Force-induced tail-autotomy mitochondrial fission and biogenesis of matrix-excluded mitochondrial-derived vesicles for quality control.

Mitochondria constantly fuse and divide for mitochondrial inheritance and functions. Here, we identified a distinct type of naturally occurring fission, tail-autotomy fission, wherein a tail-like thin tubule protrudes from the mitochondrial body and disconnects, resembling autotomy. Next, utilizing an optogenetic mitochondria-specific mechanostimulator, we revealed that mechanical tensile force drives tail-autotomy fission. This force-induced fission involves DRP1/MFF and endoplasmic reticulum tubule wrapping. It redistributes mitochondrial DNA, producing mitochondrial fragments with or without mitochondrial DNA for different fates. Moreover, tensile force can decouple outer and inner mitochondrial membranes, pulling out matrix-excluded tubule segments. Subsequent tail-autotomy fission separates the matrix-excluded tubule segments into matrix-excluded mitochondrial-derived vesicles (MDVs) which recruit Parkin and LC3B, indicating the unique role of tail-autotomy fission in segregating only outer membrane components for mitophagy. Sustained force promotes fission and MDV biogenesis more effectively than transient one. Our results uncover a mechanistically and functionally distinct type of fission and unveil the role of tensile forces in modulating fission and MDV biogenesis for quality control, underscoring the heterogeneity of fission and mechanoregulation of mitochondrial dynamics.

The alleviation of difenoconazole-induced kidney injury in common carp (Cyprinus carpio) by silybin: Involvement of inflammation, oxidative stress, and apoptosis.

Triazole fungicides, such as difenoconazole (DFZ), are frequently used to control fungus in crops that pollute water. The common carp (Cyprinus carpio) (hereafter referred to as "carp") is an excellent bio-indicator of water quality. The seeds of the silymarin plant contain a flavonolignan called silybin (SYB), which is used to treat liver disease. To explore SYB's involvement in DFZ-triggered kidney damage in carps, an H&E assay was conducted, and ROS level was also examined. The results demonstrated that SYB alleviated DFZ-induced destruction of kidney tissue structure in carps, as well as alleviating the elevation of kidney ROS level in carps. RT-qPCR and Western blot were used to detect inflammation-, oxidative stress- and apoptosis-related factors at mRNA level and protein level. The experimental findings indicated that relative to the DFZ group, SYB + DFZ co-treatment reduced inflammation-related mRNA level of il-6, il-1ß and tnf-α, elevated mRNA level of il-10. It also reduced protein expression levels of NF-κB and iNOS. In addition, SYB + DFZ co-treatment reduced DFZ-induced increase in the oxidative stress-related mRNA indicators sod and cat, and decreased the protein expression levels of Nrf2 and NQO1. SYB reduced the DFZ-induced increase in pro-apoptotic gene Bax mRNA and protein expression levels and the DFZ-induced decrease in anti-apoptotic gene Bcl-2 mRNA and protein expression levels. In summary, SYB potentially mitigates DFZ-induced kidney damage in carp by addressing inflammation, oxidative stress, and apoptosis. Our results establish a theoretical foundation for the clinical advancement of freshwater carp feeds.

A unilateral increase in the occlusal vertical dimension of growing rats results in mandibular deviation.

