Effects of intermittent overload doses of oral vitamin D3 on serum 25(OH)D concentrations and the incidence rates of fractures, falls, and mortality in elderly individuals: A systematic review and meta-analysis.

Vitamin D is commonly used to prevent and treat osteoporosis, with studies indicating its potential to reduce fractures, falls, and mortality. However, meta-analyses present inconsistent findings regarding its efficacy, particularly reflecting significant variability in data and outcomes related to various dosing regimens. In this meta-analysis, we assessed the impact of high-dose intermittent oral administration of vitamin D3 on serum 25(OH)D levels, fractures, falls, and mortality among elderly individuals. We included 14 randomized controlled trials (RCTs) and employed Review Manager 5.4 for statistical analysis. Our findings indicate that intermittent monthly administration of vitamin D3 (over 800 IU per day) significantly raised serum 25(OH)D levels at all timepoints after six months, maintaining levels above 75 nmol/L throughout the year. This regimen showed no increase in all-cause mortality, with a risk ratio (95% CI) of 0.95 (0.87-1.04). Likewise, it did not significantly reduce the risks of falls and fractures, with risk ratios of 1.02 (0.98-1.05) and 0.95 (0.87-1.04) respectively. Although one-year intermittent administration significantly increased the concentration of 25(OH)D in serum, further research is needed to determine if this method would increase the incidence of falls. Therefore, it is not recommended at this stage due to the lack of demonstrated safety in additional relevant RCTs. This study had been registered on PROSPERO (CRD42022363229).

Comparison of outcomes after anterior cervical discectomy and fusion with and without a cervical collar: a systematic review and meta-analysis.

PURPOSE: The clinical outcomes of patients who received a cervical collar after anterior cervical decompression and fusion were evaluated by comparison with those of patients who did not receive a cervical collar. METHODS: All of the comparative studies published in the PubMed, Cochrane Library, Medline, Web of Science, and EMBASE databases as of 1 October 2023 were included. All outcomes were analysed using Review Manager 5.4. RESULTS: Four studies with a total of 406 patients were included, and three of the studies were randomized controlled trials. Meta-analysis of the short-form 36 results revealed that wearing a cervical collar after anterior cervical decompression and fusion was more beneficial (P < 0.05). However, it is important to note that when considering the Neck Disability Index at the final follow-up visit, not wearing a cervical collar was found to be more advantageous. There were no statistically significant differences in postoperative cervical range of motion, fusion rate, or neck disability index at 6 weeks postoperatively (all P > 0.05) between the cervical collar group and the no cervical collar group. CONCLUSIONS: This systematic review and meta-analysis revealed no significant differences in the 6-week postoperative cervical range of motion, fusion rate, or neck disability index between the cervical collar group and the no cervical collar group. However, compared to patients who did not wear a cervical collar, patients who did wear a cervical collar had better scores on the short form 36. Interestingly, at the final follow-up visit, the neck disability index scores were better in the no cervical collar group than in the cervical collar group. PROSPERO registration number: CRD42023466583.

Percutaneous microchannel unilateral approach bilateral micro decompression for adjacent segmental degeneration after lumbar fusion at 10 years: a case report and review of literature.

Background: Adjacent segmental degeneration after lumbar fusion is one of the common long-term complications after lumbar fusion. With the continuous development of adjacent segmental degeneration, patients who fail conservative treatment often need reoperation to relieve symptoms. In recent years, the technique of bilateral microdecompression through unilateral approach under microchannel has been widely used in the treatment of lumbar degenerative diseases. However, the efficacy of this procedure for adjacent-segment degeneration after lumbar fusion has not been established. Here, we report a case of bilateral microscopic decompression via a unilateral approach through a microchannel in a patient with adjacent segmental degeneration after lumbar fusion. Case report: A 70-year-old male patient was admitted to hospital because of lumbago accompanied by left lower extremity pain, numbness and weakness for 2 years, which aggravated for 2 months. Ten years ago, he underwent PLIF for lumbar spinal stenosis, and recovered well after the operation. According to imaging data and physical examination, the diagnosis was adjacent segmental degeneration after lumbar fusion. Bilateral microdecompression was performed through a unilateral approach under a microchannel. Good clinical outcomes was observed through 1-year postoperative follow-up. Conclusions: This report reports the successful treatment of a patient with ASD 10 years after lumbar fusion. Bilateral microdecompression via a unilateral approach under a microchannel is a safe and effective method for the treatment of ASD after lumbar fusion with good surgical outcomes.

