Mitochondrial dysfunction is a critical factor in the pathogenesis of Alzheimer's disease (AD). The mitochondrial contact site and cristae organizing system (MICOS) plays a pivotal role in shaping the inner mitochondrial membrane, forming cristae junctions and establishing interaction sites between the inner and outer mitochondrial membranes and thereby serving as a cornerstone of mitochondrial structure and function. In the past decade, MICOS abnormalities have been extensively linked to AD pathogenesis. In particular, dysregulated expression of MICOS subunits and mutations in MICOS-related genes have been identified in AD, often in association with hallmark pathological features such as amyloid-β plaque accumulation, neurofibrillary tangle formation, and neuronal apoptosis. Furthermore, MICOS subunits interact with several etiologically relevant proteins, significantly influencing AD progression. The intricate crosstalk between these proteins and MICOS subunits underscores the relevance of MICOS dysfunction in AD. Therapeutic strategies targeting MICOS subunits or their interacting proteins may offer novel approaches for AD treatment. In the present review, we introduce current understanding of MICOS structures and functions, highlight MICOS pathogenesis in AD, and summarize the available MICOS-targeting drugs potentially useful for AD.

Perineural invasion (PNI) by tumor cells is a key phenotype of highly-invasive oral squamous cell carcinoma (OSCC). Since Schwann cells (SCs) and fibroblasts maintain the physiological homeostasis of the peripheral nervous system, and we have focused on cancer-associated fibroblasts (CAFs) for decades, it's imperative to elucidate the impact of CAFs on SCs in PNI⁺ OSCCs. We describe a disease progression-driven shift of PNI^- towards PNI⁺ during the progression of early-stage OSCC (31%, n = 125) to late-stage OSCC (53%, n = 97), characterized by abundant CAFs and nerve demyelination. CAFs inhibited SC proliferation/migration and reduced neurotrophic factors and myelin in vitro, and this involved up-regulated ER stress and decreased MAPK signals. Moreover, CAFs also aggravated the paralysis of the hind limb and PNI in vivo. Unexpectedly, leukemia inhibitory factor (LIF) was exclusively expressed on CAFs and up-regulated in metastatic OSCC. The LIF inhibitor EC330 restored CAF-induced SC inactivation. Thus, OSCC-derived CAFs inactivate SCs to aggravate nerve injury and PNI development.
Schwann Cells/metabolism* ; Mouth Neoplasms/metabolism* ; Humans ; Cancer-Associated Fibroblasts/metabolism* ; Animals ; Carcinoma, Squamous Cell/metabolism* ; Neoplasm Invasiveness/pathology* ; Male ; Female ; Mice ; Cell Movement/physiology* ; Cell Proliferation/physiology* ; Cell Line, Tumor ; Leukemia Inhibitory Factor/metabolism* ; Middle Aged

Objective:To analyze the clinical characteristics of a patient with Short rib-polydactyly syndrome type 6 (SRTD6) with long-term misdiagnosis, and improve its clinical recognition by reviewing the relevant literature.Methods:A patient presented at the Children′s Hospital Affiliated to Zhejiang University School of Medicine on August 19, 2024 for the discovery of liver dysfunction for 13 years and vision loss for 9 years was selected as the study subject. Her medical history, clinical data, laboratory findings and results of imaging examination were collected. High-throughput sequencing was carried out, and candidate variants were verified by Sanger sequencing. This study was approved by the Ethics Committee of the Hospital (Ethics No.: 2021-IRB-292).Results:The patient had long-term unexplained liver dysfunction, vision loss, and growth delay. Blood acylcarnitine and urinary organic acid analysis have failed to found any abnormality. Previous genetic testing revealed a homozygous c. 203A>C (p.Glu68Ala) missense variant in the ETFDH gene, leading to a misdiagnosis of various acyl-CoA dehydrogenase deficiencies. However, treatment with high-dose vitamin B2 showed a poor effect. Physical examination revealed small hands, short and stubby fingers, and a narrow chest. Medical imaging showed shortened bilateral ribs, a narrowed chest, and short, thick metacarpals. High-throughput sequencing has detected a pathogenic homozygous c. 1957C>T (p.R653*) nonsense variant in the NEK1 gene, confirming the diagnosis of SRTD6. Conclusion:SRTD6 is characterized by rib and sternum dysplasia as the primary skeletal deformities, which is often accompanied by multi-organ impairment. Genetic testing can facilitate the precise diagnosis.

