Transcriptomic analysis of reproductive organs of pregnant mice post toxoplasma gondii infection reveals the potential factors that contribute to poor prognosis.

Toxoplasma gondii is an obligate intracellular parasite of phylum Apicomplexa that poses a huge threat to pregnant hosts, and induces tragic outcomes for pregnant hosts, fetuses and newborns. However, the molecular mechanism underlying the tragic consequences caused by T. gondii remains to be revealed. In the present study, we applied RNA-seq to study the transcriptomic landscape of the whole reproductive organ of pregnant mice post T. gondii infection, aiming to reveal the key altered biological characters of reproductive organs of pregnant mice that could contribute to the tragic outcomes caused by T. gondii infection. The results of the present study showed that the transcriptome of reproductive organs of pregnant mice was significantly altered by T. gondii infection. A total of 2,598 differentially expressed genes (DEGs) were identified, including 1,449 upregulated genes and 1,149 downregulated genes. Enrichment analysis of the DEGs showed that the significantly altered features of reproductive organs of pregnant mice were excessive inflammatory responses, downregulated metabolism processes, and congenital diseases. The chemotaxis of immune cells in the reproductive organs of infected pregnant mice could also be reshaped by 19 differentially expressed chemokines and 6 differentially expressed chemokine receptors that could contribute to the damages of reproductive organ in pregnant mice. Overall, the findings of present study may help to understand the pathogenic mechanism of the acute T. gondii infection in reproductive organs of pregnant mice, and it could also help to improve toxoplasmosis therapeutics for pregnant individuals.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease : A Systematic Review and Retrospective Individual Participant-Level Meta-analysis of Clinical Trials.

BACKGROUND: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. PURPOSE: To examine the association of ACEi or ARB treatment initiation, relative to a non-ACEi or ARB comparator, with rates of KFRT and death. DATA SOURCES: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. STUDY SELECTION: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. DATA EXTRACTION: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin-creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. DATA SYNTHESIS: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). LIMITATION: Individual participant-level data for hyperkalemia or acute kidney injury were not available. CONCLUSION: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. PRIMARY FUNDING SOURCE: National Institutes of Health. (PROSPERO: CRD42022307589).

Cryptosporidium spp. Infection and Genotype Identification in Pre-Weaned and Post-Weaned Calves in Yunnan Province, China.

BACKGROUND: Cryptosporidium is a globally distributed zoonotic protozoan parasite in humans and animals. Infection is widespread in dairy cattle, especially in calves, resulting in neonatal enteritis, production losses and high mortality. However, the occurrence of Cryptosporidium spp. in pre- and post-weaned calves in Yunnan Province remains unclear. METHODS: We collected 498 fecal samples from Holstein calves on 10 different farms in four regions of Yunnan Province. Nested PCR and DNA sequencing were used to determine the infection, species and genotypes of Cryptosporidium spp. in these animals. RESULTS: The overall occurrence of Cryptosporidium spp. in Holstein calves was 32.9% (164/498), and the prevalence in pre- and post-weaned calves was 33.5% (106/316) and 31.9% (58/182), respectively. Four Cryptosporidium species were identified in these animals, namely C. bovis (n = 119), C. parvum (n = 23), C. ryanae (n = 20) and C. andersoni (n = 2). Based on sequencing analysis of the 60 kDa glycoprotein gene of C. bovis, C. parvum and C. ryanae, six subtypes of C. bovis (XXVIe, XXVIb, XXVIf, XXVIa XXVIc and XXVId), two subtypes of C. parvum (IIdA19G1 and IIdA18G1) and four subtypes of C. ryanae (XXIf, XXId, XXIe and XXIg) were identified. CONCLUSIONS: These results provide essential information to understand the infection rate, species diversity and genetic structure of Cryptosporidium spp. populations in Holstein pre-weaned and post-weaned calves in Yunnan Province. Further, the presence of IIdA18G1 and IIdA19G1 in C. parvum implies significant animal and public health concerns, which requires greater attention and more preventive measures.

