Severe Damage Research Articles

Selenomethionine Attenuates Aflatoxin B1-induced Liver Injury by Modulating the Gut Microbiota and Metabolites in Rabbits.

Dietary contamination with aflatoxin B1 (AFB1), which can lead to severe liver damage, poses a great threat to livestock and poultry breeding and has detrimental impacts on food safety. Selenomethionine (SeMet), with anti-inflammatory, antioxidative, and detoxifying effects, is regarded as a beneficial food additive. However, whether SeMet can reduce AFB1-induced liver injury and intestinal microbial disorders in rabbits remains to be revealed. Forty 35-day-old rabbits were randomly divided into a control group, an AFB1 group, and 0.2 mg/kg Se and 0.4 mg/kg Se groups. The SeMet treatment group was fed different doses of the SeMet diet every day for 21 days. On Days 17-21, the AFB1 group, 0.2 mg/kg Se, and 0.4 mg/kg Se groups were intragastrically administered 0.3 mg AFB1/kg b.w. Results showed that SeMet restored alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, alleviating AFB1-induced liver function damage. This was linked to changes in intestinal metabolites and activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway. In this study, the relationships between intestinal microorganisms and their metabolites and AFB1-induced liver injury are investigated, and the potential protective role of SeMet against liver damage induced by AFB1 offers novel insights into strategies for the prevention and treatment of AFB1-related toxicity.

GRINA alleviates hepatic ischemia‒reperfusion injury-induced apoptosis and ER-phagy by enhancing HRD1-mediated ATF6 ubiquitination.

Hepatic ischemia‒reperfusion injury (HIRI) is a critical complication of liver surgery and transplantation that contributes significantly to severe organ failure. GRINA, a calcium-regulating endoplasmic reticulum (ER) protein, plays an essential role in controlling the unfolded protein response; however, its role in HIRI remains unclear. The aim of this study was to investigate the function of GRINA in HIRI and explore its potential as a therapeutic target. Liver tissues from patients undergoing hepatectomy, alongside a mouse model of partial HIRI, were used to assess GRINA expression levels. Hepatocyte-specific Grina knockout and transgenic mouse models were generated to explore the effects of GRINA on HIRI. Key markers of inflammation, apoptosis, ER stress, and autophagy were evaluated via real-time PCR, Western blotting, immunohistochemistry, immunofluorescence, and ELISA. RNA sequencing, mass spectrometry, coimmunoprecipitation and ubiquitination assays were used to elucidate the underlying molecular mechanisms. GRINA expression was markedly reduced in hepatocytes from both patients and mice with HIRI, and its expression was inversely correlated with the severity of liver damage. Hepatocyte-specific Grina overexpression mitigated liver injury, the inflammatory response, and hepatocyte apoptosis following HIRI, whereas GRINA deficiency exacerbated these outcomes. Mechanistically, GRINA interacted directly with ATF6 and recruited HRD1 to form a multiprotein complex that catalyzed ATF6 polyubiquitination, thereby promoting its degradation. This process suppressed ER autophagy (ER-phagy), providing cellular protection following HIRI. The inhibition of ATF6 degradation attenuated the protective effects of GRINA in HIRI. Our study highlights the critical role of the GRINA-HRD1-ATF6 complex in regulating ER stress and autophagy during HIRI. These findings provide new insights into therapeutic strategies to alleviate HIRI. HIRI represents a multifaceted pathophysiological challenge commonly encountered during liver surgeries, yet its underlying molecular mechanisms remain inadequately understood. In this study, we revealed a significant negative correlation between GRINA levels and the severity of liver damage in patients with HIRI. Our findings demonstrate that GRINA alleviates endoplasmic reticulum stress by enhancing HRD1-mediated ubiquitination of ATF6, thereby maintaining calcium homeostasis and inhibiting ER-phagy. This study provides novel insights into the role of GRINA in protecting liver cells under HIRI, offering fresh perspectives for clinical prevention and management strategies for HIRI.

Emamectin Benzoate and Microplastics Led to Skeletal Muscle Atrophy in Common Carp via Induced Oxidative Stress, Mitochondrial Dysfunction, and Protein Synthesis and Degradation Imbalance.

