Search

Abstract Background Tourniquets are routinely employed to achieve hemostasis in modern limb surgeries. Nevertheless, the precise role and benefits of tourniquets in high tibial osteotomy (HTO) surgeries remain understudied. The aim of this study was to assess the application of tourniquets in high-tibial osteotomy procedures. Methods This was a prospective study of patients who underwent HTO surgery at an identical hospital. The participants were randomly assigned into two groups: Group A, with a tourniquet (n = 43); and Group B, without a tourniquet (n = 43). The same surgical technique and postoperative care were employed for both groups of patients. Knee range of motion (ROM) and pain were assessed by utilizing a visual analogue scale (VAS) after exercise and maximum calf circumference, and postoperative Hospital for Special Surgery (HSS) score, as well as inflammatory markers including CRP and IL-6, were adopted to compare and analyse the recovery of knee function in the two groups of patients following surgery. Results All participants were followed up for a period exceeding three months. No cases of vascular or nerve injuries were observed during surgery in either group. Moreover, there was no statistically significant difference in total blood loss volume throughout treatment or haemoglobin or haematocrit levels (P > 0.05). furthermore, Group A underwent a shorter operation than Group B did (P

Summary: Phenotypic screening of existing drugs is a good strategy to discover new drugs. Herein, 33 psychotherapeutic drugs in our drug library were screened by phenotypic screening and penfluridol (PFD) was found to exhibit excellent anti-endometrial cancer (EC) activity both in vitro and in vivo. Furthermore, the molecular target of PFD was identified as septin7, a tumor suppressor in EC. In septin7-deficient EC cells and xenograft mouse models, PFD exhibited weaker anti-cancer properties, indicating that septin7 was essential for the tumor inhibitory activity. Notably, PFD could induce cell apoptosis by regulating the septin7-Orai/IP3R-Ca2+-PIK3CA pathway. In addition, PFD attenuates the interaction of septin7-tubulin, thereby inhibiting microtubule polymerization. In summary, this study revealed a target and mechanistic insights into EC therapeutic strategies and identified a potential candidate agent for the treatment of EC.

Postoperative delirium (POD) represents a common neurological complication encountered predominantly among the elderly cohort undergoing surgical intervention for hip fractures. This phenomenon, particularly commonplace in geriatric populations with heightened preoperative risk profiles, pronounced comorbidities, and later stages of lifespan, poses complex clinical challenges. The impact of perioperative pharmacological interventions and anesthetic strategies on POD’s emergence cannot be understated, as it may profoundly affect the length of hospital stays, rehabilitation milestones, and the overall mortality hazard. The pharmacotherapeutic landscape for managing POD remains constrained, underscoring the imperative nature of preventive measures. Prudent preoperative risk stratification, meticulous intraoperative neuromonitoring guided by electroencephalographic studies, and a holistic postoperative patient welfare model are cornerstone recommendations in the quest to mitigate POD’s incidence. Nonetheless, an extensive exploration into the influence of anesthetic approaches and perioperative medications on the emergence of POD is yet to be satisfactorily charted. Our investigation endeavors to dissect the nexus between anesthetic modalities, perioperative pharmacological interventions, and POD incident rates among the elderly with hip fractures. This study spotlights pivotal determinants of POD in the wake of hip fracture surgery by evaluating and synthesizing data from peer-reviewed sources that adhere to rigorous inclusion criteria. Preliminary studies have revealed that certain anesthesia protocols and perioperative medications may increase the potential incidence of POD, such as higher depth of anesthesia or benzodiazepine use, and the incidence of POD in specific populations, such as patients with higher age, prior history of psychosis, and lower intraoperative oxygen saturation The findings from this study are instrumental in refining strategic perioperative plans tailored for the elderly recipients of hip fracture surgery, aimed at not only diminishing the incidence but also the gravity of POD. Despite these forward steps, the clinical uncertainty concerning the efficacy and safety of the specific drugs and surgical techniques in question remains. These lingering questions underscore the exigency for more extensive, empirically grounded research to consolidate the learnings of this investigation.