Patient-Specific Factors Predicting Renal Denervation Response in Patients With Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: The accurate selection of patients likely to respond to renal denervation (RDN) is crucial for optimizing treatment outcomes in patients with hypertension. This systematic review was designed to evaluate patient-specific factors predicting the RDN response. METHODS AND RESULTS: We focused on individuals with hypertension who underwent RDN. Patients were categorized based on their baseline characteristics. The primary outcome was blood pressure (BP) reduction after RDN. Both randomized controlled trials and nonrandomized studies were included. We assessed the risk of bias using corresponding tools and further employed the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the overall quality of evidence. A total of 50 studies were ultimately included in this systematic review, among which 17 studies were for meta-analysis. Higher baseline heart rate and lower pulse wave velocity were shown to be associated with significant antihypertensive efficacy of RDN on 24-hour systolic BP reduction (weighted mean difference, -4.05 [95% CI, -7.33 to -0.77]; weighted mean difference, -7.20 [95% CI, -9.79 to -4.62], respectively). In addition, based on qualitative analysis, higher baseline BP, orthostatic hypertension, impaired baroreflex sensitivity, and several biomarkers are also reported to be associated with significant BP reduction after RDN. CONCLUSIONS: In patients with hypertension treated with the RDN, higher heart rate, and lower pulse wave velocity were associated with significant BP reduction after RDN. Other factors, including higher baseline BP, hypertensive patients with orthostatic hypertension, BP variability, impaired cardiac baroreflex sensitivity, and some biomarkers are also reported to be associated with a better BP response to RDN.

CohortFinder: an open-source tool for data-driven partitioning of digital pathology and imaging cohorts to yield robust machine-learning models.

Batch effects (BEs) refer to systematic technical differences in data collection unrelated to biological variations whose noise is shown to negatively impact machine learning (ML) model generalizability. Here we release CohortFinder (http://cohortfinder.com), an open-source tool aimed at mitigating BEs via data-driven cohort partitioning. We demonstrate CohortFinder improves ML model performance in downstream digital pathology and medical image processing tasks. CohortFinder is freely available for download at cohortfinder.com.

m6A RNA methylation drives kidney fibrosis by upregulating ß-catenin signaling.

N6-methyladenosine (m6A) methylation plays a crucial role in various biological processes and the pathogenesis of human diseases. However, its role and mechanism in kidney fibrosis remain elusive. In this study, we show that the overall level of m6A methylated RNA was upregulated and the m6A methyltransferase METTL3 was induced in kidney tubular epithelial cells in mouse models and human kidney biopsies of chronic kidney disease (CKD). Proximal tubule-specific knockout of METTL3 in mice protected kidneys against developing fibrotic lesions after injury. Conversely, overexpression of METTL3 aggravated kidney fibrosis in vivo. Through bioinformatics analysis and experimental validation, we identified ß-catenin mRNA as a major target of METTL3-mediated m6A modification, which could be recognized by a specific m6A reader, the insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3). METTL3 stabilized ß-catenin mRNA, increased ß-catenin protein and induced its downstream profibrotic genes, whereas either knockdown of IGF2BP3 or inhibiting ß-catenin signaling abolished its effects. Collectively, these results indicate that METTL3 promotes kidney fibrosis by stimulating the m6A modification of ß-catenin mRNA, leading to its stabilization and its downstream profibrotic genes expression. Our findings suggest that targeting METTL3/IGF2BP3/ß-catenin pathway may be a novel strategy for the treatment of fibrotic CKD.

PatchSorter: a high throughput deep learning digital pathology tool for object labeling.

The discovery of patterns associated with diagnosis, prognosis, and therapy response in digital pathology images often requires intractable labeling of large quantities of histological objects. Here we release an open-source labeling tool, PatchSorter, which integrates deep learning with an intuitive web interface. Using >100,000 objects, we demonstrate a >7x improvement in labels per second over unaided labeling, with minimal impact on labeling accuracy, thus enabling high-throughput labeling of large datasets.

Advances in nanobubbles for cancer theranostics: Delivery, imaging and therapy.

Maximizing treatment efficacy and forecasting patient prognosis in cancer necessitates the strategic use of targeted therapy, coupled with the prompt precise detection of malignant tumors. Theutilizationof gaseous systems as an adaptable platform for creating nanobubbles (NBs) has garnered significant attention as theranostics, which involve combining contrast chemicals typically used for imaging with pharmaceuticals to diagnose and treattumorssynergistically in apersonalizedmanner for each patient. This review specifically examines the utilization of oxygen NBsplatforms as a theranostic weapon in the field of oncology. We thoroughly examine the key factors that impact the effectiveness of NBs preparations and the consequences of these treatment methods. This review extensively examines recent advancements in composition schemes, advanced developments in pre-clinical phases, and other groundbreaking inventions in the area of NBs. Moreover, this review offers a thorough examination of the optimistic future possibilities, addressing prospective methods for improvement and incorporation into widely accepted therapeutic practices. As we explore the ever-changing field of cancer theranostics, the incorporation of oxygen NBs appears as a promising development, providing new opportunities for precision medicine and marking a revolutionary age in cancer research and therapy.

