Cryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn²⁺ uptake into the Golgi apparatus

クライオ電子顕微鏡により、ゴルジ体の亜鉛輸送体による亜鉛輸送機構の全容を解明 細胞の亜鉛恒常性維持機構の理解に大きな進展. 京都大学プレスリリース. 2023-08-29.Zinc ions (Zn²⁺) are vital to most cells, with the intracellular concentrations of Zn²⁺ being tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. We herein present the 2.2-3.1 Å-resolution cryo-EM structures of a Golgi-localized human Zn²⁺/H+ antiporter ZnT7 (hZnT7) in Zn²⁺-bound and unbound forms. Cryo-EM analyses show that hZnT7 exists as a dimer via tight interactions in both the cytosolic and transmembrane (TM) domains of two protomers, each of which contains a single Zn²⁺-binding site in its TM domain. hZnT7 undergoes a TM-helix rearrangement to create a negatively charged cytosolic cavity for Zn²⁺ entry in the inward-facing conformation and widens the luminal cavity for Zn²⁺ release in the outward-facing conformation. An exceptionally long cytosolic histidine-rich loop characteristic of hZnT7 binds two Zn²⁺ ions, seemingly facilitating Zn²⁺ recruitment to the TM metal transport pathway. These structures permit mechanisms of hZnT7-mediated Zn²⁺ uptake into the Golgi to be proposed

The significance of opthalmologic evaluation in the early diagnosis of inborn errors of metabolism: the Cretan experience

BACKGROUND: The Inborn Errors of Metabolism (IEM) are far from the rare systemic diseases that mainly affect the neural tissue. There are very few written reports on ocular findings in subjects with IEM, thus it was interesting to study the frequency of ocular findings in the studied population and explore their contribution to the early diagnosis of IEM. METHODS: Our study involved the evaluation of IEM suspected cases, which had been identified in a rural population in Crete, Greece. Over a period of 3 years, 125 patients, who fulfilled the inclusion criteria of this study, were examined. Analytical physical examination, detailed laboratory investigation as well as a thorough ocular examination were made. RESULTS: A diagnosis of IEM was established in 23 of the 125 patients (18.4%). Ten (43.5%) of the diagnosed IEM had ocular findings, while 8 of them (34.8%) had findings which were specific for the diagnosed diseases. One patient diagnosed with glycogenosis type 1b presented a rare finding. Of the 102 non-diagnosed patients, 53 (51.96 %) presented various ophthalmic findings, some of which could be related to a metabolic disease and therefore may be very helpful in the future. CONCLUSIONS: The ocular investigation can be extremely useful for raising the suspicion and the establishment of an early diagnosis of IEM. It could also add new findings related to these diseases. The early management of the ocular symptoms can improve the quality of life to these patients

A comparison of five partial volume correction methods for Tau and Amyloid PET imaging with [18F]THK5351 and [11C]PIB

PURPOSE: To suppress partial volume effect (PVE) in brain PET, there have been many algorithms proposed. However, each methodology has different property due to its assumption and algorithms. Our aim of this study was to investigate the difference among partial volume correction (PVC) method for tau and amyloid PET study. METHODS: We investigated two of the most commonly used PVC methods, Müller-Gärtner (MG) and geometric transfer matrix (GTM) and also other three methods for clinical tau and amyloid PET imaging. One healthy control (HC) and one Alzheimer's disease (AD) PET studies of both [(18)F]THK5351 and [(11)C]PIB were performed using a Eminence STARGATE scanner (Shimadzu Inc., Kyoto, Japan). All PET images were corrected for PVE by MG, GTM, Labbé (LABBE), Regional voxel-based (RBV), and Iterative Yang (IY) methods, with segmented or parcellated anatomical information processed by FreeSurfer, derived from individual MR images. PVC results of 5 algorithms were compared with the uncorrected data. RESULTS: In regions of high uptake of [(18)F]THK5351 and [(11)C]PIB, different PVCs demonstrated different SUVRs. The degree of difference between PVE uncorrected and corrected depends on not only PVC algorithm but also type of tracer and subject condition. CONCLUSION: Presented PVC methods are straight-forward to implement but the corrected images require careful interpretation as different methods result in different levels of recovery

Extracellular Administration of BCL2 Protein Reduces Apoptosis and Improves Survival in a Murine Model of Sepsis

Severe sepsis and septic shock are major causes of morbidity and mortality worldwide. In experimental sepsis there is prominent apoptosis of various cell types, and genetic manipulation of death and survival pathways has been shown to modulate organ injury and survival.We investigated the effect of extracellular administration of two anti-apoptotic members of the BCL2 (B-cell lymphoma 2) family of intracellular regulators of cell death in a murine model of sepsis induced by cecal ligation and puncture (CLP). We show that intraperitoneal injection of picomole range doses of recombinant human (rh) BCL2 or rhBCL2A1 protein markedly improved survival as assessed by surrogate markers of death. Treatment with rhBCL2 or rhBCL2A1 protein significantly reduced the number of apoptotic cells in the intestine and heart following CLP, and this was accompanied by increased expression of endogenous mouse BCL2 protein. Further, mice treated with rhBCL2A1 protein showed an increase in the total number of neutrophils in the peritoneum following CLP with reduced neutrophil apoptosis. Finally, although neither BCL2 nor BCL2A1 are a direct TLR2 ligand, TLR2-null mice were not protected by rhBCL2A1 protein, indicating that TLR2 signaling was required for the protective activity of extracellularly adminsitered BCL2A1 protein in vivo.Treatment with rhBCL2A1 or rhBCL2 protein protects mice from sepsis by reducing apoptosis in multiple target tissues, demonstrating an unexpected, potent activity of extracellularly administered BCL2 BH4-domain proteins