Pesticides and plastics have brought convenience to agricultural production and daily life, but they have also led to environmental pollution through residual chemicals. Emamectin benzoate (EMB) is among the most widely used insecticides, which can cause environmental pollution and harm the health of organisms. Additionally, microplastics (MPs), a relatively new type of pollutant, not only are increasing in residual amounts within water bodies and aquatic organisms but also exacerbate pollution by adsorbing other pollutants, leading to a mixed pollution scenario. Nevertheless, the toxicity and mechanism of EMB and MPs on common carp skeletal muscle have not been elucidated. Therefore, we established exposure models for EMB and MPs, and methods such as hematoxylin and eosin staining, immunofluorescence staining, JC-1 staining, and western blotting were employed to investigate the underlying mechanisms of skeletal muscle damage. The results of in vivo and in vitro experiments indicated that exposure to EMB or MPs led to oxidative stress, which in turn caused mitochondrial fusion/fission imbalance (with decreased Mfn1, Mfn2, and OPA1 and increased DRP1), reduced mitochondrial membrane potential, decreased ATP content, reduced protein synthesis, and increased degradation, ultimately resulting in skeletal muscle atrophy. Joint exposure caused more severe damage than single exposure, and the addition of NAC can effectively alleviate skeletal muscle atrophy. In summary, exposure to EMB and/or MPs induced excessive reactive oxygen species (ROS) production, giving rise to mitochondrial dysfunction and an imbalance in skeletal muscle protein synthesis and degradation, ultimately resulting in skeletal muscle atrophy in common carp.

Apoptosis in kidney tissue of senior and geriatric cats with chronic kidney disease.

Apoptosis, an important pathological event associated with kidney disease progression, is expected to be a therapeutic target in chronic kidney disease (CKD). However, its role in naturally occurring CKD in aged cats remains unclear. Therefore, here, we investigated kidney tissues from aged cats (≥10 years) with or without azotemic CKD to evaluate apoptotic events using a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. The positive TUNEL signals of the renal cells were quantified and statistically analyzed for correlation with the severity of plasma creatinine (pCre) concentration, renal lesions (glomerulosclerosis, interstitial cell infiltration, peritubular capillaries, and interstitial fibrosis), and oxidative damage of the kidney tissue. Oxidative damage was evaluated using immunohistochemistry for 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxynonenal (4-HNE). In the TUNEL assay, regardless of azotemia, positive nuclear signals were observed in the tubular epithelial and intraluminal cells, interstitial infiltrating cells, and glomerular cells. Quantitative TUNEL scores showed no significant differences between the azotemic and non-azotemic groups in any compartment of the kidney tissues. In the azotemic group, TUNEL scores did not correlate with pCre or renal lesion severity. However, the scores showed a significant positive correlation with the scores of 8-OHdG and 4-HNE. These findings suggest that apoptosis associated with oxidative damage in renal tissue is an initial pathological event that leads to CKD, rather than a change following CKD progression, in aged cats. Inhibiting apoptosis by antioxidant treatment may be a key strategy to prevent the development of CKD.

Transcriptome analysis provides insights into the role of TLP16 in Musa acuminata Resistance to Fusarium oxysporum f. sp. cubense wilt

BackgroundThaumatin-like proteins (TLPs) are crucial pathogenesis-related proteins that significantly contribute to plant defense rection. Fusarium oxysporum f. sp. cubense (Foc) causes Fusarium wilt of bananas, a serious threat to global production. However, the role of TLPs in disease resistance remains unclear.ResultsThis study identified 49 TLP genes in banana, predominantly localized in the extracellular space, and distributed across 11 chromosomes. The ancestor–descendant relationship was explained, six genes remained remarkably conserved across species could represent the ancestral genes of the TLP gene family. Promoter regions, transcriptome and qRT-PCR analysis suggested that MaTLP16 might be involved in disease resistance. Furthermore, transcriptional silencing of MaTLP16 resulted in more severe leaf damage compared to the control, indicating that MaTLP16 is an important Foc resistance-related gene.ConclusionThis study conducted a comprehensive genome-wide identification and systematic analysis of the TLP gene family in bananas. Our findings establish a foundation for further functional studies of MaTLP genes and highlight MaTLP16 as a strong candidate for use in breeding programs aimed at enhancing resistance to Musa diseases.

