LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion.

Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.

[Analysis of Short-Term Results after Introduction of Robotic Gastrectomy for Gastric Cancer at Our Hospital].

BACKGROUND: Robotic gastrectomy(RG)for gastric cancer(GC)has been covered by health insurance since 2018. In this study, we examined the results of RG for GC at our hospital during the initial period of its introduction. MATERIALS AND METHOD: From August 2022 to May 2023, we retrospectively examined the surgical outcomes and short-term postoperative outcomes of the first 9 patients who underwent RG for GC at our hospital. RESULTS: The median patient age was 77(67-82) years, gender was 4 males and 5 females, and distal gastrectomy was performed in all patients. The median operative time was 410(323-486)min, blood loss was 5(1-140)mL, postoperative hospital stay was less than 9 days in all patients, and there was no conversion to laparoscopic or open surgery. There were no postoperative complications of Clavien-Dindo Grade Ⅱ or above. CONCLUSION: In this study, RG for GC was performed safely without intraoperative or postoperative complications.

Catalytic isoforms of AMP-activated protein kinase differentially regulate IMPDH activity and photoreceptor neuron function.

AMP-activated protein kinase (AMPK) plays a crucial role in maintaining ATP homeostasis in photoreceptor neurons. AMPK is a heterotrimeric protein consisting of α, ß, and γ subunits. The independent functions of the 2 isoforms of the catalytic α subunit, PRKAA1 and PRKAA2, are uncharacterized in specialized neurons, such as photoreceptors. Here, we demonstrate in mice that rod photoreceptors lacking PRKAA2, but not PRKAA1, showed altered levels of cGMP, GTP, and ATP, suggesting isoform-specific regulation of photoreceptor metabolism. Furthermore, PRKAA2-deficient mice displayed visual functional deficits on electroretinography and photoreceptor outer segment structural abnormalities on transmission electron microscopy consistent with neuronal dysfunction, but not neurodegeneration. Phosphoproteomics identified inosine monophosphate dehydrogenase (IMPDH) as a molecular driver of PRKAA2-specific photoreceptor dysfunction, and inhibition of IMPDH improved visual function in Prkaa2 rod photoreceptor-knockout mice. These findings highlight a therapeutically targetable PRKAA2 isoform-specific function of AMPK in regulating photoreceptor metabolism and function through a potentially previously uncharacterized mechanism affecting IMPDH activity.

NAD+ precursors and bile acid sequestration treat preclinical refractory environmental enteric dysfunction.

Environmental enteric dysfunction (EED) is a diffuse small bowel disorder associated with poor growth, inadequate responses to oral vaccines, and nutrient malabsorption in millions of children worldwide. We identify loss of the small intestinal Paneth and goblet cells that are critical for innate immunity, reduced villous height, increased bile acids, and dysregulated nicotinamide adenine dinucleotide (NAD+) synthesis signaling as potential mechanisms underlying EED and which also correlated with diminished length-for-age z score. Isocaloric low-protein diet (LPD) consumption in mice recapitulated EED histopathology and transcriptomic changes in a microbiota-independent manner, as well as increases in serum and fecal bile acids. Children with refractory EED harbor single-nucleotide polymorphisms in key enzymes involved in NAD+ synthesis. In mice, deletion of Nampt, the gene encoding the rate-limiting enzyme in the NAD+ salvage pathway, from intestinal epithelium also reduced Paneth cell function, a deficiency that was further aggravated by LPD. Separate supplementation with NAD+ precursors or bile acid sequestrant partially restored LPD-associated Paneth cell defects and, when combined, fully restored all histopathology defects in LPD-fed mice. Therapeutic regimens that increase protein and NAD+ contents while reducing excessive bile acids may benefit children with refractory EED.

Synthesis of sound field from moving complex sources with arbitrary trajectories by linear and spherical loudspeaker arrays.