OBJECTIVE: To analyze the clinical characteristics of a patient with Short rib-polydactyly syndrome type 6 (SRTD6) with long-term misdiagnosis, and improve its clinical recognition by reviewing the relevant literature. METHODS: A patient presented at the Children's Hospital Affiliated to Zhejiang University School of Medicine on August 19, 2024 for the discovery of liver dysfunction for 13 years and vision loss for 9 years was selected as the study subject. Her medical history, clinical data, laboratory findings and results of imaging examination were collected. High-throughput sequencing was carried out, and candidate variants were verified by Sanger sequencing. This study was approved by the Ethics Committee of the Hospital (Ethics No.: 2021-IRB-292). RESULTS: The patient had long-term unexplained liver dysfunction, vision loss, and growth delay. Blood acylcarnitine and urinary organic acid analysis have failed to found any abnormality. Previous genetic testing revealed a homozygous c.203A>C (p.Glu68Ala) missense variant in the ETFDH gene, leading to a misdiagnosis of various acyl-CoA dehydrogenase deficiencies. However, treatment with high-dose vitamin B₂ showed a poor effect. Physical examination revealed small hands, short and stubby fingers, and a narrow chest. Medical imaging showed shortened bilateral ribs, a narrowed chest, and short, thick metacarpals. High-throughput sequencing has detected a pathogenic homozygous c.1957C>T (p.R653*) nonsense variant in the NEK1 gene, confirming the diagnosis of SRTD6. CONCLUSION SRTD6 is characterized by rib and sternum dysplasia as the primary skeletal deformities, which is often accompanied by multi-organ impairment. Genetic testing can facilitate the precise diagnosis.
Humans ; Female ; Diagnostic Errors ; Short Rib-Polydactyly Syndrome/diagnosis* ; High-Throughput Nucleotide Sequencing

This study was aimed at preliminarily investigating the molecular biological functions of the PPE65 protein from Myco-bacterium tuberculosis,and providing foundational data for tuberculosis prevention and control.The basic biological properties of the PPE65 gene-encoded protein were predicted with bioinformatics tools.Sequence information for the Mycobacterium tuberculosis Rv3621c gene and PPE65 protein was retrieved from the NCBI database.The Rv3621c gene was amplified through PCR with the H37Rv genome as a template,then cloned into the pET22b(+)expression vector.The recombinant pET22b(+)-PPE65 plasmid was transformed into Escherichia coli BL21(DE3)competent cells for IPTG-induced expression.Solubility analysis,purification,and identification of the recombinant PPE65 protein were performed.BEAS-2B cells were treated with various concentrations of PPE65 protein for 24 h,and cell proliferation was assessed with CCK-8 assays.PPE65 was found to be composed of 413 amino acids and to have a molecular formula of C????H????N???O???S??,a relative molecular mass of 40 679.88,a theoretical isoelectric point of 4.60,an ali-phatic index of 81.94,and an average hydrophilicity value of 0.319,thus indicating a stable hydrophobic protein lacking signal pep-tides or transmembrane domains.Secondary structure analysis revealed 53.03%α-helix(Hh),2.66%β-sheet(Ee),and 44.31%ran-dom coil(Cc).Bioinformatics predictions identified 38 B-cell epitopes and 22 CTL/Th-cell epitopes.The full-length PPE65 gene(1 308 bp)was confirmed through double restriction enzyme digestion and sequencing,thereby validating the correct construction of the pET22b(+)-PPE65 recombinant plasmid.SDS-PAGE analysis demonstrated that the recombinant protein was found in inclusion bodies,and a single band at 43.7 kDa was observed after purification.Western blotting revealed specific binding to mouse-derived His monoclonal antibodies,thereby confirming successful expression of the PPE65 protein.BEAS-2B cells treated with a PPE65 protein concentration gradient(2.5-20 μg/mL)exhibited a dose-dependent increase in cell number.Compared with those in the PBS control group,TGF-β relative expression levels were significantly higher in all treatment groups(t2.5=4.893,P<0.001,t5.0=4.640,P<0.05,t10=7.535,P<0.05,t20=16.44,P<0.000 1).This study elucidated the structural characteristics of the PPE65 protein,successfully obtained the recombinant protein through prokaryotic expression and purification,and demonstrated its ability to promote BEAS-2B cell proliferation.The underlying mechanism might involve suppression of TGF-β/S mad signaling pathway activation.These findings provide a theoretical basis for understanding the role and regulatory mechanisms of PPE65 during M.tuberculosis infection.