Raman signatures of type A and B influenza viruses: molecular origin of the "catch and kill" inactivation mechanism mediated by micrometric silicon nitride powder.

A multiomic study of the structural characteristics of type A and B influenza viruses by means of highly spectrally resolved Raman spectroscopy is presented. Three virus strains, A H1N1, A H3N2, and B98, were selected because of their known structural variety and because they have co-circulated with variable relative prevalence within the human population since the re-emergence of the H1N1 subtype in 1977. Raman signatures of protein side chains tyrosine, tryptophan, and histidine revealed unequivocal and consistent differences for pH characteristics at the virion surface, while different conformations of two C-S bond configurations in gauche and trans methionine rotamers provided distinct low-wavenumber fingerprints for different virus lineages/subtypes. Short-term exposure to a few percent fraction of silicon nitride (Si3N4) micrometric powder in an aqueous environment completely inactivated the influenza virions, independent of lineage/subtype dependent characteristics. The molecular-scale details of the inactivation process were studied by Raman spectroscopy and interpreted in terms of a "catch and kill" mechanism, in which the hydrolyzing ceramic surface first attracts virions with high efficiency through electrochemical interactions (mimicking cellular sialic acid) and then "poisons" the viruses by local hydrolytic elution of ammonia and nitrogen radicals. The latter event causes severe damage to the virions' structures, including structural degradation of RNA purines, rotameric scrambling of methionine residues, formation of sulfhydryl and ionized carboxyl groups, and deprotonation/torsional deformation of tyrosine, tryptophan, and histidine residues. This study confirmed the antiviral effectiveness of Si3N4 powder, which is safe to the human body and simply activated by water molecules. Raman spectroscopy was confirmed as a powerful tool in molecular virology, complementary to genomics and unique in providing direct information on virus structures at the molecular scale.

RAGE-mediated intestinal pro-inflammatory responses triggered by Giardia duodenalis.

Giardia duodenalis is a waterborne zoonotic protozoan that causes gastrointestinal inflammation. Giardiasis and metabolic illnesses share features such as chronic inflammation and intestinal symptoms. Receptor for advanced glycation end products (RAGE) signaling plays a role in metabolic illnesses and intestinal inflammatory responses. The presence of protozoan viruses can influence host immunological responses triggered by protozoa. However, these effects of G. duodenalis remain unknown. In this study, mice treated with the RAGE inhibitor FPS-ZM1 showed more severe intestinal damage, including increased intestinal permeability and lesions, compared to that of the untreated group. Next, we found that G. duodenalis infection activated RAGE, leading to increased secretion of pro-inflammatory cytokines, including IL-1 β, IL-6, IL-12, TNF-α and IFN-γ in mouse intestinal epithelial cells. Notably, these pro-inflammatory responses were significantly higher in Giardiavirus (GLV)-free Giardia than those of GLV-containing Giardia, except for IFN-γ. Additionally, lactate dehydrogenase (LDH) release, GSDMD-N cleavage, and the morphological observation of pyroptosis were significantly higher in cells induced by GLV-free Giardia than those infected with GLV-carrying Giardia. Differences were also observed in the MAPK (p-JNK, p-38, p-ERK) and NF-κB pathway activation, as well as reactive oxygen species (ROS) levels, with higher activation in cells infected by GLV-free Giardia, and the ROS was involved in the regulation of p38 MAPK and JNK activation. These findings reveal the potential of RAGE as a target for developing vaccines or drugs, suggesting the differences in the regulation of host immune responses induced by GLV-free Giardia or GLV-containing Giardia, providing new insights for the prevention and treatment of Giardia.

POEMS Syndrome.

POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, Skin changes) is a syndrome that involves a monoclonal B-cell proliferation, most often plasmacytic, and a variable number of manifestations listed or not in the acronym. These manifestations include sclerotic bone lesions, plasmacytic Castleman disease, papillary edema, peripheral edema, ascites, thrombocytosis and/or polycythemia, venous and/or arterial thrombosis, and renal, pulmonary, and cardiac impairments [1]. Diagnosis is often delayed due to the rarity of this entity and its clinical polymorphism, which can mimic other neurological disorders. First-line treatment for patients without bone marrow involvement and with a limited number of bone lesions is radiation. Patients with diffuse bone lesions or bone marrow involvement should receive systemic treatment, ideally intensive treatment with autologous stem cell transplantation (ASCT) when possible. Lenalidomide and bortezomib appear to be very promising, showing very rapid efficacy on neuropathy. Early initiation of treatment, before the development of severe neurological damage, along with supportive care, especially physiotherapy, is crucial for optimal neurological recovery.