The spectral division method (SDM) and near-field compensated higher order ambisonics (NFC-HOA) are sound field synthesis techniques based on the spatial Fourier representation of sound fields. Previous studies have derived the driving functions of SDM for sound field synthesis with consideration to uniformly moving point sources and moving point sources with arbitrary trajectories. However, the driving functions of NFC-HOA for synthesizing sound fields from moving sound sources have not been proposed to date. For a more realistic auditory experience, the synthesis of a sound field produced by a moving sound source with a complex radiation property is required. This study focused on deriving the driving functions for synthesizing sound fields produced by moving sound sources with arbitrary trajectories and radiation properties. Sound fields were formulated in the angular spectrum and spherical harmonic domains and applied to SDM and NFC-HOA, respectively. Numerical and measurement experiments were conducted to evaluate the proposed method. The results reveal that the proposed method can synthesize the desired sound fields.

Adipocyte NMNAT1 expression is essential for nuclear NAD+ biosynthesis but dispensable for regulating thermogenesis and whole-body energy metabolism.

Nicotinamide adenine dinucleotide (NAD+) functions as an essential cofactor regulating a variety of biological processes. The purpose of the present study was to determine the role of nuclear NAD+ biosynthesis, mediated by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), in thermogenesis and whole-body energy metabolism. We first evaluated the relationship between NMNAT1 expression and thermogenic activity in brown adipose tissue (BAT), a key organ for non-shivering thermogenesis. We found that reduced BAT NMNAT1expression was associated with inactivation of thermogenic gene program induced by obesity and thermoneutrality. Next, we generated and characterized adiponectin-Cre-driven adipocyte-specific Nmnat1 knockout (ANMT1KO) mice. Loss of NMNAT1 markedly reduced nuclear NAD+ concentration by approximately 70% in BAT. Nonetheless, adipocyte-specific Nmnat1 deletion had no impact on thermogenic (rectal temperature, BAT temperature and whole-body oxygen consumption) responses to ß-adrenergic ligand norepinephrine administration and acute cold exposure, adrenergic-mediated lipolytic activity, and metabolic responses to obesogenic high-fat diet feeding. In addition, loss of NMNAT1 did not affect nuclear lysine acetylation or thermogenic gene program in BAT. These results demonstrate that adipocyte NMNAT1 expression is required for maintaining nuclear NAD+ concentration, but not for regulating BAT thermogenesis or whole-body energy homeostasis.

[A Case of Hepatocellular Carcinoma with Haemobilia after Transcatheter Hepatic Arterial Embolization for Tumor Rupture].

A 79-year-old man was scheduled for surgery for hepatocellular carcinoma(HCC)after transcatheter hepatic arterial embolization for rupture. Two weeks before surgery, the patient came to our hospital with a chief complaint of back pain. First, we performed biliary drainage, under the diagnosis of HCC with obstructive jaundice due to haemobilia. Hepatectomy was performed when the patient's condition stabilized. It should be kept in mind that haemobilia may occur after TAE for HCC with bile duct tumor thrombus, and appropriate treatment should be performed when bleeding occurs.

[A Case of Colon Metastasis from Gastric Cancer Treated by Laparoscopic-Assisted Segmental Colectomy].

We report a case of colon metastasis from gastric cancer treated by laparoscopic-assisted segmental colectomy. An 81-year-old man was undergone distal gastrectomy, D2 dissection and Billroth Ⅰ reconstruction for gastric cancer 3 years previously, with a final diagnosis of gastric cancer L, Post, Type 2, sig/por2, pT4a(SE), pN3b(30/56), H0, P0, M0, pStage ⅢC. Three years after gastrectomy, CT scan showed an elevated lesion in the transverse colon, which was suspected to be metastatic colorectal cancer on closer examination. As no metastatic lesions were found other than the tumor of transverse colon, we performed laparoscopic-assisted segmental colon resection. A small incision was placed in the umbilical region, and the transverse colon was extracted from the umbilical region after dissection of the adhesions by single-incision laparoscopic surgery. The transverse colon containing the mass lesion was partially resected extracorporeally and reconstructed with a functional end-to-end anastomosis. The postoperative pathological findings revealed tumor cells predominantly below the submucosal layer and partly showing the signet ring cell carcinoma, and the transvers colon tumor was diagnosed as a metastasis from gastric cancer. The postoperative course was uneventful and the patient was discharged 8 days after surgery, and is alive for 10 months after the segmental colon resection followed by chemotherapy.