HDAC1 Promotes Mitochondrial Pathway Apoptosis and Inhibits the Endoplasmic Reticulum Stress Response in High Glucose-Treated Schwann Cells via Decreased U4 Spliceosomal RNA.

Dysfunction of Schwann cells, including cell apoptosis, autophagy inhibition, dedifferentiation, and pyroptosis, is a pivotal pathogenic factor in induced diabetic peripheral neuropathy (DPN). Histone deacetylases (HDACs) are an important family of proteins that epigenetically regulate gene transcription by affecting chromatin dynamics. Here, we explored the effect of HDAC1 on high glucose-cultured Schwann cells. HDAC1 expression was increased in diabetic mice and high glucose-cultured RSC96 cells, accompanied by cell apoptosis. High glucose also increased the mitochondrial pathway apoptosis-related Bax/Bcl-2 and cleaved caspase-9/caspase-9 ratios and decreased endoplasmic reticulum response-related GRP78, CHOP, and ATF4 expression in RSC96 cells (P < 0.05). Furthermore, overexpression of HDAC1 increased the ratios of Bax/Bcl-2, cleaved caspase-9/caspase-9, and cleaved caspase-3 and reduced the levels of GRP78, CHOP, and ATF4 in RSC96 cells (P < 0.05). In contrast, knockdown of HDAC1 inhibited high glucose-promoted mitochondrial pathway apoptosis and suppressed the endoplasmic reticulum response. Moreover, RNA sequencing revealed that U4 spliceosomal RNA was significantly reduced in HDAC1-overexpressing RSC96 cells. Silencing of U4 spliceosomal RNA led to an increase in Bax/Bcl-2 and cleaved caspase-9 and a decrease in CHOP and ATF4. Conversely, overexpression of U4 spliceosomal RNA blocked HDAC1-promoted mitochondrial pathway apoptosis and inhibited the endoplasmic reticulum response. In addition, alternative splicing analysis of HDAC1-overexpressing RSC96 cells showed that significantly differential intron retention (IR) of Rpl21, Cdc34, and Mtmr11 might be dominant downstream targets that mediate U4 deficiency-induced Schwann cell dysfunction. Taken together, these findings indicate that HDAC1 promotes mitochondrial pathway-mediated apoptosis and inhibits the endoplasmic reticulum stress response in high glucose-cultured Schwann cells by decreasing the U4 spliceosomal RNA/IR of Rpl21, Cdc34, and Mtmr11.

FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury.

Acute kidney injury (AKI) is in high prevalence worldwide but with no therapeutic strategies. Programmed cell death in tubular epithelial cells has been reported to accelerate a variety of AKI, but the major pathways and underlying mechanisms are not defined. Herein, we identified that pyroptosis was responsible for AKI progression and related to ATP depletion in renal tubular cells. We found that FAM3A, a mitochondrial protein that assists ATP synthesis, was decreased and negatively correlated with tubular cell injury and pyroptosis in both mice and patients with AKI. Knockout of FAM3A worsened kidney function decline, increased macrophage and neutrophil cell infiltration, and facilitated tubular cell pyroptosis in ischemia/reperfusion injury model. Conversely, FAM3A overexpression alleviated tubular cell pyroptosis, and inhibited kidney injury in ischemic AKI. Mechanistically, FAM3A promoted PI3K/AKT/NRF2 signaling, thus blocking mitochondrial reactive oxygen species (mt-ROS) accumulation. NLRP3 inflammasome sensed the overload of mt-ROS and then activated Caspase-1, which cleaved GSDMD, pro-IL-1ß, and pro-IL-18 into their mature forms to mediate pyroptosis. Of interest, NRF2 activator alleviated the pro-pyroptotic effects of FAM3A depletion, whereas the deletion of NRF2 blocked the anti-pyroptotic function of FAM3A. Thus, our study provides new mechanisms for AKI progression and demonstrates that FAM3A is a potential therapeutic target for treating AKI.

Real-world effectiveness of early insulin therapy on the incidence of cardiovascular events in newly diagnosed type 2 diabetes.