OBJECTIVE: The effects of unilateral increased occlusal vertical dimension (iOVD) on bilateral craniofacial, mandibular and alveolar development in growing rats were investigated via cone-beam computed tomography (CBCT). The role of Wnt/ß-catenin signalling in this process was examined. MATERIALS AND METHODS: Forty-eight female Sprague-Dawley rats were randomly allocated into unilateral iOVD and sham groups. At 2, 4 and 8 weeks, the rats were scanned via CBCT to analyse cranial, maxillary, mandibular and dental morphology. Changes in temporomandibular joint (TMJ) cartilage histology and Wnt/ß-catenin signalling were assessed by histochemical and immunohistochemical staining and qRT-PCR. RESULTS: Dorsal cephalograms revealed that the mandible in the iOVD group tilted approximately 4° to the right. Unilateral iOVD had little effect on cranial and maxillary growth but inhibited mandibular growth (mandibular length and ramal height), especially on the deviated side (DS). Moreover, unilateral iOVD increased the length of the lower incisors and decreased the height of the molars on the DS. Unilateral iOVD induced bilateral osteoarthritis-like changes in the bilateral TMJ condylar cartilage and activated Wnt/ß-catenin signalling in the condylar cartilage, especially on the contralateral side (CLS). CONCLUSION: Occlusion with unilateral iOVD induced mandibular deviation, significantly inhibited mandibular growth and produced compensatory changes in the alveolar bone. In the iOVD group, the mandibular body length and ramal height were greater on the CLS than on the DS. Moreover, the greater ß-catenin protein expression in the TMJ condylar cartilage on the CLS than on the DS may account for the difference in asymmetrical mandibular development.

Digital-assisted diagnosis and orthodontic management of an impacted mandibular lateral incisor: a case report.

BACKGROUND: The impaction of mandibular lateral incisors presents significant aesthetic and functional challenges in orthodontics, including Bolton ratio discrepancies and anterior occlusal anomalies. The increasing preference for nonextraction treatment further complicates space management within the dental arch. However, the advent of digital-assisted orthodontic technologies, particularly advanced digital simulations, has revolutionized the precision and effectiveness of diagnosis and treatment planning. These technologies enable clinicians to strategically leverage natural jaw development and create the necessary space for the alignment of impacted teeth without resorting to extraction. CASE PRESENTATION: This case report details the treatment of a 12-year-old male with an impacted mandibular lateral incisor, which resulted in both aesthetic concerns and functional impairments, alongside Class II malocclusion. By employing a digital-assisted diagnostic approach, including comprehensive digital simulations, we meticulously evaluated the feasibility of a nonextraction treatment plan. The strategy centred on harnessing the patient's mandibular growth potential to expand the available space naturally. The treatment involved surgical exposure of the impacted tooth, followed by precise orthodontic traction guided by continuous digital monitoring. The integration of digital tools throughout the treatment process was crucial in achieving successful eruption and alignment of the impacted tooth, thus restoring optimal aesthetics and function without the need for extraction. CONCLUSION: This case highlights the transformative impact of digital-assisted technologies in the management of complex orthodontic cases, such as impacted mandibular lateral incisors. The successful integration of these advanced tools with a nonextraction treatment approach underscores their potential to significantly enhance clinical outcomes. Digital technologies not only improve the accuracy and effectiveness of treatment but also facilitate a multidisciplinary approach that elevates the standard of patient care in addressing complex orthodontic challenges.

5-ALA Improves the Low Temperature Tolerance of Common Bean Seedlings through a Combination of Hormone Transduction Pathways and Chlorophyll Metabolism.

Low-temperature stress is a key factor limiting the yield and quality of the common bean. 5-aminolevulinic acid (5-ALA), an antioxidant in plants, has been shown to modulate plant cold stress responses. However, the molecular mechanisms of 5-ALA-induced physiological and chemical changes in common bean seedlings under cold stress remains unknown. This study explored the physiological and transcriptome changes of common bean seedlings in response to cold stress after 5-ALA pretreatment. Physiological results showed that exogenous 5-ALA promotes the growth of common bean plants under cold stress, increases the activity of antioxidant enzymes (superoxide dismutase: 23.8%; peroxidase: 10.71%; catalase: 9.09%) and proline content (24.24%), decreases the relative conductivity (23.83%), malondialdehyde (33.65%), and active oxygen content, and alleviates the damage caused by cold to common bean seedlings. Transcriptome analysis revealed that 214 differentially expressed genes (DEGs) participate in response to cold stress. The DEGs are mainly concentrated in indole alkaloid biosynthesis, carotenoid biosynthesis, porphyrin, and chlorophyll metabolism. It is evident that exogenous 5-ALA alters the expression of genes associated with porphyrin and chlorophyll metabolism, as well as the plant hormone signal transduction pathway, which helps to maintain the energy supply and metabolic homeostasis under low-temperature stress. The results reveal the effect that applying exogenous 5-ALA has on the cold tolerance of the common bean and the molecular mechanism of its response to cold tolerance, which provides a theoretical basis for exploring and improving plant tolerance to low temperatures.