Androgenic Anabolic Steroids Cause Thiol Imbalance in the Vascular Endothelial Cells.

Androgenic anabolic steroids (AASs) are synthetic drugs structurally related to testosterone, with the ability to bind to androgen receptors. Their uncontrolled use by professional and recreational sportspeople is a widespread problem. AAS abuse is correlated with severe damage to the cardiovascular system, including changes in homeostasis and coagulation disorders. AASs alter vascular function by blocking nitric oxide (NO)-mediated dilation, impairing endothelial growth and by potentiating vasoconstrictor signals. This paper demonstrated that long-term use of AASs (nandrolone and boldenone), negatively affects the basic cell functions of vascular endothelial cells. The susceptibility of endothelial cells to AASs depends on the expression of androgen receptors, although cells without androgen receptors can also be affected by high doses of AASs to a limited extent. Seven-day incubation with AASs diminishes endothelial cell proliferation and migration (determined by transwell and scratch migration assay) and monolayer formation (using transendothelial electrical resistance assay). Disturbances in cell function were accompanied by downregulation of peroxiredoxins (PRDX1 and PRDX2), involved in maintaining the thiol-disulphide balance. In addition, AASs increased oxidation of the non-enzymatic thiol buffer, glutathione (GSH), reduced secretion of thiol oxidoreductase protein disulphide isomerase (PDI) from endothelial cells and affected the thiol pattern of PDI. These changes may be related to a thiol-disulfide imbalance and vascular endothelium dysfunction, that are often correlated with abnormal platelet aggregation, inflammation, increased vascular permeability, and vascular smooth muscle cell proliferation-all of which are observed in athletes who abuse AASs.

Interleukin-6 is significantly increased in severe pneumonia after allo-HSCT and might induce lung injury via IL-6/sIL-6R/JAK1/STAT3 pathway.

Severe pneumonia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with high mortality. Given that cytokine, including Interleukin-6 (IL-6), play a critical role in immune-mediated organ injury in patients with severe COVID-19, we hypothesized that cytokines may also contribute to the pathogenesis of severe pneumonia after allo-HSCT. This study aimed to investigate the role of IL-6 in severe pneumonia post-allo-HSCT and explore its underlying mechanism. Serum cytokine levels were prospectively measured in patients with severe and non-severe pneumonia following allo-HSCT. A mouse model of acute lung injury (ALI) and in vitro experiment using primary murine pulmonary microvascular endothelial cells (PMVECs) were conducted to assess the effects of IL-6 blockade, the mechanism of IL-6 in ALI, and immune-induced ALI. Serum IL-6 and sIL-6R levels were higher in the severe pneumonia group than in the non-severe group and were associated with disease progression. In a mouse model, preventive IL-6 blockade reduced ALI and improved survival. In vitro, the IL-6 trans-signaling complex caused more severe damage to mouse PMVECs than the classical signaling pathway. Soluble glycoprotein 130 and ruxolitinib effectively blocked the JAK1/STAT3 pathway activated by IL-6 trans-signaling in mouse PMVECs and reduced downstream inflammatory responses. IL-6 levels were elevated in patients with severe pneumonia after allo-HSCT and were linked to disease progression. This injury may be driven by the IL-6/sIL-6R/JAK1/STAT3 pathway. This preliminary study suggests that targeting the IL-6 trans-signaling pathway may be a promising therapeutic approach for severe pneumonia/ALI following allo-HSCT.

Single-cell sequencing revealed the necessity of macrophages in brain microenvironment remodeling by breast cancer metastasis.