Autophagy collaborates with apoptosis pathways to control oligodendrocyte number.

Oligodendrocytes are the sole myelin-producing cells in the central nervous system. Oligodendrocyte number is tightly controlled across diverse brain regions to match local axon type and number, yet the underlying mechanisms remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under physiological conditions, elicits premyelinating oligodendrocyte apoptosis during development. Autophagy flux is increased in premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy functions cell autonomously in the premyelinating oligodendrocyte to trigger cell apoptosis, and it genetically interacts with the TFEB pathway to limit oligodendrocyte number across diverse brain regions. Our results provide in vivo evidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrogenesis.

Optimization of fermentation, purification, and properties of blue pigment produced from Quambalaria cyanescens QY229.

AIM: Blue pigments have broad applications in foods, cosmetics, and clothing. However, natural blue pigments are rare. At present, the majority of blue pigments for sale are chemically synthetic. Owing to the safety risks of chemical pigments, it is an urgent demand to develop novel natural blue pigments. METHODS AND RESULTS: The fermentation medium and culture conditions of blue pigment produced by Quambalaria cyanescens QY229 were optimized by Plackett-Burman (PB) experimental design and response surface methodology (RSM) for the first time. The stability, bioactivity, and toxicity of the obtained blue pigment were studied after isolation and purification. CONCLUSION: The results showed that the optimal fermentation parameters were 34.61 g·L-1 of peptone concentration, 31.67°C of growing temperature, and 72.33 mL of medium volume in a 250-mL flask, and the yield of blue pigment reached 348.2 ± 7.1 U·mL-1. QY229 blue pigment is stable to light, heat, pH, most metal ions, and additives, and has certain antioxidant and inhibitory activity of α-glucosidase in vitro. QY229 blue pigment at concentrations of 0-1.25 mg·mL-1 was nontoxic to Caenorhabditis elegans in an acute toxicity trial.

Comparison of outcomes between tubular microdiscectomy and conventional microdiscectomy for lumbar disc herniation: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The clinical outcomes of using a tubular microdiscectomy for lumbar disc herniation were evaluated by comparison with conventional microdiscectomy. METHODS: All of the comparative studies published in the PubMed, Cochrane Library, Medline, Web of Science, and EMBASE databases as of 1 May 2023 were included. All outcomes were analysed using Review Manager 5.4. RESULTS: This meta-analysis included four randomized controlled studies with a total of 523 patients. The results showed that using tubular microdiscectomy for lumbar disc herniation was more effective than conventional microdiscectomy in improving the Oswestry Disability Index (P < 0.05). However, there were no significant differences in operating time, intraoperative blood loss, hospital stay, Visual Analogue Scale, reoperation rate, postoperative recurrence rate, dural tear incidence, and complications rate (all P > 0.05) between the tubular microdiscectomy and conventional microdiscectomy groups. CONCLUSIONS: Based on our meta-analysis, it was found that the tubular microdiscectomy group had better outcomes than the conventional microdiscectomy group in terms of Oswestry Disability Index. However, there were no significant differences between the two groups in terms of operating time, intraoperative blood loss, hospital stay, Visual Analogue Scale, reoperation rate, postoperative recurrence rate, dural tear incidence, and complications rate. Current research suggests that tubular microdiscectomy can achieve clinical results similar to those of conventional microdiscectomy. PROSPERO registration number is: CRD42023407995.

Autophagy collaborates with apoptosis pathways to control myelination specificity and function.

Oligodendrocytes are the sole myelin producing cells in the central nervous system. Oligodendrocyte numbers are tightly controlled across diverse brain regions to match local axon type and number, but the underlying mechanisms and functional significance remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under canonical settings, elicits premyelinating oligodendrocyte apoptosis during development and regulates critical aspects of nerve pulse propagation. Autophagy flux is increased in premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy acts in the TFEB-Bax/Bak pathway and elevates PUMA mRNA levels to trigger premyelinating oligodendrocyte apoptosis cell-autonomously. Autophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath numbers and fine-tune nerve pulse propagation. Our results provide in vivo evidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrocyte number. HIGHLIGHTS: Autophagy flux increases in the premyelinating and myelinating oligodendrocytesAutophagy promotes premyelinating oligodendrocyte (pre-OL) apoptosis to control myelination location and timing Autophagy acts in the TFEB-PUMA-Bax/Bak pathway and elevates PUMA mRNA levels to determine pre-OL fate Autophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath thickness and finetune nerve pulse propagation.