Spatially eutrophication potential and policy implication of nitrogen emission for surface water: A case study in Guangzhou city, China.

Understanding the spatial distribution and path tracing of eutrophication caused by nitrogen (N) enrichment in urban freshwater is crucial for whole-process and precise damage effect control. This study constructed a site-specific life cycle impact assessment (LCIA) model, covering the overall cause-effect chain from source emission to endpoint effect, to assess N-induced eutrophication potential at the species damage level. Applied to Guangzhou city, China, marked spatial disparities in eutrophication potential were derived, with higher values in the downtown areas driven by anthropogenic disturbances, such as wastewater discharge. Spatially differentiated measures were provided through eutrophication hotspot identification and driver tracking. This study offers a necessary complement for eutrophication impact category indicators in LCIA methodology and lays a scientific foundation for potential hotpots diagnosis and targeted mitigation policy-making.

Current Status and Potential Assessment of China's Ocean Carbon Sinks.

The role of ocean carbon sinks in global climate change mitigation and carbon neutrality is still affected by lack of research. Aiming at overcoming the present limitations, a comprehensive and holistic framework and accounting method of ocean carbon sink evaluation are proposed in this study, which consider both carbon sink types and their characteristic carbon storage cycle timescales. The results show that (1) China's total ocean carbon sink is 69.83-106.46 Tg C/year, among which the mariculture, coastal wetlands, and offshore carbon sinks are 2.27-4.06, 2.86-5.85, and 64.70-96.55 Tg C/year, respectively; (2) ocean-based solutions such as coastal protection and restoration, mariculture development, ocean alkalization, ocean fertilization, and marine bioenergy with carbon capture and storage have substantial mitigation potential, but further investigation is required before large-scale deployment; (3) although China's ocean carbon sinks only counterbalanced 3.27-4.99% of its fossil fuel emissions, their tremendous enhancing potential and specific advantages cannot be ignored, and enhancing measures must be taken according to regional characteristics; (4) some uncertainties and limitations still exist, and problems such as double counting, carbon sink offset, and so forth need to be further considered. In a word, this study provides a basis for the development of ocean-based solutions on closing climate mitigation gaps.

Effects of functional mandibular lateral shift on craniofacial growth and development in growing rats.

BACKGROUND: Unilateral posterior crossbite, one of the most frequent malocclusions, is often associated with functional lateral shift of the mandible. Although the effects of functional lateral shift on the mandible and temporomandibular joint have been examined in various animal experiments, cranial and maxillary changes have received less attention. OBJECTIVE: The aim of this study was to investigate the effects of functional lateral shift on the craniofacial complex in growing rats. METHODS: Eighty 5-week-old male Sprague-Dawley rats were randomly divided into an experimental group (n = 40), which received an oblique guide appliance that shifted the mandible to the left during closure, and a control group (n = 40). The rats were scanned by cone-beam computed tomography at 3 days and 1, 2, 4 and 8 weeks. The dimensions of the mandibular bone, condyle, maxilla and cranium were measured. RESULTS: The mandibles of rats in the experimental group were smaller than those of the rats in the control group and were asymmetrical. The condyles of the rats in the experimental group were thinner than those of the control rats. The condylar length on the ipsilateral side was shorter and wider than that on the contralateral side from 4 to 8 weeks. No significant differences in cranial length or height were observed between the experimental and control groups. The height of the upper first molar and alveolar bone on the contralateral side was significantly smaller than that on the ipsilateral side and in the controls from 4 to 8 weeks. CONCLUSION: Functional shift in the mandible produces morphological asymmetries in the mandible and maxillary region and may cause bilateral condylar degenerative changes.