Objective To investigate the antibacterial performance and biocompatibility of silver nanoparticles-coated root canal nickel titanium instruments(AgNPs-NiTi). Methods AgNPs-NiTi was prepared using pulse electrochemical deposition. The morphology of AgNPs-NiTi was observed using field emission scanning electron microscopy(FE-SEM), and the elemental composition and content were analyzed using X-ray diffraction(XRD)and energy dispersive spectroscopy(EDS). The mechanical properties of AgNPs-NiTi were tested. After Co-culturing AgNPs-NiTi with E. faecalis, the antibacterial effect was detected by colony-forming units method. By constructing an in vitro model of E. faecalis biofilm in the root canal of teeth, the antibacterial effect of AgNPs-NiTi was observed using FE-SEM and live/dead bacterial staining. In addition, AgNPs-NiTi was co-cultured with Raw 264.7 cells, and its cytotoxicity was detected by CCK-8. Results The pulse electrochemical deposition was used to construct a silver nanoparticle(AgNPs)coating on NiTi instruments with no significant change in the mechanical properties. AgNPs-NiTi significantly inhibited the proliferation of E. faecalis and damaged E. faecalis biofilm in the root canal. AgNPs-NiTi had no significant influence on the proliferation of Raw264.7 cells and had no cytotoxicity. Conclusion The mechanical properties of AgNPs-NiTi are similar to those of nickel titanium instruments. AgNPs-NiTi inhibits E. faecalis proliferation with good biocompatibility.

Abstract Background and purpose Peripherally inserted central catheter (PICC) used in neurosurgical patients requires changes in patients' head positions. However, such changes can worsen pressure on the brain tissue, lead to sudden acute brain herniation and respiratory arrest, resulting in a higher chance of patient death. This paper addresses the aforementioned problems by introducing a new PICC catheterization method. Method In a retrospective study, the records of patients with PICC from April 2020 to April 2023 were reviewed, and they were divided into three groups based on the methods employed. The first group as the conventional group, involved changing patients’ body positions during catheterization. The second group, as the intracavitary electrocardiographic (IECG) group, utilized intracavitary electrocardiographic monitoring and involved changing patients’ body positions during catheterization. The third group as the intracavitary electrocardiographic with improved body positioning (IECG-IBP) group, catheterization was performed with guidance from intracavitary electrocardiographs and without changing the patients’ body positions. The ECG changes among patients undergoing different catheter delivery methods were then compared, as well as the rate of catheter tip misplacement. Result The study encompassed a total of 354 cases. Our findings reveal distinct P wave amplitude percentages among the groups: 0% in the conventional group, 88.46% in the IECG group, and 91.78% in the IECG-IBP group. Furthermore, the following catheter tip misplacement rates were recorded: 11.54% for the conventional group, 5.39% for the IECG group, and 5.47% for the IECG-IBP group. Significantly notable differences were observed in these two key indicators between the conventional group and the IECG-IBP group. Notably, the IECG-IBP group demonstrated a more favorable outcome compared to the IECG group. Conclusion In patients with neurosurgical diseases, especially those with tracheostomy and nuchal stiffness, the IECG-IBP PICC catheter insertion method can effectively reduce the patient's neck resistance, does not increase the patient's headache and dizziness symptoms, and does not reduce the success of one-time catheterization. Rate and does not increase the incidence of jugular venous ectopia.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by diverse clinical features. EEG biomarkers such as spectral power and functional connectivity have emerged as potential tools for enhancing early diagnosis and understanding of the neural processes underlying ASD. However, existing studies yield conflicting results, necessitating a comprehensive, data-driven analysis. We conducted a retrospective cross-sectional study involving 246 children with ASD and 42 control children. EEG was collected, and diverse EEG features, including spectral power and spectral coherence were extracted. Statistical inference methods, coupled with machine learning models, were employed to identify differences in EEG features between ASD and control groups and develop classification models for diagnostic purposes. Our analysis revealed statistically significant differences in spectral coherence, particularly in gamma and beta frequency bands, indicating elevated long range functional connectivity between frontal and parietal regions in the ASD group. Machine learning models achieved modest classification performance of ROC-AUC at 0.65. While machine learning approaches offer some discriminative power classifying individuals with ASD from controls, they also indicate the need for further refinement.

