (P>0.05). At 3 days after operation, VAS of treatment group 3.68±0.62 was significantly higher than that of control group 4.00±0.72 (P<0.05). There were no significant difference in VAS and ODI between two groups at 3 and 12 months after operation (P>0.05). There were no significant difference in local kyphotic angle, vertebral wedge angle and vertebral anterior margin height between two groups at 3 days and 12 months after operation (P>0.05). CONCLUSION: Compared with PKP, bone setting manipulation combined with PVP for the treatment of OVCFs has advantages in early postoperative pain relief. In terms of vertebral height recovery, bone setting manipulation combined with PVP and PKP alone have similar clinical effects.

Temporal Dynamics and Influential Factors of Taste and Odor Compounds in the Eastern Drinking Water Source of Chaohu Lake, China: A Comparative Analysis of Global Freshwaters.

The escalating proliferation of cyanobacteria poses significant taste and odor (T/O) challenges, impacting freshwater ecosystems, public health, and water treatment costs. We examined monthly variations in four T/O compounds from September 2011 to August 2012 in Chaohu Lake's eastern drinking water source (DECL). More importantly, we compared the reported T/O occurrence and the related factors in freshwater bodies worldwide. The assessment of T/O issues indicated a severe and widespread problem, with many cases surpassing odor threshold values. Remarkably, China reported the highest frequency and severity of odor-related problems. A temporal analysis revealed variations in odor occurrences within the same water body across different years, emphasizing the need to consider high values in all seasons for water safety. Globally, T/O issues were widespread, demanding attention to variations within the same water body and across different layers. Algae were crucial contributors to odor compounds, necessitating targeted interventions due to diverse odorant sources and properties. A correlation analysis alone lacked definitive answers, emphasizing the essential role of further validation, such as algae isolation. Nutrients are likely to have influenced the T/O, as GSM and MIB correlated positively with nitrate and ammonia nitrogen in DECL, resulting in proposed control recommendations. This study offers recommendations for freshwater ecosystem management and serves as a foundation for future research and management strategies to address T/O challenges.

OLFM4 promotes the progression of intestinal metaplasia through activation of the MYH9/GSK3ß/ß-catenin pathway.

BACKGROUND: Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring the critical need for early screening measures. In addition to the complexities associated with diagnosis, the exact mechanisms driving the progression of gastric cancer in IIM patients remain poorly understood. OLFM4 is overexpressed in several types of tumors, including colorectal, gastric, pancreatic, and ovarian cancers, and its expression has been associated with tumor progression. METHODS: In this study, we used pathological sections from two clinical centers, biopsies of IM tissues, precancerous lesions of gastric cancer (PLGC) cell models, animal models, and organoids to explore the role of OLFM4 in IIM. RESULTS: Our results show that OLFM4 expression is highly increased in IIM, with superior diagnostic accuracy of IIM when compared to CDX2 and MUC2. OLFM4, along with MYH9, was overexpressed in IM organoids and PLGC animal models. Furthermore, OLFM4, in combination with Myosin heavy chain 9 (MYH9), accelerated the ubiquitination of GSK3ß and resulted in increased ß-catenin levels through the Wnt signaling pathway, promoting the proliferation and invasion abilities of PLGC cells. CONCLUSIONS: OLFM4 represents a novel biomarker for IIM and could be utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. Finally, our study identifies cell signaling pathways involved in the progression of IM.

High Energy Storage Performance in BiFeO3-Based Lead-Free High-Entropy Ferroelectrics.