Genome-Wide Identification of Polyamine Oxidase (PAO) Family Genes: Roles of CaPAO2 and CaPAO4 in the Cold Tolerance of Pepper (Capsicum annuum L.).

Polyamine oxidases (PAOs), which are flavin adenine dinucleotide-dependent enzymes, catalyze polyamine (PA) catabolism, producing hydrogen peroxide (H2O2). Several PAO family members have been identified in plants, but their expression in pepper plants remains unclear. Here, six PAO genes were identified in the 'Zunla-1' pepper genome (named CaPAO1-CaPAO6 according to their chromosomal positions). The PAO proteins were divided into four subfamilies according to phylogenetics: CaPAO1 belongs to subfamily I; CaPAO3 and CaPAO5 belong to subfamily III; and CaPAO2, CaPAO4, and CaPAO6 belong to subfamily IV (none belong to subfamily II). CaPAO2, CaPAO4, and CaPAO6 were ubiquitously and highly expressed in all tissues, CaPAO1 was mainly expressed in flowers, whereas CaPAO3 and CaPAO5 were expressed at very low levels in all tissues. RNA-seq analysis revealed that CaPAO2 and CaPAO4 were notably upregulated by cold stress. CaPAO2 and CaPAO4 were localized in the peroxisome, and spermine was the preferred substrate for PA catabolism. CaPAO2 and CaPAO4 overexpression in Arabidopsis thaliana significantly enhanced freezing-stress tolerance by increasing antioxidant enzyme activity and decreasing malondialdehyde, H2O2, and superoxide accumulation, accompanied by the upregulation of cold-responsive genes (AtCOR15A, AtRD29A, AtCOR47, and AtKIN1). Thus, we identified candidate PAO genes for breeding cold-stress-tolerant transgenic pepper cultivars.

Decomposition of residential electricity-related CO2 emissions in China, a spatial-temporal study.

The COVID-19 pandemic brings a surge in household electricity consumption, thereby enabling extensive research interest on residential carbon emissions as one of the hot topics in carbon reduction. However, research on spatial-temporal driving forces for the increase of residential CO2 emissions between regions still remains unknown in terms of emissions mitigation in post-pandemic era. Therefore, we studied the residential CO2 emissions from the electricity consumption of China during the period 1997-2019. Afterward, the regional specified production emission factors, combining with electricity use pattern, living standard and household size, were modelled to reveal the spatial-temporal driving forces at national and provincial scales. We observed that the national residential electricity-related CO2 increased from 1997 to 2013, before fluctuating to a peak in 2019. Guangdong, Shandong and Jiangsu, from East China were the top emitters with 27% of the national scale. The decomposition results showed that the income improvement was the primary driving force behind the emission increase in most provinces, while the household size and production emission effects were the main negative effects. For the spatial decomposition, differences in the total households between regions further widen the gaps of total emissions. At the provincial scale of temporal decomposition, eastern developed regions exhibited the most significant decrease in production emissions. In contrast, electricity intensity effect showed negative emission influences in the east and central regions, and positive in north-eastern and western China. The research identified the different incremental patterns of residential electricity-related CO2 emissions in various Chinese provinces, thereby providing scientific ways to save energy and reduce emissions.

Abnormal eruption of teeth in relation to FGFR1 heterozygote mutation: a rare case of osteoglophonic dysplasia with 4-year follow-up.