In the past two decades, the rapid increase in the incidence of metabolic diseases, including obesity, diabetes, dyslipidemia, non-alcoholic fatty liver disease, hypertension, and hyperuricemia, has been attributed to high-fat diets (HFD) and decreased physical activity levels. Although the phenotypes and pathologies of these metabolic diseases vary, patients with these diseases exhibit disease-specific alterations in the composition and function of their gut microbiota. Studies in germ-free mice have shown that both HFD and gut microbiota can promote the development of metabolic diseases, and HFD can disrupt the balance of gut microbiota. Therefore, investigating the interaction between gut microbiota and HFD in the pathogenesis of metabolic diseases is crucial for identifying novel therapeutic strategies for these diseases. This review takes HFD as the starting point, providing a detailed analysis of the pivotal role of HFD in the development of metabolic disorders. It comprehensively elucidates the impact of HFD on the balance of intestinal microbiota, analyzes the mechanisms underlying gut microbiota dysbiosis leading to metabolic disruptions, and explores the associated genetic factors. Finally, the potential of targeting the gut microbiota as a means to address metabolic disturbances induced by HFD is discussed. In summary, this review offers theoretical support and proposes new research avenues for investigating the role of nutrition-related factors in the pathogenesis of metabolic disorders in the organism.

Abstract Background This study examined the associations of diet quality assessed by Healthy Eating Index 2015 (HEI-2015), Alternative Healthy Eating Index 2010 (AHEI-2010), Mediterranean Diet (MedDiet) and overweight/obesity in children and adolescents. Methods This cross-sectional study used data of participants aged 2–19 years from National Health and Nutrition Examination Survey (NHANES) 2005–2018. The weighted logistic regression model was adopted to explore the association between diet quality scores and overweight, obesity in children and adolescents. Subgroup analysis was also performed based on sex. Results A total of 9,724 participants were included in children group (2–11 years old), and 5,934 were adolescent group (12–19 years old). All participants were divided into based on the BMI-for-age: underweight and normal, overweight and obesity groups. After adjusting for age, race, poverty-income ratio, maternal smoking during pregnancy and total energy, HEI-2015 and MedDiet scores were related to the risk of overweight in children, and only MedDiet scores remained associated with a decreased risk of obesity in children. MedDiet scores were associated with a decreased risk of overweight, obesity in adolescents, respectively, after adjusting age, sex, race, poverty-income ratio, cotinine, total energy and physical activity. The similar results in male participants were also found. Conclusion Higher MedDiet scores were associated with lower the risk of overweight and obesity, respectively, particularly for male children and adolescents. The higher HEI-2015 scores were also related to the risk of overweight in children.

Abstract It is interesting that high iron is an independent inducer or cofactor of hepatocellular carcinoma (HCC) while the amount of iron is decreased in the liver tumor tissues. Due to the previous findings that iron deficiency promoted HCC metastasis, it is of significance to identify the underlying mechanism of iron deficiency in HCC. The tumor iron content and expressions of iron‐metabolic molecules were observed in the primary liver cancers of rats and mice. The molecules that changed independently of iron were identified by comparing the expression profiles in the human HCC tissues and iron‐deprived HCC cells. The downstream effects of these molecules on regulating intracellular iron content were investigated in vitro and further validated in vivo. Both in primary liver cancers of rats and mice, we confirmed the decreased iron content in tumor tissues and the altered expressions of iron‐metabolic molecules, including transferrin receptor 1 (TfR1), six‐transmembrane epithelial antigen of prostate 3 (STEAP3), divalent metal transporter 1 (DMT1), SLC46A1, ferroportin, hepcidin, and ferritin. Among these, STEAP3, DMT1, and SLC46A1 were altered free of iron deficiency. However, only silence or overexpression of SLC46A1 controlled the intracellular iron content of HCC cells. The interventions of STEAP3 or DMT1 could not change the intracellular iron content. Lentivirus‐mediated regain of SLC46A1 expression restored the iron content in orthotopically implanted tumors, with correspondingly changes in the iron‐metabolic molecules as iron increasing. Conclusion: Taken together, these results suggest that the loss of SLC46A1 expression leads to iron deficiency in liver tumor tissues, which would be an effective target to manage iron homeostasis in HCC.