This study was aimed at preliminarily investigating the molecular biological functions of the PPE65 protein from Myco-bacterium tuberculosis,and providing foundational data for tuberculosis prevention and control.The basic biological properties of the PPE65 gene-encoded protein were predicted with bioinformatics tools.Sequence information for the Mycobacterium tuberculosis Rv3621c gene and PPE65 protein was retrieved from the NCBI database.The Rv3621c gene was amplified through PCR with the H37Rv genome as a template,then cloned into the pET22b(+)expression vector.The recombinant pET22b(+)-PPE65 plasmid was transformed into Escherichia coli BL21(DE3)competent cells for IPTG-induced expression.Solubility analysis,purification,and identification of the recombinant PPE65 protein were performed.BEAS-2B cells were treated with various concentrations of PPE65 protein for 24 h,and cell proliferation was assessed with CCK-8 assays.PPE65 was found to be composed of 413 amino acids and to have a molecular formula of C????H????N???O???S??,a relative molecular mass of 40 679.88,a theoretical isoelectric point of 4.60,an ali-phatic index of 81.94,and an average hydrophilicity value of 0.319,thus indicating a stable hydrophobic protein lacking signal pep-tides or transmembrane domains.Secondary structure analysis revealed 53.03%α-helix(Hh),2.66%β-sheet(Ee),and 44.31%ran-dom coil(Cc).Bioinformatics predictions identified 38 B-cell epitopes and 22 CTL/Th-cell epitopes.The full-length PPE65 gene(1 308 bp)was confirmed through double restriction enzyme digestion and sequencing,thereby validating the correct construction of the pET22b(+)-PPE65 recombinant plasmid.SDS-PAGE analysis demonstrated that the recombinant protein was found in inclusion bodies,and a single band at 43.7 kDa was observed after purification.Western blotting revealed specific binding to mouse-derived His monoclonal antibodies,thereby confirming successful expression of the PPE65 protein.BEAS-2B cells treated with a PPE65 protein concentration gradient(2.5-20 μg/mL)exhibited a dose-dependent increase in cell number.Compared with those in the PBS control group,TGF-β relative expression levels were significantly higher in all treatment groups(t2.5=4.893,P<0.001,t5.0=4.640,P<0.05,t10=7.535,P<0.05,t20=16.44,P<0.000 1).This study elucidated the structural characteristics of the PPE65 protein,successfully obtained the recombinant protein through prokaryotic expression and purification,and demonstrated its ability to promote BEAS-2B cell proliferation.The underlying mechanism might involve suppression of TGF-β/S mad signaling pathway activation.These findings provide a theoretical basis for understanding the role and regulatory mechanisms of PPE65 during M.tuberculosis infection.