Breast cancer is one of the most common cancers worldwide, 30-50 % of patients with advanced breast cancer develop brain metastasis, causing severe damage to their life quality. Due to the existence of the blood-brain barrier (BBB), brain lesions were recognized to be a unique microenvironment with limited infiltration of circulating immune cells and drugs. However, emerging studies reported the immunology of the brain tumor microenvironment (TME) and indicated the potential of immunotherapy against brain metastases. Therefore, it is of great value to comprehensively investigate the TME and identify the pro-tumoral mechanisms facilitating brain metastases and the crucial molecules involved in this process. In this research, we re-analyzed public data on three brain surgical specimens of breast cancer metastases and identified the immunosuppressive roles of macrophages in the metastatic TME. Then, we conducted the first single-cell RNA sequencing on a murine model of breast cancer brain metastasis. In the brain TME, immune cells showed prominent heterogeneity, especially the mononuclear phagocyte system (MPS). We identified the alteration of macrophage subclusters in the central nerve system (CNS) after breast cancer invasion and found that metastatic cancer cells re-shaped the TME cellular interactions for immune evasion and nutrition supply. Finally, this research could serve as a reference for further analysis of new therapies against brain metastatic lesions.

MANGROVE REFORESTATION IN GAMPONG LAMPAGEUSUB-DISTRICT PEUKAN BADA-ACEH BESAR

Mangroves are tropical trees that thrive in intolerable conditions of mostly salty wood, coastal waters, and endless tides. Thanks to their ability to store large amounts of carbon, mangroves are a key weapon in the fight against climate change but are under threat around the world. By protecting mangroves, we can help protect the future of our planet. Referring to data from the Central Bureau of Statistics, the area of mangrove ecosystems in Aceh reaches 3.63 million hectares or 20.37% of the world's total area. With this significant area, Indonesia has a great responsibility in preserving the global mangrove ecosystem. Therefore, World Mangrove Day is an important moment to reflect on the efforts that have been made and take concrete actions in maintaining and preserving mangrove forests which are an important part of Indonesia's natural wealth. Mangroves play a crucial role in coastal ecosystems, serving as natural fortresses that protect beaches from erosion and storms, absorb carbon dioxide from the atmosphere, and provide habitat for a variety of marine and bird species. Given the severe environmental damage that occurred in Lampageu village due to the tsunami disaster, the tsunami survivors wanted to reforest the mangroves so that they returned to their original state. This is because mangrove ecosystems have so many functions and benefits for the lives of local villagers.

The Combination of α-Fe2O3 NP and Trichoderma sp. Improves Antifungal Activity Against Fusarium Wilt.

Soil-borne plant pathogens are the most damaging pathogens responsible for severe crop damage. A conventional chemotherapy approach to these pathogens has numerous environmental issues, while biological control agents (BCAs) are less promising under field conditions. There is an immediate need to develop an integrated strategy for utilizing nanoparticles and biocontrol to manage soil-borne pathogens, such as Fusarium wilt, effectively. Simulation of BCA metabolites to nanoparticle biocontrol metabolites is considered the most effective biocontrol approach. Combining Fe2O3 nanoparticles and Trichoderma in nursery and field conditions manages pathogens and increases plant growth characteristics. The present study evaluated the commercial biocontrol strains and the use of NPFe in combination with Trichoderma harzianum to enhance the biocontrol potential of T. harzianum against soil-borne pathogens. The effectiveness of (NPFe + T. harzianum) was evaluated under in vitro conditions where combination was found most effective upto (87.63%) mycelial growth inhibition of pathogen and under field conditions lowest pooled Fusarium wilt incidence (19.54%) was recorded. Nanocomposites are beneficial for agricultural sustainability and environmental safety by upregulating the expression of genes linked to these processes, Fe NPs can activate plant defense mechanisms and increase plant resistance to pathogenic invasions. Additionally, as iron is a necessary component for plant growth and development, Fe NPs promote better nutrient uptake.

BMP6 participates in the molecular mechanisms involved in APAP hepatotoxicity.