Postoperative delirium (POD) is a frequent complication in geriatric patients with hip fractures, which is linked to poorer functional recovery, longer hospital stays, and higher short-and long-term mortality. Patients with increased age, preoperative cognitive impairment, comorbidities, perioperative polypharmacy, and delayed surgery are more prone to develop POD after hip fracture surgery. In this narrative review, we outlined the latest findings on postoperative delirium in geriatric patients with hip fractures, focusing on its pathophysiology, diagnosis, prevention, and treatment. Perioperative risk prediction, avoidance of certain medications, and orthogeriatric comprehensive care are all examples of effective interventions. Choices of anesthesia technique may not be associated with a significant difference in the incidence of postoperative delirium in geriatric patients with hip fractures. There are few pharmaceutical measures available for POD treatment. Dexmedetomidine and multimodal analgesia may be effective for managing postoperative delirium, and adverse complications should be considered when using antipsychotics. In conclusion, perioperative risk intervention based on orthogeriatric comprehensive care is the most effective strategy for preventing postoperative delirium in geriatric patients with hip fractures.

BackgroundNon-small cell lung cancer (NSCLC) driven by MET exon 14 skipping (METex14) occurs in 3-4% of NSCLC cases and defines a subset of patients with distinct characteristics. While MET targeted therapy has led to strong clinical results in METex14 patients, acquired drug resistance seemed to be unavoidable during treatment. Limited information is available regarding acquired resistance during MET targeted therapy, nor has there been any report on such patient-derived xenografts (PDXs) model facilitating the research.MethodsWe describe a patient case harboring METex14 who exhibited drug resistance after treatment with crizotinib. Subcutaneous xenografts were generated from pretreatment and post-resistance patient specimens. PDX mice were then treated with MET inhibitors (crizotinib and tepotinib) and EGFR-MET bispecific antibodies (EMB-01 and amivantamab) to evaluate their drug response in vivo. DNA and RNA sequencing analysis was performed on patient tumor specimens and matching xenografts.ResultsPDXs preserved most of the histological and molecular profiles of the parental tumors. Drug resistance to MET targeted therapy was confirmed in PDX models through in vivo drug analysis. Newly acquired MET D1228H mutations and EGFR amplificated were detected in patient-resistant tumor specimens. Although the mutations were not detected in the PDX, EGFR overexpression was observed in RNA sequencing analysis indicating possible off-target resistance through the EGFR bypass signaling pathway. As expected, EGFR-MET bispecific antibodies overcome drug resistant in the PDX model.ConclusionsWe detected a novel MET splice site deletion mutation that could lead to METex14. We also established and characterized a pair of METex14 NSCLC PDXs, including the first crizotinib resistant METex14 PDX. And dual inhibition of MET and EGFR might be a therapeutic strategy for EGFR-driven drug resistance METex14 lung cancer.

Copyright of Journal of Medical Biochemistry is the property of Society of Medical Biochemists of Serbia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Medroxyprogesterone acetate (MPA) is the main conservative treatment for endometrial cancer (EC) patients desirable to preserve fertility and those who cannot suffer from surgery. Considering the high incidence of progestin resistance and recurrence of MPA treatment, we reproposed antipsychotics chlorpromazine (CPZ) as a new strategy for both progestin-sensitive and -resistant endometrial cancer. Cytobiology experiments indicated that CPZ could significantly suppress proliferation, migration/invasion and induce apoptosis in Ishikawa (ISK) and KLE EC cell lines. And xenograft mouse models were constructed to validate the antitumor effect and toxicity of CPZ in-vivo. CPZ inhibited the growth at a low dose of 3mg/kg and the mice exhibited no signs of toxicity. Next, concomitant treatment and sequential treatment with CPZ and MPA were proceeded to analysis the synergistic effect in EC cells. Concomitant treatment only performed a limited synergistic effect on apoptosis in ISK and KLE cells. Nevertheless, sequential treatment showed favorable synergistic effects in progestin-resistant KLE cells. Finally, a stable MPA-resistant cell line shRNA was established to explore the mechanism of CPZ reversing progestin resistance. Immunoblot data showed that CPZ inhibited the activation of PI3K/AKT signal in ISK and KLE cells and upregulated PRB expression in progestin-resistant cells, by which CPZ overcame progestin resistance to MPA. Thus, CPZ might act as a candidate drug for conservative treatment and sequential treatment with CPZ and MPA could be a suitable therapeutic option for progestin resistant patients.