BACKGROUND: We report a case and its 4-year follow-up of Osteoglophonic dysplasia (OD), a rare disease that disturbs both skeletal and dental development, which is usually caused by heterozygous FGFR1 mutations. CASE PRESENTATION: This article presents a case where a 6-year-old male patient suffered dysregulation of tooth eruption and was diagnosed with osteogenic dysplasia from a fibroblast growth factor receptor 1 (FGFR1) heterozygote mutation. However, the number of teeth is within the normal range, and their roots are well developed. Several interventions were implemented with varying degrees of results. The details of the 4-year follow-up showed that the signs of OD were more pronounced, including dwarfism, frontal bossing, delayed skeletal maturation, anteverted nares, micrognathia, and prominent ears, but the patient's impacted teeth and edentulous jaws remained unchanged. CONCLUSIONS: FGFR1 heterozygote mutation and OD present significant difficulty for teeth eruption and subsequent intervention. Further measures ought to be taken in recognizing various symptoms presented by the patient. This case supports the significance of careful inquiry, comprehensive physical examination and correct diagnosis as indispensable steps for clinical practice in patients with unerupted teeth. Additionally, the detailed case and its 4-year follow-up length may provide new insights into osteogenic dysplasia and patients with impacted teeth while encouraging further exploration in treatment methods.

Mechanical force system of double key loop with finite element analysis.

BACKGROUND: The mechanics of double key loop (DKL) are not well defined, and this finite element study was designed to explore its force system. METHODS: A simplified 3-dimensional finite element model of single and double key loops with an archwire between the lateral incisor and second premolar was established in Ansys Workbench 17.0. Activation in Type-1 (retraction at the distal end), Type-2 (retraction at the distal key) and Type-3 (Type-2 plus ligation between keys) was simulated. The vertical force, load/deflection ratio and moment/force ratio of stainless-steel and titanium-molybdenum alloy (TMA) loops were calculated and compared. RESULTS: The double key loop generated approximately 40% of the force of a single key loop. Type-2 loading of DKL showed a higher L/D ratio than Type-1 loading with a similar M/F ratio. Type-3 loading of DKL showed the highest M/F ratio with a similar L/D ratio as single key loop. The M/F ratio in Type-3 loading increased with the decreasing of retraction force. The DKL of TMA produced approximately 40% of the force and moment compared with those of SS in all loading types. When activated at equal distances below 1 mm, the M/F ratios of SS and TMA DKL with equal preactivation angles were almost the same. CONCLUSION: The M/F ratio on anterior teeth increases with the preactivation angle and deactivation of DKL. The M/F ratio at a certain distance of activation mainly depends on the preactivation angle instead of the wire material. TMA is recommended as a substitute for SS in DKL for a lower magnitude of force.

Stress overload-induced periodontal remodelling coupled with changes in high mobility group protein B1 during tooth movement: an in-vivo study.

High mobility group protein B1 (HMGB1), a bone-active cytokine and an osteocyte alarmin, might have dual functions in bone metabolism that could benefit bone formation and accelerate osteoclastogenic activity. High mobility group protein B1 was recently shown to be involved in tooth movement. Here, we investigated the expression of HMGB1, which remains poorly elucidated, under stress overload-induced periodontal remodelling conditions in vivo. Thirty-six Sprague-Dawley rats (male, 180-200 g) were randomly divided into three groups: two experimental groups, in which 50 or 100 g of force was applied to the first molars for 7 d to induce movement; and one control group, in which no force was applied. These stresses induced tooth movement over significantly different distances, and marked morphological changes were consistently observed in the periodontal tissues of the experimental rats, as demonstrated by histological staining. A real-time PCR analysis showed upregulation of the receptor activator of nuclear factor-kappaB ligand-to-osteoprotegerin ratio and downregulation of the Hmgb1 gene. Changes in both location and expression of the HMGB1 were observed through immunofluorescence analysis. Our data suggest that HMGB1 expression during orthodontic tooth movement might be regulated in a time- and force-dependent manner that is substantially more complex than anticipated.

An improved method for evaluating ecological suitability of hydropower development by considering water footprint and transportation connectivity in Tibet, China.

Ecological suitability evaluation for hydropower development is effective in locating the most suitable area for construction and emphasizes a clear direction for water resources governance. In this paper, water footprints and transportation connectivity were introduced to improve the existing ecological suitability evaluation application for hydropower development by revising the defects of the traditional indicator system. The following conclusions were reached. (1) Tibet was in a state of water use surplus; the prospect of further hydropower development is positive. (2) Chamdo, Lhasa and Nyingchi excelled in water use efficiency, and Ali was placed last. Nakchu was slightly superior to Ali, but it lagged behind the southern regions. Lhasa, Chamdo, Nyingchi, Xigaze and Shannan were suitable for hydropower development, which could further meet local needs and benefit other regions of China. (3) The evaluation results were in accordance with the actual eco-environmental conditions of the built hydropower projects, indicating that current hydropower development planning was basically reasonable.