[A Case of Recurrent Esophageal Cancer with Long-Term Survival Treated by S-1 Monotherapy].

We report a case of recurrent esophageal cancer with long-term survival treated by S-1 monotherapy. A 66-year-old man underwent subtotal esophagectomy, two-field lymphadenectomy after 2 courses of DCF chemotherapy for esophageal cancer 1 year earlier. The final diagnosis was esophageal cancer, Lt, CT-Type 2, ypT3, ypN0(0/62), M0, ypStage Ⅲ. At 6 months after esophagectomy, CT scan revealed mediastinal lymph node metastasis and pleural dissemination, and paclitaxel monotherapy was performed, but lymph node re-enlargement was observed on CT at 12 months after esophagectomy. Chemotherapy with S-1 monotherapy was performed, and 3 months after initiation of S-1 monotherapy, CT showed reduced lymph node metastases and pleural dissemination remained reduced. Adverse events were CTCAE v5.0 Grade 2 thrombocytopenia and diarrhoea, but no Grade 3 or higher adverse events were observed. Long-term survival was achieved with no disease progression for more than 2.5 years after initiation of S-1 monotherapy.

Computational reduction of the spectral division method for synthesizing moving sources by source trajectory approximation.

This paper proposes a method to reduce the computational cost of the spectral division method that synthesizes moving sources. The proposed method consists of two approximations: that of the secondary source driving function and that of the trajectory of the moving sources. Combining these two approximations simplifies the integral calculations that traditionally appear in the driving functions, replacing them with a correction of the frequency magnitude and phase of the source signals. Numerical simulations and subjective experiments show that the computational cost can be reduced by a factor of 50-100 compared to the conventional method without significantly affecting the synthesized sound field and the sense of localization.

[A Rare Case of Advanced Gastric Cancer with Duodenal Intramural Metastasis].

Here we report the case of a patient with advanced gastric cancer who presented with duodenal intramural metastasis based on the pathological results after surgery. The patient was 78-year-old female, who was referred to our department for further evaluation and treatment of upper abdominal pain. An upper gastrointestinal series demonstrated a tumor occupying the lesser curvature of the gastric body. Biopsy specimens from the tumor demonstrated moderately to poorly differentiated adenocarcinoma. A computed tomography scan showed thickening of the gastric wall and swelling of the regional lymph nodes. The patient underwent distal gastrectomy and D2 lymph node dissection for gastric cancer. A histopathological examination disclosed that the gastric tumor was poorly differentiated adenocarcinoma with severe lymphatic permeation and also demonstrated the other poorly differentiated adenocarcinoma occupying the part of the muscularis propria layer of the duodenum. The gastric tumor was not contiguous with the duodenal tumor, and the duodenal cancer cells had the same pathological characteristics as the primary gastric cancer cells; therefore, we diagnosed the duodenal tumor as an intramural metastasis from gastric cancer. The patient's disease was staged as pT4aN3bM1, Stage Ⅳ according to the TNM classification. We report this rare case along with a discussion of the literature.

[A Case of Sigmoid Rectal Cancer with a Vesicoconstrictor Fistula Curatively Resected after Neoadjuvant Chemotherapy].

A 50-year-old man presented with fecaluria and was diagnosed with sigmoid colon cancer with a colovesical fistula. Total bladder resection was determined to be necessary for curative resection at the time of diagnosis. In anticipation of bladder preservation, 6 courses of mFOLFOX6 plus panitumumab were administered after transverse colostomy, resulting in marked tumor regression and a decision to proceed with surgery. The patient underwent robotic-assisted low anterior resection of the rectum and partial cystectomy, which yielded pathological radical treatment. We report a case of sigmoid colon cancer with a colovesical fistula complicated by bladder invasion, in which preoperative chemotherapy was effective and total cystectomy was avoided, allowing bladder preservation.

A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication.

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in MpzT124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along MpzT124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the MpzT124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons.

A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model.