Astrocytic Piezo1-mediated mechanotransduction determines adult neurogenesis and cognitive functions.

Adult brain activities are generally believed to be dominated by chemical and electrical transduction mechanisms. However, the importance of mechanotransduction mediated by mechano-gated ion channels in brain functions is less appreciated. Here, we show that the mechano-gated Piezo1 channel is expressed in the exploratory processes of astrocytes and utilizes its mechanosensitivity to mediate mechanically evoked Ca2+ responses and ATP release, establishing Piezo1-mediated mechano-chemo transduction in astrocytes. Piezo1 deletion in astrocytes causes a striking reduction of hippocampal volume and brain weight and severely impaired (but ATP-rescuable) adult neurogenesis in vivo, and it abolishes ATP-dependent potentiation of neural stem cell (NSC) proliferation in vitro. Piezo1-deficient mice show impaired hippocampal long-term potentiation (LTP) and learning and memory behaviors. By contrast, overexpression of Piezo1 in astrocytes sufficiently enhances mechanotransduction, LTP, and learning and memory performance. Thus, astrocytes utilize Piezo1-mediated mechanotransduction mechanisms to robustly regulate adult neurogenesis and cognitive functions, conceptually highlighting the importance of mechanotransduction in brain structure and function.

Management of procedural pain in the intensive care unit.

Pain is a common experience for inpatients, and intensive care unit (ICU) patients undergo more pain than other departmental patients, with an incidence of 50% at rest and up to 80% during common care procedures. At present, the management of persistent pain in ICU patients has attracted considerable attention, and there are many related clinical studies and guidelines. However, the management of transient pain caused by certain ICU procedures has not received sufficient attention. We reviewed the different management strategies for procedural pain in the ICU and reached a conclusion. Pain management is a process of continuous quality improvement that requires multidisciplinary team cooperation, pain-related training of all relevant personnel, effective relief of all kinds of pain, and improvement of patients' quality of life. In clinical work, which involves complex and diverse patients, we should pay attention to the following points for procedural pain: (1) Consider not only the patient's persistent pain but also his or her procedural pain; (2) Conduct multimodal pain management; (3) Provide combined sedation on the basis of pain management; and (4) Perform individualized pain management. Until now, the pain management of procedural pain in the ICU has not attracted extensive attention. Therefore, we expect additional studies to solve the existing problems of procedural pain management in the ICU.

Comparison of outcomes between Zero-p implant and anterior cervical plate interbody fusion systems for anterior cervical decompression and fusion: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The clinical outcomes of using a zero-profile for anterior cervical decompression and fusion were evaluated by comparison with anterior cervical plates. METHODS: All of the comparative studies published in the PubMed, Cochrane Library, Medline, Web of Science, EBSOChost, and EMBASE databases as of 1 October 2021 were included. All outcomes were analysed using Review Manager 5.4. RESULTS: Seven randomized controlled studies were included with a total of 528 patients, and all studies were randomized controlled studies. The meta-analysis outcomes indicated that the use of zero-profile fixation for anterior cervical decompression and fusion was better than anterior cervical plate fixation regarding the incidence of postoperative dysphagia (P < 0.05), adjacent-level ossification (P < 0.05), and operational time (P < 0.05). However, there were no statistically significant differences in intraoperative blood loss, Visual Analogue Scale, Neck Disability Index, or Japanese Orthopaedic Association scale (all P > 0.05) between the zero-profile and anterior cervical plate groups. CONCLUSIONS: The systematic review and meta-analysis indicated that zero-profile and anterior cervical plates could result in good postoperative outcomes in anterior cervical decompression and fusion. No significant differences were found in intraoperative blood loss, Visual Analogue Scale, Neck Disability Index, or Japanese Orthopaedic Association scale. However, the zero-profile is superior to the anterior cervical plate in the following measures: incidence of postoperative dysphagia, adjacent-level ossification, and operational time. PROSPERO registration CRD42021278214.

Open-Door versus French-Door Laminoplasty for Patients with Multisegmental Cervical Spondylotic Myelopathy: A Systematic Review and Meta-analysis.