Given the lack of accurate diagnostic methods of acetaminophen (APAP)-induced acute liver failure (ALF), the search for new biomarkers for its diagnosis is an urgent need. The aim of this study was to evaluate the role of bone morphogenetic protein 6 (BMP6) in APAP-induced ALF progression and its potential value as a biomarker of ALF. Hepatic and circulating BMP6 expression was assessed in APAP-treated mice and in serum samples from patients with APAP overdose. In addition, BMP6 expression and release was evaluated in hepatocytes after APAP exposure. BMP6 gene was silenced in Huh7 cells prior to APAP treatment and the culture medium (CM) was added to THP1 cells to evaluate the paracrine effects of hepatocyte BMP6 on APAP toxicity. Hepatic and serum BMP6 levels were increased in mice after APAP-induced ALF. In addition, a positive correlation was observed between circulating BMP6 and ALT activity in patients exposed to APAP overdose. Moreover, hepatocytes expressed and released BMP6 to the CM after APAP treatment. Indeed, the CM from APAP-treated Huh7 cells upregulated M1 and M2 markers in THP1 monocytes. The CM from BMP6-silenced Huh7, which was depleted of BMP6, reduced the expression of M2 markers in THP1 cells. In fact, expression of M2 markers was increased in THP1 cells exposed to BMP6. This study reveals that hepatic BMP6 expression is increased in APAP-induced acute liver injury, positioning it as a potential new biomarker of liver damage severity. Moreover, our data indicate that BMP6 might play a role in the hepatocyte-macrophage crosstalk during APAP-induced hepatotoxicity.

HMGB2 knockdown ameliorates retinal ganglion cell injury by inhibiting NLRP3 inflammasome activation after retinal ischemia.

To explore the neuroprotective effects of high mobility group box 2 (HMGB2) knockdown on retinal ganglion cells (RGCs) in the retinal ischemia-reperfusion injury (RIRI). Oxygen-glucose deprivation (OGD)-injured RGCs from postnatal three-day C57BL/6 mice pups and high intraocular pressure (IOP)-induced RIRI mice were used as cellular and animal models of RIRI. The expression of HMGB2 in the retina of RIRI mice and OGD-injured RGCs was detected through reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting. The effects of HMGB2 silencing on the morphological changes, RGCs survival, and cell apoptosis in mouse retinal tissues were observed through H&E staining, immunofluorescence staining with RNA-binding protein with multiple splicing (RBPMS) antibody, and TUNEL staining, respectively. RGC viability and apoptosis were examined by CCK-8 and flow cytometry assays. The levels of proteins associated with NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis [NLRP3, Caspase-1, GSDMD-N, interleukin (IL)-1β, IL-18] in vivo and in vitro were measured by Western blotting. HMGB2 protein and NLRP3 were upregulated in the retina of RIRI mice and OGD-injured RGCs (P<0.001). The retina was edematous, accompanied by disorganized cell arrangement and decreased thickness of all layers, and obvious vacuoles in ganglion cell layer. HMGB2 silencing alleviated the reduction in total retinal thickness and the severity of retinal tissue damage as well as suppressed RGC loss and retinal cell apoptosis in RIRI mice. OGD-induced RGC apoptosis was ameliorated after downregulation of HMGB2 in vitro. Intravitreal injection of the AAV-sh-HMGB2 and si-HMGB2 resulted in significantly decrease of NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18 protein levels in the retinal tissues of RIRI mice and OGD-injured RGCs, respectively (all P<0.001). HMGB2 knockdown protects against RGC apoptosis and pyroptosis after RIRI through suppressing NLRP3 inflammasome activation.

Joint replacement for rheumatoid arthritis: When, why, and how! Insights from an orthopedic surgeon.