Charcot-Marie-Tooth disease type 2A (CMT2A) is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying the axonal pathology is unknown. Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1), the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration, neuromuscular junction (NMJ) abnormalities, muscle atrophy, and mitochondrial abnormalities - all hallmarks of the human disease. We generated Sarm1-KO (Sarm1-/-) and Mfn2H361Y Sarm1 double-mutant rats and found that deletion of Sarm1 rescued axonal, synaptic, muscle, and functional phenotypes, demonstrating that SARM1 was responsible for much of the neuropathology in this model. Despite the presence of mutant MFN2 protein in these double-mutant rats, loss of SARM1 also dramatically suppressed many mitochondrial defects, including the number, size, and cristae density defects of synaptic mitochondria. This surprising finding indicates that dysfunctional mitochondria activated SARM1 and that activated SARM1 fed back on mitochondria to exacerbate the mitochondrial pathology. As such, this work identifies SARM1 inhibition as a therapeutic candidate for the treatment of CMT2A and other neurodegenerative diseases with prominent mitochondrial pathology.

Macrophage depletion blocks congenital SARM1-dependent neuropathy.

Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induced inflammatory neuropathy and highlight the potential of immune therapy as a treatment for this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.

[Analysis of Short-Term Outcomes and Nutritional Assessment of Elderly Gastric Cancer Surgery Cases].

BACKGROUND: We analyzed the short-term outcomes and nutritional assessment of gastric cancer surgery patients who underwent exercise intervention after gastrectomy. MATERIALS AND METHOD: Gastric cancer patients who underwent gastrectomy at our department from January 2021 were included in the study. Postoperative exercise intervention(lower limb training) was performed in gastric cancer patients aged 75 years or older(group H: 7 patients)and compared retrospectively with gastric cancer patients younger than 75 years(group L: 10 patients)who did not receive exercise intervention. The rate of decrease in each index after 1 week was compared between the 2 groups. RESULTS: Postoperative complications(yes/no) were 3/4(42.8%)in group H and 2/8(20.0%)in group L(p=0.59); postoperative hospital stay was 11.5(10.8-21.3) days in group H and 11.0(9.0-14.0)days in group L(p=0.37). The percentage decrease in each index was as follows: for BMI in groups H/L: 2.9/5.6%(p=0.17), grip strength in groups H/L: 2.4/－7.6%(p=0.07), skeletal muscle mass in groups H/L: －2.3/7.0%(p=1.00), PNI in groups H/L: 26.6/18.1%(p=0.12). CONCLUSION: In this study, no significant differences were noted in postoperative complication rates or postoperative hospital stay between groups H and L.

Age- and sex-based changes in spike protein antibody status after SARS-CoV-2 vaccination and effect of past-infection in healthcare workers in Osaka.

OBJECTIVE: We aimed to compare the changes in SARS-CoV-2 spike protein antibody titres based on age group and sex using paired blood sampling after vaccination in association with the presence of nucleocapsid protein antibody. METHODS: All participants were healthcare workers at Yao Municipal Hospital in Osaka who voluntarily provided peripheral blood samples (n = 636, men/women 151/485, mean age 45 years). We investigated the serial changes in SARS-CoV-2 spike protein antibody titres at 1 and 7 months after the second vaccination regarding their relationship with sex and age group. At 7 months, we also examined anti-nucleocapsid assays. Antibody titres were shown as logarithmic values and the differences were assessed using a paired or unpaired student's t-test as appropriate. RESULTS: Among participants younger than 30 years, the antibody titres of spike protein were significantly higher in women one (p = 0.005) and seven (p = 0.038) months after vaccination. However, among those aged 30-49 years, the antibody titres were not different between the sexes at either follow-up time point. In contrast, among those aged 50-59 years, between-sex differences in antibody titres were observed only at 7 months, which was associated with a significant reduction in men. A significant negative correlation was observed between the antibody titres for spike protein at both time points in participants with positive nucleocapsid protein antibody at 7 months (r = - 0.467, p = 0.043), although a significant positive correlation was observed in those with negative results (r = 0.645, p < 0.001), CONCLUSIONS: Between-sex differences in SARS-CoV-2 spike protein antibody titres by paired blood sampling at different time points after vaccination depended on age group. The presence of nucleocapsid protein antibody was associated with changes in spike protein antibody titres after vaccination.