Carbonyl reductase as a significant predictor of survival and lymph node metastasis in epithelial ovarian cancer

We have recently reported a novel function for carbonyl reductase (CR), namely, its ability to modulate the metastatic potential of malignant mouse cells. Because there are currently no data addressing a similar function for CR in human cancers, the aim of this study was to assess a correlation between survival and metastasis, and CR level in epithelial ovarian cancer. Using anti-CR antibody, immunohistochemical staining was performed on 73 epithelial ovarian cancers, 13 borderline malignant tumours, and 25 benign ovarian tumours for a total of 111 specimens. The combined rate for strongly and weakly positive reactions for CR was 32.0% for benign tumours, 38.5% for borderline malignant tumours, and 61.6% for ovarian cancers. The CR-positive rate was 35.7% (weakly positive alone) for ovarian cancers with retroperitoneal lymph node (RLN) metastasis and 67.8% for those without RLN metastasis (P< 0.05). The 5-year survival rate was 62.7% for the patients with CR-negative cancer and 86.1% for those with CR-positive cancer (P< 0.05). The present results indicate that decreased CR expression in epithelial ovarian cancer is associated with RLN metastasis and poor survival.© 2001 Cancer Research Campaignhttp://www.bjcancer.co

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches

Monophasic synovial sarcoma of the pharynx: a case report

Synovial sarcomas are a rare form of soft tissue sarcomas. We present a case of a 62 year-old male presenting with a left thyroid lump initially though to be a thyroid adenoma but subsequently diagnosed as a monophasic synovial sarcoma of the pharynx. We discuss the diagnosis and treatment of this case

The Effects of Host-Feeding on Synovigenic Egg Development in An Endoparasitic Wasp, Itoplectis naranyae

Many adult parasitoids feed on host insects, a behavior known as host-feeding. Feeding on hosts is essential to maximizing female fecundity, but its contribution to reproduction varies from species to species. The relationship between fecundity and host-feeding was examined in the solitary endoparasitoid wasp Itoplectis naranyae Ashmead, (Hymenoptera: Ichneumonidae) to assess the significance of host-feeding in female reproduction. Adult female wasps did not respond to hosts when they were 0–1 days old, but subsequently increased their oviposition and host-feeding activities with increasing female age. While newly emerging females had no mature eggs in their ovary, the number of mature eggs increased rapidly thereafter, a process termed synovigeny. Female wasps were capable of maturing eggs without host-feeding, and this suggested that they produced a certain portion of eggs from nutritional reserves that had been stored during the larval stage. Behavioral observations revealed that I. naranyae was a destructive host-feeder as the host was damaged during feeding. Female fecundity was greater in females that had previously fed on hosts than those did not, indicating that host-feeding was involved in egg production. There was a time-delayed relation between host-feeding events and additional egg production; at least 3 days were required to mature eggs from nutrients gained via feeding on hosts. The significance of host-feeding in I. naranyae reproduction is discussed in the context of its life history traits

The Flavonoid Luteolin Inhibits Fcγ-Dependent Respiratory Burst in Granulocytes, but Not Skin Blistering in a New Model of Pemphigoid in Adult Mice

Bullous pemphigoid is an autoimmune blistering skin disease associated with autoantibodies against the dermal-epidermal junction. Passive transfer of antibodies against BP180/collagen (C) XVII, a major hemidesmosomal pemphigoid antigen, into neonatal mice results in dermal-epidermal separation upon applying gentle pressure to their skin, but not in spontaneous skin blistering. In addition, this neonatal mouse model precludes treatment and observation of diseased animals beyond 2–3 days. Therefore, in the present study we have developed a new disease model in mice reproducing the spontaneous blistering and the chronic course characteristic of the human condition. Adult mice were pre-immunized with rabbit IgG followed by injection of BP180/CXVII rabbit IgG. Mice pre-immunized against rabbit IgG and injected 6 times every second day with the BP180/CXVII-specific antibodies (n = 35) developed spontaneous sustained blistering of the skin, while mice pre-immunized and then treated with normal rabbit IgG (n = 5) did not. Blistering was associated with IgG and complement C3 deposits at the epidermal basement membrane and recruitment of inflammatory cells, and was partly dependent on Ly-6G-positive cells. We further used this new experimental model to investigate the therapeutic potential of luteolin, a plant flavonoid with potent anti-inflammatory and anti-oxidative properties and good safety profile, in experimental BP. Luteolin inhibited the Fcγ-dependent respiratory burst in immune complex-stimulated granulocytes and the autoantibody-induced dermal-epidermal separation in skin cryosections, but was not effective in suppressing the skin blistering in vivo. These studies establish a robust animal model that will be a useful tool for dissecting the mechanisms of blister formation and will facilitate the development of more effective therapeutic strategies for managing pemphigoid diseases