Dielectric capacitors are widely used in advanced electrical and electronic systems due to the rapid charge/discharge rates and high power density. High comprehensive energy storage properties are the ultimate ambition in the field of application achievements. Here, the high-entropy strategy is proposed to design and fabricate single-phase homogeneous (Bi0.5Ba0.1Sr0.1Ca0.2Na0.1)(Fe0.5Ti0.3Zr0.1Nb0.1)O3 ceramic, the hierarchical heterostructure including rhombohedral-tetragonal multiphase nanoclusters and locally disordered oxygen octahedral tilt can lead to the increased dielectric relaxation, diffused phase transition, diverse local polarization configurations, grain refinement, ultrasmall polar nanoregions, large random field, delayed polarization saturation and improved breakdown field. Accordingly, a giant Wrec ≈13.3 J cm-3 and a high η ≈78% at 66.4 kV mm-1 can be simultaneously achieved in the lead-free high-entropy BiFeO3-based ceramic, showing an obvious advantage in overall energy-storage properties over BiFeO3-based lead-free ceramics. Moreover, an ultrafast discharge rate (t0.9 = 18 ns) can be achieved at room temperature, concomitant with favorable temperature stability in the range of 20-160 °C, due to the enhanced diffuse phase transition and fast polarization response. This work provides a feasible pathway to design and generate dielectric materials exhibiting high comprehensive energy-storage performance.

Association between physical activity and risk of premenstrual syndrome among female college students: a systematic review and meta-analysis.

BACKGROUND: This study aimed to analyze the relationship between physical activity and the risk of premenstrual syndrome among college students. METHODS: Eligible studies were searched from the PubMed, Web of Science, and Embase databases. The link between physical activity and the risk of premenstrual syndrome was evaluated using odds ratio (OR) and 95% confidence interval (CI). The heterogeneity of the included studies was tested and their sources were explored by subgroup analysis. A sensitivity analysis was performed to assess the effect of a single study on the pooled results. The included studies were evaluated for publication bias. Five moderate-quality studies were included in this meta-analysis. RESULTS: Physical activity levels were negatively associated with risk of premenstrual syndrome among college students (OR [95%CI] = 1.46 [1.09, 1.96], P = .011). The pooled results were not influenced after being stratified by the study region and whether multi-factor correction was performed or not. Publication bias was not observed in the included studies. CONCLUSION: A high level of physical activity is dramatically associated with a reduced risk of premenstrual syndrome among female college students.

Outcomes of patients in nasopharyngeal adenoid cystic carcinoma in the IMRT era: a single-center experience.

OBJECTIVE: Nasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with special biological features. Controversies exist regarding the treatment approach and prognostic factors in the IMRT era. This study aimed to evaluate the long-term outcomes and management approaches in NACC. METHODS: Fifty patients with NACC at our institution between 2010 and 2020 were reviewed. Sixteen patients received primary radiotherapy (RT), and 34 patients underwent primary surgery. RESULTS: Between January 2010 and October 2020, a total of 50 patients with pathologically proven NACC were included in our analysis. The median follow-up time was 58.5 months (range: 6.0-151.0 months). The 5-year overall survival rate (OS) and progression-free survival rate (PFS) were 83.9% and 67.5%, respectively. The 5-year OS rates of patients whose primary treatment was surgery and RT were 90.0% and 67.3%, respectively (log-rank P = 0.028). The 5-year PFS rates of patients whose primary treatment was surgery or RT were 80.8% and 40.7%, respectively (log-rank P = 0.024). Multivariate analyses showed that nerve invasion and the pattern of primary treatment were independent factors associated with PFS. CONCLUSIONS: Due to the relative insensitivity to radiation, primary surgery seemed to provide a better chance of disease control and improved survival in NACC. Meanwhile, postoperative radiotherapy should be performed for advanced stage or residual tumours. Cranial nerve invasion and treatment pattern might be important factors affecting the prognosis of patients with NACC.

Toward High-Performance Hydrogenation at Room Temperature Through Tailoring Nickel Catalysts Stable in Aqueous Solution.