The past several decades have seen significant advancements in joint replacement surgery for rheumatoid arthritis (RA). Joint replacement procedures have become vital options for patients with severe joint damage and functional impairment. There has been an increased emphasis on personalized surgical strategies that tailor joint replacement decisions based on a patient's unique clinical characteristics and the extent of joint damage. Achieving personalized outcomes requires clearly understanding the patient's baseline joint function and comparative data on different prosthetic designs and techniques. Comprehensive preoperative preparation is fundamental to ensuring surgical success. This includes thoroughly evaluating the patient's medication history, the extent of joint damage, and overall systemic health. Despite careful surgical planning, trade-offs between different replacement options often remain. In this paper, we review the perioperative preparation and surgical techniques in joint replacement surgery for RA. Additionally, we discuss the challenges in optimizing postoperative rehabilitation and preventing complications, which remains a key factor in achieving full recovery and maximizing the benefits of joint replacement surgery for RA patients. The pathological basis of RA is an acute or chronic inflammation of the synovial membrane. As a result, synovial joints throughout the body can be affected, including joints in the upper limbs (shoulders, elbows, wrists, metacarpophalangeal joints, and interphalangeal joints) as well as in the lower limbs (hips, knees, and ankles). If drug treatments fail to control inflammation adequately, recurrent synovitis in the affected joints can lead to swelling, effusion, cartilage erosion, and eventual cartilage loss. Due to decreased weight-bearing, along with the use of various medications-particularly glucocorticoids-widespread subchondral bone osteoporosis, bone marrow edema, and bone destruction may occur, leading to cystic degeneration and even extensive bone defects. In the advanced stages of RA, deformities can develop, such as "boutonniere" and "swan-neck" deformities in the fingers, ulnar deviation of the wrist, "otto pelvic" due to central acetabular erosion and dislocation of the hip, varus or valgus deformities of the knee, flexion contractures, and destruction or fusion of the ankle joint. The foot can also present deformities, such as hallux valgus and overlapping toes. Total joint replacement surgery has become the most effective surgical treatment for severe joint destruction and deformities in late-stage RA. Among all joints, the hip and knee are the most frequently replaced, as their dysfunction severely impacts the patient's ability to walk, leading to disability and loss of mobility. In this review, we provided a comprehensive discussion on the perioperative management of patients with RA, focusing on preoperative preparation, intraoperative planning, and postoperative rehabilitation and assessment. Rheumatology Department Perspective on Preoperative Preparation for RA Joint Replacement Surgery.

Subventricular Zone Microstructure in Pediatric-Onset Multiple Sclerosis.

The aim of this study was to explore the microstructural dynamics of the subventricular zone (SVZ) with aging and their associations with clinical disability and brain structural damage in pediatric-onset multiple sclerosis (MS) patients. One-hundred and forty-one pediatric-onset MS patients (67 pediatric and 74 adults with pediatric-onset) and 233 healthy controls (HC) underwent neurological and 3.0 T MRI assessment. Fractional anisotropy (FA) and mean diffusivity (MD) were extracted from the SVZ and the thalamus (as control region). In HC, SVZ FA was higher until age 40 then declined, whereas MD was lower until age 35 before rising (false discovery rate p value [pFDR] ≤ 0.008). Thalamic FA was higher until age 30 and then declined, whereas MD was higher until age 50 (pFDR ≤ 0.007). Pediatric MS patients showed significantly higher SVZ FA than pediatric HC (pFDR < 0.001), while adult patients showed no differences compared to adult HC (pFDR ≤ 0.724). Adult patients had lower thalamic FA and higher MD (pFDR < 0.001). Adults had lower SVZ FA and MD, but higher thalamic MD compared to pediatric patients (pFDR < 0.001). In pediatric MS, higher SVZ FA and MD were associated with higher white matter (WM) lesion volume (LV) and choroid plexus volume and lower brain and thalamic volumes (pFDR ≤ 0.047). In adult patients, higher SVZ MD associated with higher WM LV, lower brain volumes, and lower z-SDMT (pFDR≤0.019). Thalamic microstructural abnormalities were associated with more severe disability and brain damage in both groups (pFDR ≤ 0.018). Our findings suggest that microstructural changes in the SVZ occur early in pediatric MS and are associated with brain structural damage but not with clinical impairment. ANN NEUROL 2025.

CDK14 regulates the development and repair of lung

Cyclin-dependent kinases (CDK) 14 regulates cell cycle, tumor expansion by influencing the downstream targets of the canonical Wnt signaling pathway. However, the function of CDK14 during organ development and regeneration has not been investigated in genetically-modified animals. Here, we found that genetic ablation of Cdk14 influenced pulmonary vascular endothelial cells and alveolar epithelial cells during mice embryonic development as well as repair of lung after bleomycin or lipopolysaccharide induced injury. Genetic knockout of Cdk14 and the CDK14 covalent inhibitor FMF-04-159-2 resulted in reduction of pulmonary vessel covered area and epithelial cell number, exhibiting increased mortality and more severe lung damage after injury. Mechanistically, Cdk14 ablation inhibited the proliferation of epithelial and vascular endothelial cells, inducing cell cycle arrest at the G2/M phase. Through RNA-seq analysis of both endothelial and epithelial cells, we found that knockdown of Cdk14 controls the expression of signal transducers and activator of transcription 1 (STAT1) as well as associated genes in interferon signaling. Disruption of Cdk14 interferes with IFN-γ induced lung repair in vivo, suggesting potential crosstalk of CDK14 signaling and IFN-γ pathway. Our work highlights the importance of Cdk14 in lung development and regenerative repair through an uncharacterized CDK14- IFN-γ signaling axis.