Risk Prediction Models for Gastric Cancer: A Scoping Review.

Background: Gastric cancer is a significant contributor to the global cancer burden. Risk prediction models aim to estimate future risk based on current and past information, and can be utilized for risk stratification in population screening programs for gastric cancer. This review aims to explore the research design of existing models, as well as the methods, variables, and performance of model construction. Methods: Six databases were searched through to November 4, 2023 to identify appropriate studies. PRISMA extension for scoping reviews and the Arksey and O'Malley framework were followed. Data sources included PubMed, Embase, Web of Science, CNKI, Wanfang, and VIP, focusing on gastric cancer risk prediction model studies. Results: A total of 29 articles met the inclusion criteria, from which 28 original risk prediction models were identified that met the analysis criteria. The risk prediction model is screened, and the data extracted includes research characteristics, prediction variables selection, model construction methods and evaluation indicators. The area under the curve (AUC) of the models ranged from 0.560 to 0.989, while the C-statistics varied between 0.684 and 0.940. The number of predictor variables is mainly concentrated between 5 to 11. The top 5 most frequently included variables were age, helicobacter pylori (Hp), precancerous lesion, pepsinogen (PG), sex, and smoking. Age and Hp were the most consistently included variables. Conclusion: This review enhances understanding of current gastric cancer risk prediction research and its future directions. The findings provide a strong scientific basis and technical support for developing more accurate gastric cancer risk models. We expect that these conclusions will point the way for future research and clinical practice in this area to assist in the early prevention and treatment of gastric cancer.

Effect of prehabilitation for patients undergoing gastric cancer surgery: a protocol of a systematic review and meta-analysis.

INTRODUCTION: Gastric cancer is a high-risk cancer with surgical treatments often leading to significant postoperative complications and mortality. Prehabilitation, involving exercise, nutrition and psychological support before surgery, aims to boost patients' physical and mental health. While effective in other cancers, its benefits for gastric cancer need further study. This research will evaluate the impact of trimodal prehabilitation on patient outcomes in gastric cancer surgery, aiming to reduce complications and expedite recovery. METHODS AND ANALYSIS: This study will systematically review randomised controlled trials and cohort studies evaluating the role of prehabilitation in people undergoing gastric cancer resection. The primary outcomes of interest will include overall postoperative complications and length of hospital stay. The secondary outcomes of interest will include mortality, readmission rate or functional recovery. Databases including PubMed, EMBASE, CINAHL, CENTRAL, Chinese BioMedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database and Chinese Science and Technology Periodicals (VIP) will be searched. All studies will be screened and selected using the criteria described in 'population, intervention/exposure, comparison, outcome and study design' format. Two independent reviewers will screen studies for relevance and methodological validity. Data from included studies will be extracted through a customised, preset data extraction sheet. The Cochrane Review Manager (V.5.3, Nordic Cochrane Centre, Copenhagen, Denmark) software will be used to perform the meta-analysis. ETHICS AND DISSEMINATION: Ethics approval is not required for this study as all results will be based on published papers. No primary data collection will be needed. Study findings will be presented at scientific conferences or published in a peer-reviewed scientific journal. PROSPERO REGISTRATION NUMBER: CRD42023488469.

The dynamic progression of temporomandibular joint osteoarthritis-like lesions elicited by mandibular shift in a rat model.