We sought develop and characterize a diet-induced model of metabolic syndrome and its related diseases.The experimental animals (Spague-Dawley rats) were randomly divided into two groups, and each group was fed a different feed for 48 weeks as follows: 1) standard control diet (SC), and 2) a high sucrose and high fat diet (HSHF). The blood, small intestine, liver, pancreas, and adipose tissues were sampled for analysis and characterization.Typical metabolic syndrome (MS), non-alcoholic fatty liver disease (NAFLD), and type II diabetes (T2DM) were common in the HSHF group after a 48 week feeding period. The rats fed HSHF exhibited signs of obesity, dyslipidemia, hyperglycaemia, glucose intolerance, and insulin resistance (IR). At the same time, these animals had significantly increased levels of circulating LPS, TNFα, and IL-6 and increased ALP in their intestinal tissue homogenates. These animals also showed a significant reduction in the expression of occluding protein. The HSHF rats showed fatty degeneration, inflammation, fibrosis, cirrhosis, and lipid accumulation when their liver pathologies were examined. The HSHF rats also displayed increased islet diameters from 12 to 24 weeks, while reduced islet diameters occurred from 36 to 48 weeks with inflammatory cell infiltration and islet fat deposition. The morphometry of adipocytes in HSHF rats showed hypertrophy and inflammatory cell infiltration. HSHF CD68 analysis showed macrophage infiltration and significant increases in fat and pancreas size. HSHF Tunel analysis showed significant increases in liver and pancreas cell apoptosis.This work demonstrated the following: 1) a characteristic rat model of metabolic syndrome (MS) can be induced by a high sucrose and high fat diet, 2) this model can be used to research metabolic syndrome and its related diseases, such as NAFLD and T2DM, and 3) intestinal endotoxemia (IETM) may play an important role in the pathogenesis of MS and related diseases, such as NAFLD and T2DM.

Translationally controlled tumor protein (TCTP) is an abundant protein that is highly conserved in eukaryotes. However, its primary function is still not clear. Human TCTP interacts with the metazoan-specific eukaryotic elongation factor 1Bδ (eEF1Bδ) and inhibits its guanine nucleotide exchange factor (GEF) activity, but the structural mechanism remains unknown. The interaction between TCTP and eEF1Bδ was investigated by NMR titration, structure determination, paramagnetic relaxation enhancement, site-directed mutagenesis, isothermal titration calorimetry, and HADDOCK docking. We first demonstrated that the catalytic GEF domain of eEF1Bδ is not responsible for binding to TCTP but rather a previously unnoticed central acidic region (CAR) domain in eEF1Bδ. The mutagenesis data and the structural model of the TCTP-eEF1Bδ CAR domain complex revealed the key binding residues. These residues are highly conserved in eukaryotic TCTPs and in eEF1B GEFs, including the eukaryotically conserved eEF1Bα, implying the interaction may be conserved in all eukaryotes. Interactions were confirmed between TCTP and the eEF1Bα CAR domain for human, fission yeast, and unicellular photosynthetic microalgal proteins, suggesting that involvement in protein translation through the conserved interaction with eEF1B represents a primary function of TCTP. [ABSTRACT FROM AUTHOR]

Background: Ceramide accumulation is considered a contributing factor to neuronal dysfunction and damage. However, the underlying mechanisms that occur following ischemic insult are still unclear.Methods: In the present study, we established cerebral ischemia models using four-vessel occlusion and oxygen-glucose deprivation methods. The hippocampus neural cells were subjected to immunohistochemistry and immunofluorescence staining for ceramide and neutral sphingomyelinase 2 (nSMase2) levels; immunoprecipitation and immunoblot analysis for nSMase2, receptor for activated C kinase 1 (RACK1), embryonic ectoderm development (EED), p38 mitogen-activated protein kinase (p38MAPK) and phosphorylated p38MAPK expression; SMase assay for nSMase and acid sphingomyelinase (aSMase) activity; real-time reverse transcription polymerase chain reaction for cytokine expression; and Nissl, microtubule-associated protein 2 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining.Results: We found considerable production of ceramide in astrocytes, but not in neurons, during early cerebral ischemia. This was accompanied by the induction of nSMase (but not aSMase) activity in the rat hippocampi. The inhibition of nSMase2 activity effectively reduced ceramide accumulation in astrocytes and alleviated neuronal damage to some extent. Meanwhile, the expression levels of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6, were found to be upregulated, which may have played an import role in neuronal damage mediated by the nSMase2/ceramide pathway. Although enhanced binding of nSMase2 with RACK1 and EED were also observed after cerebral ischemia, nSMase2 activity was not blocked by the TNF-α receptor inhibitor through RACK1/EED signaling. p38MAPK, but not protein kinase Cζ or protein phosphatase 2B, was able to induce nSMase2 activation after ischemia. p38MAPK can be induced by A2B adenosine receptor (A2BAR) activity.Conclusions: These results indicate that the inhibition of ceramide production in astrocytes by targeting A2BAR/p38MAPK/nSMase2 signaling may represent a viable approach for attenuating inflammatory responses and neuronal damage after cerebral ischemia. [ABSTRACT FROM AUTHOR]