This study aimed to evaluate the superiority of open-door versus French-door posterior cervical laminoplasty in the treatment of multisegmental cervical spondylotic myelopathy by comparing the intraoperative parameters and clinical and radiologic outcomes of these 2 procedures. PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, the Wanfang database, the Weipu database, and China Biology Medicine disk were searched. Articles were retrieved from database establishment through May 22, 2020. Data analysis was carried out on the retrieved articles using RevMan 5.3 software. This meta-analysis included 14 studies involving 1010 patients, among which 6 were randomized controlled trials and 8 were retrospective analyses. Comparing the open-door and French-door groups, no statistically significant differences were found in operative time (weighted mean difference [WMD] = -4.47, 95% CI [-17.85, 8.92], P = 0.51), postoperative Japanese Orthopaedic Association score (WMD= -0.24, 95% CI [-0.87, 0.38], P = 0.45), recovery rate (WMD= -0.58, 95% CI [-3.61, 2.45], P = 0.71), postoperative cervical lordosis (WMD= -0.15, 95% CI [-1.93, 1.63], P = 0.87), cervical range of motion (WMD = -3.04, 95% CI [-8.68, 2.59], P = 0.29), sagittal diameter of the spinal canal (WMD = -0.24, 95% CI [-0.54, 0.07], P = 0.13), incidence of C5 palsy (OR = 1.78, 95% CI [0.64, 4.93], P = 0.27), or incidence of cerebrospinal fluid leakage (OR = 1.51, 95% CI [0.48, 4.71], P = 0.48). However, the French-door group was associated with less intraoperative bleeding (WMD = 54.96, 95% CI [21.37, 88.55], P = 0.001) and a lower incidence of axial symptoms (OR = 2.50, 95% CI [1.32, 4.72], P = 0.005). This analysis suggests that both methods can achieve good postoperative outcomes. However, less intraoperative bleeding and a lower incidence of postoperative axial symptoms were found in the French-door group. This requires further validation and investigation in larger sample-size and well-designed randomized controlled studies.

A Plug-and-Latch Mechanism for Gating the Mechanosensitive Piezo Channel.

The mechanosensitive Piezo1 and Piezo2 channels convert mechanical force into cation permeation. However, their precise mechanogating and regulatory mechanisms remain elusive. Here, we report that Piezo1 utilizes three lateral ion-conducting portals equipped with physical gates for cooperative gating and splicing regulation. Mutating residues lining the portal converts Piezo1 into an anion-selective channel, demonstrating the portal-based cation-permeating pathway. Intriguingly, the portal is physically blocked with a plug domain, which undergoes alternative splicing in both Piezo1 and Piezo2. The Piezo1 isoform has local openings of the portals, enlarged single-channel conductance and sensitized mechanosensitivity. Remarkably, the three plugs are strategically latched onto the central axis for coordinated gating of the three portals. Disrupting the latching induces three quantal sub-conductance states in Piezo1, but not in the isoform. Together, we propose that Piezo utilizes an elegant plug-and-latch mechanism to physically and coordinately gate the lateral portals through the spliceable plug gates.

Oncogenic KRAS-Driven Metabolic Reprogramming in Pancreatic Cancer Cells Utilizes Cytokines from the Tumor Microenvironment.

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is an exuberant stroma comprised of diverse cell types that enable or suppress tumor progression. Here, we explored the role of oncogenic KRAS in protumorigenic signaling interactions between cancer cells and host cells. We show that KRAS mutation (KRAS*) drives cell-autonomous expression of type I cytokine receptor complexes (IL2rγ-IL4rα and IL2rγ-IL13rα1) in cancer cells that in turn are capable of receiving cytokine growth signals (IL4 or IL13) provided by invading Th2 cells in the microenvironment. Early neoplastic lesions show close proximity of cancer cells harboring KRAS* and Th2 cells producing IL4 and IL13. Activated IL2rγ-IL4rα and IL2rγ-IL13rα1 receptors signal primarily via JAK1-STAT6. Integrated transcriptomic, chromatin occupancy, and metabolomic studies identified MYC as a direct target of activated STAT6 and that MYC drives glycolysis. Thus, paracrine signaling in the tumor microenvironment plays a key role in the KRAS*-driven metabolic reprogramming of PDAC. SIGNIFICANCE: Type II cytokines, secreted by Th2 cells in the tumor microenvironment, can stimulate cancer cell-intrinsic MYC transcriptional upregulation to drive glycolysis. This KRAS*-driven heterotypic signaling circuit in the early and advanced tumor microenvironment enables cooperative protumorigenic interactions, providing candidate therapeutic targets in the KRAS* pathway for this intractable disease.