BACKGROUND: Temporomandibular joint osteoarthritis (TMJ-OA) presents significant challenges due to its complex etiology, often insidious onset, high incidence, and progressive structural deterioration. While research has explored genetic and molecular factors, treatment outcomes remain suboptimal, emphasizing the need for a deeper understanding of disease progression. OBJECTIVE: This study employs a specific mandibular shift rat model to explore the dynamic progression of TMJ-OA-like lesions and evaluate the potential for self-repair at different stages, aiming to inform early diagnosis and preventative strategies. METHODS: Seventy-two female Sprague-Dawley rats were randomized into three groups: a control group (n=24; average weight: 157.23±1.63 g) receiving sham surgery. an experimental group (n=24; average weight: 157.78±1.88 g) subjected to mandibular shift induction, and a removal group (n=24; average weight: 158.11±2.20 g) experiencing mandibular shift for one, two, or four weeks followed by a one-month recovery period (designated as 1w Removal, 2w Removal and 4w Removal, respectively). Histomorphological and molecular analyses were conducted at designated time points. RESULTS: Rats in the 1-week removal group exhibited substantial recovery in condylar morphology, cartilage thickness, extracellular matrix composition, and expression of OA-related genes. Conversely, the 4-week removal group mirrored the experimental group, indicating limited self-repair capacity at later stages. The 2-week removal group presented with variable outcomes, with some animals showing signs of recovery and others resembling the experimental group, indicating a potential transitional phase in the disease process. CONCLUSION: Recovery from early-stage TMJ-OA involves eliminating provoking factors such as occlusal interference or reducing joint loading. However, advanced stages exhibit diminished self-repair capabilities, necessitating additional therapeutic interventions. These findings emphasize the importance of early diagnosis and intervention in TMJ-OA management.

Using an ER-specific optogenetic mechanostimulator to understand the mechanosensitivity of the endoplasmic reticulum.

The ability of cells to perceive and respond to mechanical cues is essential for numerous biological activities. Emerging evidence indicates important contributions of organelles to cellular mechanosensitivity and mechanotransduction. However, whether and how the endoplasmic reticulum (ER) senses and reacts to mechanical forces remains elusive. To fill the knowledge gap, after developing a light-inducible ER-specific mechanostimulator (LIMER), we identify that mechanostimulation of ER elicits a transient, rapid efflux of Ca2+ from ER in monkey kidney COS-7 cells, which is dependent on the cation channels transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and polycystin-2 (PKD2) in an additive manner. This ER Ca2+ release can be repeatedly stimulated and tuned by varying the intensity and duration of force application. Moreover, ER-specific mechanostimulation inhibits ER-to-Golgi trafficking. Sustained mechanostimuli increase the levels of binding-immunoglobulin protein (BiP) expression and phosphorylated eIF2α, two markers for ER stress. Our results provide direct evidence for ER mechanosensitivity and tight mechanoregulation of ER functions, placing ER as an important player on the intricate map of cellular mechanotransduction.

FOXP4-mediated induction of PTK7 activates the Wnt/ß-catenin pathway and promotes ovarian cancer development.

Ovarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4's function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.

A Robust FISH Assay to Detect FGFR2 Translocations in Intrahepatic Cholangiocarcinoma Patients.

FGFR fusions retaining the FGFR kinase domain are active kinases that are either overexpressed or constitutively activated throughout diverse cancer types. The presence of FGFR translocations enhances tumor cell proliferation and contributes to significant sensitivity to FGFR kinase inhibitors. FGFR2 as an actionable target in intrahepatic cholangiocarcinoma (iCCA) has been tested in many clinical trials. FISH (fluorescence in situ hybridization) and NGS (next-generation sequence) are well-known tools to investigate the translocations of FGFR with multiple or unknown translocation partners. A rapid and robust FISH assay was developed and validated to detect FGFR2 translocations from FFPE specimens in iCCA. The analytical performance of the FISH assay was evaluated for probe localization, probe sensitivity and specificity, and assay precision. Twenty-five archival FFPE specimens from local iCCA patients were tested for FGFR2 translocations. FISH results were correlated with that of NGS on some samples. Biallelic translocations and a novel FGFR2 translocation involving the partner gene, SHROOM3, t(4;10) (q21;q26), were identified in a local iCCA patient.