The development of highly active, reusable catalysts for aqueous-phase reactions is challenging. Herein, metallic nickel is encapsulated in a nitrogen-doped carbon-silica composite (SiO2@Ni@NC) as a catalyst for the selective hydrogenation of vanillin in aqueous media. The constructed catalyst achieved 99.8% vanillin conversion and 100% 4-hydroxymethyl-2-methoxyphenol selectivity at room temperature. Based on combined scanning transmission electron microscopy, X-ray photoelectron spectroscopy, and Raman analyses, the satisfactory catalytic performance is attributed to the composite structure consisting of an active metal, carbon, and silica. The hydrophilic silica core promoted dispersion of the catalyst in aqueous media. Moreover, the external hydrophobic NC layer has multiple functions, including preventing oxidation or leaching of the internal metal, acting as a reducing agent to reduce the internal metal, regulating the active-site microenvironment by enriching the concentrations of H2 and organic reactants, and modifying the electronic structure of the active metal via metal-support interactions. Density functional theory calculations indicated that NC facilitates vanillin adsorption and hydrogen dissociation to promote aqueous-phase hydrogenation. This study provides an efficient strategy for constructing encapsulated Ni-based amphiphilic catalysts to upgrade biomass-derived compounds.

SS-31 inhibits the inflammatory response by increasing ATG5 and promoting autophagy in lipopolysaccharide-stimulated HepG2 cells.

SS-31 is a mitochondria-targeting short peptide. Recent studies have indicated its hepatoprotective effects. In our study, we investigated the impact of SS-31 on LPS-induced autophagy in HepG2 cells. The results obtained from a dual-fluorescence autophagy detection system revealed that SS-31 promotes the formation of autolysosomes and autophagosomes, thereby facilitating autophagic flux to a certain degree. Additionally, both ELISA and qPCR analyses provided further evidence that SS-31 safeguards HepG2 cells against inflammatory responses triggered by LPS through ATG5-dependent autophagy. In summary, our study demonstrates that SS-31 inhibits LPS-stimulated inflammation in HepG2 cells by upregulating ATG5-dependent autophagy.

Identification of an anaplastic subtype of prostate cancer amenable to therapies targeting SP1 or translation elongation.

Histopathological heterogeneity is a hallmark of prostate cancer (PCa). Using spatial and parallel single-nucleus transcriptomics, we report an androgen receptor (AR)-positive but neuroendocrine-null primary PCa subtype with morphologic and molecular characteristics of small cell carcinoma. Such small cell-like PCa (SCLPC) is clinically aggressive with low AR, but high stemness and proliferation, activity. Molecular characterization prioritizes protein translation, represented by up-regulation of many ribosomal protein genes, and SP1, a transcriptional factor that drives SCLPC phenotype and overexpresses in castration-resistant PCa (CRPC), as two potential therapeutic targets in AR-indifferent CRPC. An SP1-specific inhibitor, plicamycin, effectively suppresses CRPC growth in vivo. Homoharringtonine, a Food And Drug Administration-approved translation elongation inhibitor, impedes CRPC progression in preclinical models and patients with CRPC. We construct an SCLPC-specific signature capable of stratifying patients for drug selectivity. Our studies reveal the existence of SCLPC in admixed PCa pathology, which may mediate tumor relapse, and establish SP1 and translation elongation as actionable therapeutic targets for CRPC.

An integrated ceRNA network identifies miR-375 as an upregulated miRNA playing a tumor suppressive role in aggressive prostate cancer.

Prostate cancer (PCa) remains a significant cause of morbidity and mortality among men worldwide. A number of genes have been implicated in prostate tumorigenesis, but the mechanisms underlying their dysregulation are still incompletely understood. Evidence has established the competing endogenous RNA (ceRNA) theory as a novel regulatory mechanism for post-transcriptional alterations. Yet, a comprehensive characterization of ceRNA network in PCa lacks. Here we utilize stringent in-silico methods to construct a large ceRNA network across different PCa stages, and provide experimental demonstration for the competing regulation among protumorigenic SEC23A, PHTF2, and their corresponding ceRNA pairs. Using machine learning, we establish a ceRNA-based signature (ceRNA_sig) predictive of androgen receptor (AR) activity, tumor aggressiveness, and patient outcomes. Importantly, we identify miR-375 as a key node in PCa ceRNA network, which is upregulated in PCa relative to normal tissues. Forced expression of miR-375 significantly inhibits, while its inhibition promotes, aggressive behaviors of both AR+ and AR- PCa cells in vitro and in vivo. Mechanistically, we show that miR-375 predominantly targets genes possessing oncogenic roles (e.g., proliferation, DNA repair, and metastasis), and thus release targets with tumor suppressive functions. This action model well clarifies why an upregulated miRNA plays a tumor suppressive role in PCa. Together, our study provides new insights into understanding of transcriptomic aberrations during PCa evolution, and nominates miR-375 as a potential therapeutic target for combating aggressive PCa.

Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

The impact of urbanization and economic growth on carbon dioxide emission in sub-Saharan African countries: a perspective from the spatial-temporal approach.

Sub-Saharan Africa (SSA) is seeing exceptional urbanization and economic expansion rates. Therefore, the STIRPAT (Stochastic Impacts by Regression on Population, Affluence, and Technology) parameters and the spatial econometric framework are used in this work to examine the influence of economic growth and urbanization on SSA's CO2 emissions. Likewise, to determine the spatial effect and understand how factors influence the spatial dependence of carbon emissions, the study builds a spatial Durbin model (SDM). In line with the findings, the spatial correlation test revealed the spatial correlations across various countries. This indicates that the changes in sub-Saharan African country's CO2 emissions impacted nearby countries and the countries themselves. Additionally, the findings reveal that, in the SSA's countries, urbanization, economic growth, industrial structure, trade, and population, excluding energy intensity, which failed the significant test, all positively influence CO2 outflows, in line with the spatial econometric model's findings. Thus, energy intensity shares an adverse impact on carbon emissions. As an outcome, energy intensity reduces carbon dioxide emissions in nearby nations and the entire region. Thus, the study recommends that policymakers account for the effects of spatial spillover when establishing low-carbon policies, encouraging a low-carbon lifestyle, promoting environmentally friendly technologies, and improving regional collaboration.

A cysteine-specific solubilizing tag strategy enables efficient chemical protein synthesis of difficult targets.

We developed a new cysteine-specific solubilizing tag strategy via a cysteine-conjugated succinimide. This solubilizing tag remains stable under common native chemical ligation conditions and can be efficiently removed with palladium-based catalysts. Utilizing this approach, we synthesized two proteins containing notably difficult peptide segments: interleukin-2 (IL-2) and insulin. This IL-2 chemical synthesis represents the simplest and most efficient approach to date, which is enabled by the cysteine-specific solubilizing tag to synthesize and ligate long peptide segments. Additionally, we synthesized a T8P insulin variant, previously identified in an infant with neonatal diabetes. We show that T8P insulin exhibits reduced bioactivity (a 30-fold decrease compared to standard insulin), potentially contributing to the onset of diabetes in these patients. In summary, our work provides an efficient tool to synthesize challenging proteins and opens new avenues for exploring research directions in understanding their biological functions.

Epigenetic, transcriptional, and functional characterization of myeloid cells in familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by variation in MEFV. FMF is known for IL-1ß dysregulation, but the innate immune landscape of this disease has not been comprehensively described. Therefore, we studied circulating inflammatory proteins, and the function of monocytes and (albeit less extensively) neutrophils in treated FMF patients in remission. We found that monocyte IL-1ß and IL-6 production was enhanced upon stimulation, in concordance with alterations in the plasma inflammatory proteome. We did not observe changes in neutrophil functional assays. Subtle differences in chromatin accessibility and transcriptomics in our small patient cohort further argued for monocyte dysregulation. Together, these observations suggest that the MEFV-mutation-mediated primary immune dysregulation in monocytes leads to chronic inflammation that is subsequently associated with counterregulatory epigenetic/transcriptional changes reminiscent of tolerance. These data increase our understanding of the innate immune changes in FMF, aiding future management of chronic inflammation in these patients.