Geniposide promotes the proliferation and differentiation of MC3T3-E1 and ATDC5 cells by regulation of microRNA-214.

The research plans to make sure how Geniposide (GEN) functions in osteoblast proliferation and differentiation. The MC3T3-E1 and ATDC5 cells were treated with the GEN, XAV-939 and/or transfected with microRNA (miR)-214 mimic or corresponding control. Cell viability was detected with the CCK-8. The CyclinD1, Runx2, Osx, Ocn, Wnt3a and ß-catenin were individually quantified via western blot. The cell cycle was tested by cell cycle analysis assay. The ALP activity was tested by ALP assay. qRT-PCR was used to examine the miR-214 expression level. The cell viability and the expressions of the CyclinD1, Runx2, Osx, Ocn Wnt3a and ß-catenin, as well as the ALP activity were individually and significantly promoted by the GEN. Besides, miR-214 was down-regulated by the GEN. The XAV-939 or the miR-214 mimic destroyed the promotional effect of GEN on these elements above. In conclusion, GEN induced the proliferation and differentiation of the MC3T3-E1 and ATDC5 cells by targeting the miR-214 through Wnt/ß-catenin activation.

Calcium-sensing receptor activating ERK1/2 and PI3K-Akt pathways to induce the proliferation of osteosarcoma cells.

Our results showed that the expression of calcium-sensing receptor (CaSR) and the concentration of intracellular calcium were enhanced in the osteosarcoma cells MG-63 compared with in the normal osteoblasts hFOB1.19. GdCl3 (CaSR agonist) significantly increased the proliferation rate of MG-63 cells, the expression of PCNA and Cyclin D1 and decreased the expression of p21Cip/WAF-1 . The effect of NPS2390 (CaSR antagonist) on the above indicators was opposite to GdCl3 . In addition, GdCl3 up-regulated the phosphorylation of ERK1/2, PI3K and Akt and the proliferation rate of MG-63 cells. However, these effects of GdCl3 were cancelled by LY294002 (a PI3K inhibitor) or PD98059 (an ERK1/2 inhibitor). Our results demonstrate that activation of CaSR promotes osteosarcoma cell multiplication by up-regulating ERK1/2 and PI3K-Akt pathways.

NFIL3 Acts as a Nuclear Factor to Increase Osteosarcoma Progression.

PURPOSE: Osteosarcoma is one of the most common primary malignant, aggressive bone neoplasms. However, the mechanisms of osteosarcoma proliferation, migration, and invasion are not well understood. To explore the possible mechanism of osteosarcoma progression, we used a public database for gene analysis to identify the possible factors that are important in osteosarcoma progression. Nuclear factor interleukin 3 (NFIL3) regulated was highly expressed in sarcoma tissues. In this study, we meant to probe the function of NFIL3 in osteosarcoma proliferation, migration, and invasion. METHODS: The expression of NFIL3 in osteosarcoma tissues was analysed via RT-PCR and immunohistochemistry staining. In order to elucidate the function of NFIL3 in osteosarcoma, we performed cell growth assays and colony formation assays to explore the role of NFIL3 in proliferation in osteosarcoma cells. Futhermore, we analysed osteosarcoma cell migration and invasion via wound healing assays and transwell migration and invasion assays. RESULTS: NFIL3 is overexpressed in osteosarcoma tissues; 15 of the 20 osteosarcoma tissues analysed highly expressed NFIL3. Our in vitro experiments confirmed that NFIL3 promoted the proliferation of M6-63 and SaOS2 cells (P < 0.01). In addition, NFIL3 promoted the migration and invasion of osteosarcoma cells (P < 0.05). CONCLUSION: NFIL3 is highly expressed in osteosarcoma tissues and thus promotes the proliferation, migration, and invasion of osteosarcoma cells. NFIL3 is potential to become a new target for development of novel treatment strategies of osteosarcoma.

Comparison of outcomes between cortical screws and traditional pedicle screws for lumbar interbody fusion: a systematic review and meta-analysis.