Early insulin therapy is capable to achieve glycemic control and restore ß-cell function in newly diagnosed type 2 diabetes (T2D), but its effect on cardiovascular outcomes in these patients remains unclear. In this nationwide real-world study, we analyzed electronic health record data from 19 medical centers across China between 1 January 2000, and 26 May 2022. We included 5424 eligible patients (mean age 56 years, 2176 women/3248 men) who were diagnosed T2D within six months and did not have prior cardiovascular disease. Multivariable Cox regression models were used to estimate the associations of early insulin therapy (defined as the first-line therapy for at least two weeks in newly diagnosed T2D patients) with the incidence of major cardiovascular events including coronary heart disease (CHD), stroke, and hospitalization for heart failure (HF). During 17,158 persons years of observation, we documented 834 incident CHD cases, 719 stroke cases, and 230 hospitalized cases for HF. Newly diagnosed T2D patients who received early insulin therapy, compared with those who did not receive such treatment, had 31% lower risk of incident stroke, and 28% lower risk of hospitalization for HF. No significant difference in the risk of CHD was observed. We found similar results when repeating the aforesaid analysis in a propensity-score matched population of 4578 patients and with inverse probability of treatment weighting models. These findings suggest that early insulin therapy in newly diagnosed T2D may have cardiovascular benefits by reducing the risk of incident stroke and hospitalization for HF.

Rotating twisted templates for imprinting polarization gratings with a sub- to dozen-micron period.

In this Letter, we report and experimentally demonstrate what is to our knowledge a novel scheme for imprinting polarization gratings (PGs) with a pair of templates. Compared with the traditional method that a single template can only imprint PG with a single period, cascading two templates can control the period of imprinted PG at will. However, the low diffraction efficiency is inevitably caused by cascading two templates. Therefore, a rigorous coupled wave analysis (RCWA) is adopted to design a multi-twisted template to address this challenge. As a proof of concept, two multi-twisted templates with a period of 1.6 µm were fabricated, and PGs with a large period range from 0.4 to 48.6 µm were successfully imprinted. The proposed scheme is expected to enable rapid, robust, and high-quality mass production of beam steering, large-angle deflectors, and diffractive optical couplers.

Cyanobacterial blooms in Lake Taihu: Temporal trends and potential drivers.

Lake Taihu, an inland lake, frequently experiences Cyanobacterial blooms that have historically posed severe threats to its aquatic ecosystem. Combining field observations and satellite remote-sensed data, factors that influence algal bloom intensity in Lake Taihu over an eight-year period, from 2016 to 2023, are examined, and changes in phytoplankton community composition, climate, water quality, economic activities, and food web dynamics are reported. Sentinel-2 MSI data analysis reveals a dramatic decrease in Cyanobacterial blooms in 2023, with a reduction in the annual maximum bloom area of 76.90 % from 2016 values. From 2016 to 2022, the ratio of Cyanobacteria to other phytoplankton ranged 82.09 %-98.29 %, but in 2023, this dropped to 60.98 %. Concurrently, Cyanobacteria density dropped to an historic low of 2.29 × 107 cells/L (16.4 % of 2021 peak values). Redundancy and random forest analyses indicated that nitrogen has a greater influence on phytoplankton than phosphorus, with temperature and permanganate index being the important parameters to affect phytoplankton community structure. We attribute the decrease in Cyanobacterial blooms in Lake Taihu in 2023 to be largely caused by shifts in phytoplankton community structure, particularly the sharp decline in Microcystis sp. density, a genus often linked to bloom formation. Meteorological conditions such as reduced rainfall and wind speed during the winter and spring of 2023 also contributed to diminishing Cyanobacterial blooms. Ongoing improvements in water quality, reduced economic activities because of pandemic restrictions, and implementation of a fishing ban since 2020 have likely further contributed to reductions in bloom frequency. These results improve our understanding of the processes that affect algal blooms in Lake Taihu, and potentially other eutrophic inland lakes.

Establishment and Verification of an Artificial Intelligence Prediction Model for Children With Sepsis.

BACKGROUND: Early identification of high-risk groups of children with sepsis is beneficial to reduce sepsis mortality. This article used artificial intelligence (AI) technology to predict the risk of death effectively and quickly in children with sepsis in the pediatric intensive care unit (PICU). STUDY DESIGN: This retrospective observational study was conducted in the PICUs of the First Affiliated Hospital of Sun Yat-sen University from December 2016 to June 2019 and Shenzhen Children's Hospital from January 2019 to July 2020. The children were divided into a death group and a survival group. Different machine language (ML) models were used to predict the risk of death in children with sepsis. RESULTS: A total of 671 children with sepsis were enrolled. The accuracy (ACC) of the artificial neural network model was better than that of support vector machine, logical regression analysis, Bayesian, K nearest neighbor method and decision tree models, with a training set ACC of 0.99 and a test set ACC of 0.96. CONCLUSIONS: The AI model can be used to predict the risk of death due to sepsis in children in the PICU, and the artificial neural network model is better than other AI models in predicting mortality risk.