Background: The inactivation of c-Jun N-terminal kinase (JNK) is associated with anti-apoptotic and anti-inflammatory effects in cerebral ischemia, which can be induced by an imbalance between upstream phosphatases and kinases. Result: Mitogen-activated protein kinase phosphatase 7 (MKP-7) was upregulated significantly at 4 h of reperfusion postischemia in rat hippocampi. By administration of cycloheximide or siRNA against mitogen-activated protein kinase phosphatase 7 (MKP-7) in a rat model of ischemia/reperfusion, an obvious enhancement of JNK activity was observed in 4 h of reperfusion following ischemia, suggesting MKP-7 was involved in JNK inactivation after ischemia. The subcellular localization of MKP-7 altered after ischemia, and the inhibition of MKP-7 nuclear export by Leptomycin B up-regulated JNK activity. Although PI3K/Akt inhibition could block downregulation of JNK activity through SEK1 and MKK-7 activation, PI3K/Akt activity was not associated with the regulation of JNK by MKP-7. Conclusions: MKP-7, independently of PI3K/Akt pathway, played a key role in downregulation of JNK activity after ischemia in the rat hippocampus, and the export of MKP-7 from the nucleus was involved in downregulation of cytoplasmic JNK activity in response to ischemic stimuli. [ABSTRACT FROM AUTHOR]

Heat shock protein 70 (Hsp70) proteins are a family of ancient and conserved chaperones. Cysteine modifications have been widely detected among different Hsp70 family members in vivo, but their effects on Hsp70 structure and function are unclear. Here, we treated HeLa cells with diamide, which typically induces disulfide bond formation except in the presence of excess GSH, when glutathionylated cysteines predominate. We show that in these cells, HspA1A (hHsp70) undergoes reversible cysteine modifications, including glutathionylation, potentially at all five cysteine residues. In vitro experiments revealed that modification of cysteines in the nucleotide-binding domain of hHsp70 is prevented by nucleotide binding but that Cys-574 and Cys-603, located in the C-terminalα-helical lid of the substratebinding domain, can undergo glutathionylation in both the presence and absence of nucleotide. We found that glutathionylation of these cysteine residues results in unfolding of the α-helical lid structure. The unfolded region mimics substrate by binding to and blocking the substrate-binding site, thereby promoting intrinsic ATPase activity and competing with binding of external substrates, including heat shock transcription factor 1 (Hsf1). Thus, post-translational modification can alter the structure and regulate the function of hHsp70. [ABSTRACT FROM AUTHOR]

The allosteric coupling of the highly conserved nucleotideand substrate-binding domains of Hsp70 has been studied intensively. In contrast, the role of the disordered, highly variable C-terminal region of Hsp70 remains unclear. In many eukaryotic Hsp70s, the extreme C-terminal EEVD motif binds to the tetratricopeptide-repeat domains of Hsp70 co-chaperones. Here, we discovered that the TVEEVD sequence of Saccharomyces cerevisiae cytoplasmic Hsp70 (Ssa1) functions as a SUMO-interacting motif. A second C-terminal motif of ~15 amino acids between the α-helical lid and the extreme C terminus, previously identified in bacterial and eukaryotic organellar Hsp70s, is known to enhance chaperone function by transiently interacting with folding clients. Using structural analysis, interaction studies, fibril formation assays, and in vivo functional assays, we investigated the individual contributions of the α-helical bundle and the C-terminal disordered region of Ssa1 in the inhibition of fibril formation of the prion protein Ure2. Our results revealed that although the α-helical bundle of the Ssa1 substrate-binding domain (SBDα) does not directly bind to Ure2, the SBDα enhances the ability of Hsp70 to inhibit fibril formation. We found that a 20-residue C-terminal motif in Ssa1, containing GGAP and GGAP-like tetrapeptide repeats, can directly bind to Ure2, the Hsp40 co-chaperone Ydj1, and α-synuclein, but not to the SUMO-like protein SMT3 or BSA. Deletion or substitution of the Ssa1 GGAP motif impaired yeast cell tolerance to temperature and cell-wall damage stress. This study highlights that the C-terminal GGAP motif of Hsp70 is important for substrate recognition and mediation of the heat shock response. [ABSTRACT FROM AUTHOR]