Distinct developmental and degenerative functions of SARM1 require NAD+ hydrolase activity.

SARM1 is the founding member of the TIR-domain family of NAD+ hydrolases and the central executioner of pathological axon degeneration. SARM1-dependent degeneration requires NAD+ hydrolysis. Prior to the discovery that SARM1 is an enzyme, SARM1 was studied as a TIR-domain adaptor protein with non-degenerative signaling roles in innate immunity and invertebrate neurodevelopment, including at the Drosophila neuromuscular junction (NMJ). Here we explore whether the NADase activity of SARM1 also contributes to developmental signaling. We developed transgenic Drosophila lines that express SARM1 variants with normal, deficient, and enhanced NADase activity and tested their function in NMJ development. We find that NMJ overgrowth scales with the amount of NADase activity, suggesting an instructive role for NAD+ hydrolysis in this developmental signaling pathway. While degenerative and developmental SARM1 signaling share a requirement for NAD+ hydrolysis, we demonstrate that these signals use distinct upstream and downstream mechanisms. These results identify SARM1-dependent NAD+ hydrolysis as a heretofore unappreciated component of developmental signaling. SARM1 now joins sirtuins and Parps as enzymes that regulate signal transduction pathways via mechanisms that involve NAD+ cleavage, greatly expanding the potential scope of SARM1 TIR NADase functions.

Products of gut microbial Toll/interleukin-1 receptor domain NADase activities in gnotobiotic mice and Bangladeshi children with malnutrition.

Perturbed gut microbiome development has been linked to childhood malnutrition. Here, we characterize bacterial Toll/interleukin-1 receptor (TIR) protein domains that metabolize nicotinamide adenine dinucleotide (NAD), a co-enzyme with far-reaching effects on human physiology. A consortium of 26 human gut bacterial strains, representing the diversity of TIRs observed in the microbiome and the NAD hydrolase (NADase) activities of a subset of 152 bacterial TIRs assayed in vitro, was introduced into germ-free mice. Integrating mass spectrometry and microbial RNA sequencing (RNA-seq) with consortium membership manipulation disclosed that a variant of cyclic-ADPR (v-cADPR-x) is a specific product of TIR NADase activity and a prominent, colonization-discriminatory, taxon-specific metabolite. Guided by bioinformatic analyses of biochemically validated TIRs, we find that acute malnutrition is associated with decreased fecal levels of genes encoding TIRs known or predicted to generate v-cADPR-x, as well as decreased levels of the metabolite itself. These results underscore the need to consider microbiome TIR NADases when evaluating NAD metabolism in the human holobiont.

[Analysis of Chemotherapy-Induced Nausea and Vomiting during Chemotherapy for Gastric Cancer].

BACKGROUND: Chemotherapy-induced nausea and vomiting(CINV)are typical side effects caused by chemotherapy. We analyzed CINV during first-line chemotherapy for gastric cancer. MATERIALS AND METHOD: Thirty-one patients who received first-line chemotherapy for gastric cancer were retrospectively assessed for CINV. RESULTS: The median age was 70 years, and the gender(male/female)was 23/8 cases. NK1 receptor antagonist, 5-HT3 receptor antagonist, and dexamethasone were used as antiemetic agents in 29 patients(94%). Sixteen patients(52%)had Grade 1 or higher nausea, and 6 patients (19%)had Grade 1 or higher vomiting, and complete control of nausea and vomiting was achieved in 21 patients(68%). Nausea was significantly more frequent in patients with liver metastasis(p=0.0008), but there was no significant difference in vomiting(p=1.0000). There was no significant difference in the occurrence of CINV between chemotherapy regimens or combination of olanzapine. CONCLUSION: During first-line chemotherapy for gastric cancer, 3 antiemetic agents were used in 94% of cases, and the complete control rate of CINV was 67.8%.