The Application of Numerical Simulation in Debris Flow Disaster Early Warning: A Case Study of Shiyang Gully, China

This study explores the application of numerical simulation in debris flow disaster early warning, using the Shiyang Gully in China as a case study. Using both the HEC-HMS and FLO-2D, the 18 June 2017 debris flow event was reconstructed to analyze the impacts of cumulative rainfall, rainfall intensity, and rainfall range on debris flow hazards. Simulation results showed that cumulative rainfall exceeding 90 mm or rainfall intensity surpassing 200 mm/8 h significantly increases debris flow depth, impact force, and affected areas, leading to severe structural damage. Expanding the rainfall range to the entire basin further amplifies disaster risks, increasing both inundation depth and exposed elements. Based on these findings, a four-tier debris flow early warning system was developed: (1) blue (IV) warning for cumulative rainfall of up to and including 20 mm or intensity of 200 mm/24 h, indicating preparation and monitoring; (2) yellow (III) warning for rainfall exceeding 20 mm but below 60 mm, requiring enhanced inspections and safety measures; (3) orange (II) warning for rainfall between 60 and 90 mm or intensity of 200 mm/12 h, necessitating immediate evacuation preparations; and (4) red (I) warning for rainfall over 90 mm or intensity of 200 mm/8 h, demanding full evacuation and emergency responses. This study demonstrates the value of numerical simulation in refining early warning systems by integrating multi-scenario analyses of rainfall parameters. The proposed system offers scientific and practical insights for enhancing debris flow disaster management, particularly in small, high-risk watersheds, providing a framework for cross-regional disaster mitigation strategies.

Peripheral neuropathy in neuronal intranuclear inclusion disease: a clinical and electrophysiological cross-sectional study.

Neuronal intranuclear inclusion disease (NIID) is a multifaceted disorder impacting both the central and peripheral nervous systems. This study aims to investigate the clinical and electrophysiological characteristics of peripheral neuropathy in patients with NIID. In this cross-sectional study, patients diagnosed with NIID were prospectively recruited from multiple centers across China between October 2017 and May 2024. Comprehensive neurological examinations, brain magnetic resonance imaging, and NOTCH2NLC gene analysis were performed. All participants underwent electrophysiological evaluations, which encompassed nerve conduction studies, F-wave studies, and needle electromyography. This analysis included a total of 78 patients diagnosed with NIID, with a mean age of 61.0 ± 9.9years, of whom 60.2% were female. Among these patients, 85.9% exhibited peripheral neuropathy. Specifically, 19 patients (24.4%) presented with symptomatic peripheral neuropathy, with 17 of these individuals demonstrating sensorimotor polyneuropathy. Additionally, 48 patients (61.5%) exhibited subclinical peripheral nerve damage. Segmental motor conduction studies indicated that both distal and proximal nerve segments were uniformly affected. F-wave latency prolongation was observed in 84.6% of tibial nerves, demonstrating high sensitivity (66/67) and specificity (11/11) for detecting peripheral neuropathy in NIID. The severity of peripheral neuropathy was stratified into four levels, with approximately two-thirds of cases presenting with pure demyelination and one-third displaying a combination of demyelination and axonal degeneration. Severe axonal damage was exclusively identified in the neuromuscular disease-dominant subtype of NIID. Importantly, male patients exhibited more pronounced peripheral nerve damage compared to female patients. This study identified a significant prevalence of peripheral neuropathy in NIID, exhibiting a spectrum of severity ranging from mild demyelination to severe axonal damage. Prolongation of F-wave latency emerged as a sensitive marker for the detection of peripheral nerve impairment. Furthermore, the findings underscore the potential influence of gender in the pathophysiology of NIID, warranting further investigation.