PURPOSE: The clinical outcomes of using a cortical screw (CS) for lumbar interbody fusion were evaluated by comparison with conventional pedicle screw (PS) fixation. METHODS: All of the comparative studies published in the PubMed, Cochrane Library, MEDLINE, Web of Science, and EMBASE databases recently as 18 March 2019, were included. All outcomes were analyzed by using Review Manager 5.3. RESULTS: Twelve studies were included with a total of 835 patients, and two of the studies were randomized controlled trials. The outcomes of the meta-analysis indicated that the use of CS fixation for lumbar interbody fusion was better than conventional PS fixation in regard to operating time (p = 0.02), intraoperative blood loss (p < 0.00001), length of stay (p = 0.02), incidence of complications (p = 0.02), adjacent segmental disease (ASD) incidence (p = 0.03), and Oswestry Disability Index (ODI) (p = 0.03). However, there were no statistically significant differences in the back and leg pain visual analog scale (VAS), Japanese Orthopaedic Association (JOA) scale, and intervertebral fusion rate (all p > 0.05) between the CS fixation group and the PS fixation group. CONCLUSIONS: Based on this systematic review and meta-analysis, our outcomes indicated that both CS and conventional PS can result in good postoperative outcomes in lumbar interbody fusion. No significant differences were found in the back and leg pain VAS, JOA scale, and intervertebral fusion rate. However, CS fixation is superior to PS fixation in the following measures: operating time, intraoperative blood loss, length of stay, incidence of complications, ASD incidence, and ODI. TRIAL REGISTRATION: PROSPERO registration number is CRD 42019132226 .

Author Correction: Structure and mechanogating mechanism of the Piezo1 channel.

In Extended Data Fig. 9a of this Article, the bottom micrographs of mPiezo1-ΔL3-4-IRES-GFP and mPiezo1-ΔL7-8-IRES-GFP (labelled 'permeabilized') are inadvertently the same images. The corrected figure panels are shown in the accompanying Amendment.

Structure and mechanogating mechanism of the Piezo1 channel.

The mechanosensitive Piezo channels function as key eukaryotic mechanotransducers. However, their structures and mechanogating mechanisms remain unknown. Here we determine the three-bladed, propeller-like electron cryo-microscopy structure of mouse Piezo1 and functionally reveal its mechanotransduction components. Despite the lack of sequence repetition, we identify nine repetitive units consisting of four transmembrane helices each-which we term transmembrane helical units (THUs)-which assemble into a highly curved blade-like structure. The last transmembrane helix encloses a hydrophobic pore, followed by three intracellular fenestration sites and side portals that contain pore-property-determining residues. The central region forms a 90 Å-long intracellular beam-like structure, which undergoes a lever-like motion to connect THUs to the pore via the interfaces of the C-terminal domain, the anchor-resembling domain and the outer helix. Deleting extracellular loops in the distal THUs or mutating single residues in the beam impairs the mechanical activation of Piezo1. Overall, Piezo1 possesses a unique 38-transmembrane-helix topology and designated mechanotransduction components, which enable a lever-like mechanogating mechanism.

A protein interaction mechanism for suppressing the mechanosensitive Piezo channels.

Piezo proteins are bona fide mammalian mechanotransduction channels for various cell types including endothelial cells. The mouse Piezo1 of 2547 residues forms a three-bladed, propeller-like homo-trimer comprising a central pore-module and three propeller-structures that might serve as mechanotransduction-modules. However, the mechanogating and regulation of Piezo channels remain unclear. Here we identify the sarcoplasmic /endoplasmic-reticulum Ca2+ ATPase (SERCA), including the widely expressed SERCA2, as Piezo interacting proteins. SERCA2 strategically suppresses Piezo1 via acting on a 14-residue-constituted intracellular linker connecting the pore-module and mechanotransduction-module. Mutating the linker impairs mechanogating and SERCA2-mediated modulation of Piezo1. Furthermore, the synthetic linker-peptide disrupts the modulatory effects of SERCA2, demonstrating the key role of the linker in mechanogating and regulation. Importantly, the SERCA2-mediated regulation affects Piezo1-dependent migration of endothelial cells. Collectively, we identify SERCA-mediated regulation of Piezos and the functional significance of the linker, providing important insights into the mechanogating and regulation mechanisms of Piezo channels.