Objective:To analyze the clinical characteristics of a patient with Short rib-polydactyly syndrome type 6 (SRTD6) with long-term misdiagnosis, and improve its clinical recognition by reviewing the relevant literature.Methods:A patient presented at the Children′s Hospital Affiliated to Zhejiang University School of Medicine on August 19, 2024 for the discovery of liver dysfunction for 13 years and vision loss for 9 years was selected as the study subject. Her medical history, clinical data, laboratory findings and results of imaging examination were collected. High-throughput sequencing was carried out, and candidate variants were verified by Sanger sequencing. This study was approved by the Ethics Committee of the Hospital (Ethics No.: 2021-IRB-292).Results:The patient had long-term unexplained liver dysfunction, vision loss, and growth delay. Blood acylcarnitine and urinary organic acid analysis have failed to found any abnormality. Previous genetic testing revealed a homozygous c. 203A>C (p.Glu68Ala) missense variant in the ETFDH gene, leading to a misdiagnosis of various acyl-CoA dehydrogenase deficiencies. However, treatment with high-dose vitamin B2 showed a poor effect. Physical examination revealed small hands, short and stubby fingers, and a narrow chest. Medical imaging showed shortened bilateral ribs, a narrowed chest, and short, thick metacarpals. High-throughput sequencing has detected a pathogenic homozygous c. 1957C>T (p.R653*) nonsense variant in the NEK1 gene, confirming the diagnosis of SRTD6. Conclusion:SRTD6 is characterized by rib and sternum dysplasia as the primary skeletal deformities, which is often accompanied by multi-organ impairment. Genetic testing can facilitate the precise diagnosis.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective To investigate the effect of blood flow restriction combined with low-intensity plyometric jump training(LI-PJT+BFR)on lower limb dynamic postural control of functional ankle instability(FAI)in college students. Methods From March to May,2023,40 FAI college students were recruited from Xi'an Physical Education University,and randomly divided into high-intensity plyometric jump training(HI-PJT,n = 14)group,low-intensity plyomet-ric jump training(LI-PJT,n = 13)group and LI-PJT+BFR group(n = 13).All the groups finished the six-week corresponding training.The maximum voluntary isometric contraction(MVIC)of tibialis anterior,peroneus lon-gus,lateral head of gastrocnemius,gluteus maximus,vastus lateralis,biceps femoris and semitendinosus were measured,and the root mean square(RMS)of electromyography of these muscles was measured during the sin-gle-leg landing(SLL),using wireless surface electromyography before and after intervention.Moreover,they were assessed with Y-balance test and Cumberland Ankle Instability Tool(CAIT). Results MVIC and RMS of the target muscles improved after intervention in all the groups(t>2.218,P<0.05),except MVIC and RMS of peroneus longus,gluteus maximus,biceps femoris and semitendinosus in LI-PJT group,and RMS of peroneus longus in LI-PJT+BFR group;and MVIC and RMS of the target muscles were the least in LI-PJT group(F>3.262,P<0.05),except those of peroneus longus.The extension scores of Y-balance test and the total score improved after intervention(t>2.485,P<0.05),and they were the least in LI-PJT group(F>5.042,P<0.05).The CAIT score improved after intervention(t>5.227,P<0.001),and it was the least in LI-PJT group(F = 4.640,P<0.05). Conclusion LI-PJT+BFR could improve lower limb dynamic postural control of FAI college students,which is similar to HI-PJT.

OBJECTIVE: To evaluate the efficacy and safety of glyceryl phenylbutyrate (GPB) therapy for patients with Ornithine transcarbamylase deficiency (OTCD). METHODS: Two children with OTCD were selected as the study subjects, and their clinical manifestations, blood ammonia, liver enzymes, growth and development information following the treatment with GPB were retrospectively analyzed. A literature review was also carried out by searching the PubMed database for studies on the GPB treatment for urea cycle disorders. RESULTS: With the GPB treatment, the blood ammonia and liver enzyme level in both patients have decreased to the normal range within 3 months. Motor development in child 2 has improved. No adverse reaction was noted, except for transient palmar greasy smell and loss of appetite in child 1. Analysis of the literature showed that patients had lower ammonia exposure, lower annual incidence of hyperammonemic crisis, more actual protein intake and fewer adverse events during GPB treatment. CONCLUSION GPB is safe and effective for the treatment of OTCD.
Child ; Humans ; Ornithine Carbamoyltransferase Deficiency Disease/drug therapy* ; Phenylbutyrates/therapeutic use* ; Ammonia ; Retrospective Studies