Double-stranded RNA-dependent protein kinase (PKR), an intracellular pathogen recognition receptor, is involved both in insulin resistance in peripheral tissues and in downregulation of pancreatic β-cell function in a kinase-dependent manner, indicating PKR as a core component in the progression of type 2 diabetes. PKR also acts as an adaptor protein via its protein-binding domain. Here, the PKR protein-binding function promoted β-cell proliferation without its kinase activity, which is associated with enhanced physical interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF6. In addition, the transcription of the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-dependent survival gene c-Myc was upregulated significantly and is necessary for proliferation. Upregulation of the PKR protein-binding function induced the NF-κB pathway, as observed by dose-dependent degradation of IκBα, induced nuclear translocation of p65 and elevated NF-κB-dependent reporter gene expression. NF-κB-dependent reporter activity and β-cell proliferation both were suppressed by TRAF2-siRNA, but not by TRAF6-siRNA. TRAF2-siRNA blocked the ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1) induced by PKR protein binding. Furthermore, RIP1-siRNA inhibited β-cell proliferation. Proinflammatory cytokines (TNFα) and glucolipitoxicity also promoted the physical interaction of PKR with TRAF2. Collectively, these data indicate a pivotal role for PKR's protein-binding function on the proliferation of pancreatic β cells through TRAF2/RIP1/NF-κB/c-Myc pathways. Therapeutic opportunities for type 2 diabetes may arise when its kinase catalytic function, but not its protein-binding function, is downregulated. [ABSTRACT FROM AUTHOR]

Background: Medical education has evolved rapidly, with the development of flipped classrooms and team-based learning based on lecture-based learning, but the novel model of combining flipped classrooms with team-based learning has been poorly investigated in orthopedic education., Methods: A femoral neck fracture teaching mode was chosen to 109 clinical internship students to explore the effectiveness of flipped classroom combined with team-based learning in internship education. They were enrolled and randomly divided into either the flipped classroom combined with team-based learning group (FTG, n = 55) or the traditional lecture-based classroom group (n = 54). All students completed the learning according to the course flow and took before-class and after-class tests. The questionnaires were used to compare students perceptions and satisfaction with the different teaching methods and were utilized to assess the strengths and weaknesses of the 2 groups., Results: The post-class test scores of both groups significantly improved compared to pre-class test scores. Regarding the post-class test scores, FTG's was significantly higher than the traditional lecture-based classroom group's, mainly in clinical areas such as imaging analysis, fracture classification, treatment options, and management of postoperative complications, but there was no significant difference in the mastery of basic theoretical knowledge. The students were more satisfied with the FTG and believed that it improved their various competencies, but with significantly more time spent., Conclusion: FTG is generally recognized as a promising option for training clinical interns and is worth spreading as it has outstanding merits in developing students clinical competence., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

There are three traditional surgical approaches to hemiarthroplasty (HA) for femoral neck fractures, respectively, the anterior approach (AA), the lateral approach (LA) and the posterior approach (PA). However, the optimum approach is still controversial, the purpose of this meta-analysis is to identify the merits and demerits of all three approaches. All clinical published studies in PubMed, Web of Science, Embase, and the Cochrane Library from January 2000 to April 2022 were searched which compared different surgical approaches and covered surgery-related outcomes and frequent complications. Five randomized controlled trials and 26 cohort studies for a total of 31 clinical trials were included in the meta-analysis. The dislocation of PA was significantly higher than LA (OR: 3.00 95% CI: 2.25-4.01 I 2  = 27% P  < 0.00001) and AA (OR: 6.61 95% CI: 2.28-19.13 I 2  = 0% P  = 0.0005); PA was substantially more than LA in terms of risk of postoperative reoperation ( P  < 0.05); meanwhile, AA has markedly shorter hospital length of stays than LA. The remaining items showed no significant differences in the results.The results of this meta-analysis demonstrated that the risk of PA dislocation and reoperation is higher with hemiarthroplasty, and AA has markedly shorter hospital length of stays than LA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Shuai, Huiwen, Shihao, Fangyuan, Juehua and Jun.)