Optical coherence elastography under homolateral parallel acoustic radiation force excitation for ocular elasticity quantification.

Alteration in the elastic properties of biological tissues may indicate changes in the structure and components. Acoustic radiation force optical coherence elastography (ARF-OCE) can assess the elastic properties of the ocular tissues non-invasively. However, coupling the ultrasound beam and the optical beam remains challenging. In this Letter, we proposed an OCE method incorporating homolateral parallel ARF excitation for measuring the elasticity of the ocular tissues. An acoustic-optic coupling unit was established to reflect the ultrasound beam while transmitting the light beam. The ARF excited the ocular tissue in the direction parallel to the light beam from the same side of the light beam. We demonstrated the method on the agar phantoms, the porcine cornea, and the porcine retina. The results show that the ARF-OCE method can measure the elasticity of the cornea and the retina, resulting in higher detection sensitivity and a more extensive scanning range.

Peripherally targeted analgesia via AAV-mediated sensory neuron-specific inhibition of multiple pronociceptive sodium channels.

This study reports that targeting intrinsically disordered regions of the voltage-gated sodium channel 1.7 (NaV1.7) protein facilitates discovery of sodium channel inhibitory peptide aptamers (NaViPA) for adeno-associated virus-mediated (AAV-mediated), sensory neuron-specific analgesia. A multipronged inhibition of INa1.7, INa1.6, INa1.3, and INa1.1 - but not INa1.5 and INa1.8 - was found for a prototype and named NaViPA1, which was derived from the NaV1.7 intracellular loop 1, and is conserved among the TTXs NaV subtypes. NaViPA1 expression in primary sensory neurons (PSNs) of dorsal root ganglia (DRG) produced significant inhibition of TTXs INa but not TTXr INa. DRG injection of AAV6-encoded NaViPA1 significantly attenuated evoked and spontaneous pain behaviors in both male and female rats with neuropathic pain induced by tibial nerve injury (TNI). Whole-cell current clamp of the PSNs showed that NaViPA1 expression normalized PSN excitability in TNI rats, suggesting that NaViPA1 attenuated pain by reversal of injury-induced neuronal hypersensitivity. IHC revealed efficient NaViPA1 expression restricted in PSNs and their central and peripheral terminals, indicating PSN-restricted AAV biodistribution. Inhibition of sodium channels by NaViPA1 was replicated in the human iPSC-derived sensory neurons. These results summate that NaViPA1 is a promising analgesic lead that, combined with AAV-mediated PSN-specific block of multiple TTXs NaVs, has potential as a peripheral nerve-restricted analgesic therapeutic.

Urinary cytokeratin 20 as a predictor for chronic kidney disease following acute kidney injury.

BACKGROUNDIdentifying patients with acute kidney injury (AKI) at high risk of chronic kidney disease (CKD) progression remains a challenge.METHODSKidney transcriptome sequencing was applied to identify the top upregulated genes in mice with AKI. The product of the top-ranking gene was identified in tubular cells and urine in mouse and human AKI. Two cohorts of patients with prehospitalization estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2 who survived over 90 days after AKI were used to derive and validate the predictive models. AKI-CKD progression was defined as eGFR < 60 mL/min/1.73 m2 and with minimum 25% reduction from baseline 90 days after AKI in patients with prehospitalization eGFR ≥ 60 mL/min/1.73 m2. AKI-advanced CKD was defined as eGFR < 30 mL/min/1.73 m2 90 days after AKI in those with prehospitalization eGFR 45-59 mL/min/1.73 m2.RESULTSKidney cytokeratin 20 (CK20) was upregulated in injured proximal tubular cells and detectable in urine within 7 days after AKI. High concentrations of urinary CK20 (uCK20) were independently associated with the severity of histological AKI and the risk of AKI-CKD progression. In the Test set, the AUC of uCK20 for predicting AKI-CKD was 0.80, outperforming reported biomarkers for predicting AKI. Adding uCK20 to clinical variables improved the ability to predict AKI-CKD progression, with an AUC of 0.90, and improved the risk reclassification.CONCLUSIONThese findings highlight uCK20 as a useful predictor for AKI-CKD progression and may provide a tool to identify patients at high risk of CKD following AKI.FUNDINGNational Natural Science Foundation of China, National Key R&D Program of China, 111 Plan, Guangdong Key R&D Program.