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Background and study aims An important therapeutic aim in ulcerative colitis (UC) is endoscopic remission. Although an endoscopic score with white light imaging (WLI) is mainly used to evaluate endoscopic findings, the usefulness of linked color imaging (LCI) has been reported. We evaluated the relationship between LCI and histopathological findings and attempted to establish a new LCI endoscopic evaluation index for UC.

Background and study aims Colorectal premalignant polyps and hemorrhoids are important findings in colonoscopy; however, the association between them is unclear. Therefore, we investigated the association between the presence and severity of hemorrhoids and the detection of precancerous colorectal polyps on colonoscopy.

Although patients with SLE have autoantibodies to thyroid pcroxidase (TPO), IgG from sera of SLE patients does not inhibit TPO activities, in contrast with IgG from sera of patients with thyroid disorders. This finding suggests that the specificities of anti-TPO autoantibodies in SLE are different from those in cases of thyroid disorders. These autoantibodies to TPO should be considered when searching for associations between SLE and autoimmune thyroid disorders. [ABSTRACT FROM AUTHOR]

Conjugation plays a major role in dissemination of antimicrobial resistance genes. Following transfer of IncF-like plasmids, recipients become refractory to a second wave of conjugation with the same plasmid via entry (TraS) and surface (TraT) exclusion mechanisms. Here, we show that TraT from the pKpQIL and F plasmids (TraT pKpQIL and TraT F ) exhibits plasmid surface exclusion specificity. The cryo-EM structures of TraT pKpQIL and TraT F reveal that they oligomerise into decameric champagne bottle cork-like structures, which are anchored to the outer membrane via a diacylglycerol and palmitic acid modified α-helical barrel domain. Unexpectedly, we identify chromosomal TraT homologues from multiple Gram-negative phyla which form numerous divergent lineages in a phylogenetic tree of TraT sequences. Plasmid-associated TraT sequences are found in multiple distinct lineages, including two separate clades incorporating TraT from Enterobacteriaceae IncF/F-like and Legionellaceae F-like plasmids. These findings suggest that different plasmid backbones have acquired and co-opted TraT on independent occasions., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Conjugation, the major driver of the spread of antimicrobial resistance genes, relies on a conjugation pilus for DNA transfer. Conjugative pili, such as the F-pilus, are dynamic tubular structures, composed of a polymerized pilin, that mediate the initial donor-recipient interactions, a process known as mating pair formation (MPF). IncH are low-copy-number plasmids, traditionally considered broad host range, which are found in bacteria infecting both humans and animals. The reference IncHI1 plasmid R27, isolated from Salmonella enterica serovar Typhi, encodes the conjugative H-pilus subunit TrhA containing 74 residues after cleavage of the signal sequence. Here, we show that the H-pilus forms long filamentous structures that mediate MPF, and describe its cryo electron-microscopic (cryo-EM) structure at 2.2 Å resolution. Like the F pilus, the H-pilin subunits form helical assemblies with phospholipid molecules at a stochiometric ratio of 1:1. While there were previous reports that the T-pilus from Agrobacterium tumefaciens was composed of cyclic subunits, three recent cryo-EM structures of the T-pilus found no such cyclization. Here, we report that the H-pilin is cyclic, with a covalent bond connecting the peptide backbone between the N- and C-termini. Both the cryo-EM map and mass spectrometry revealed cleavage of the last five residues of the pilin, followed by cyclization via condensation of the amine and carboxylate residues. The cyclic nature of the pilin could stabilize the pilus and may explain the high incidence of IncH plasmid dissemination., Competing Interests: Competing interests The authors declare no competing interests.

Macaque restricts hepatitis B virus (HBV) infection because its receptor homologue, NTCP (mNTCP), cannot bind preS1 on viral surface. To reveal how mNTCP loses the viral receptor function, we here solve the cryo-electron microscopy structure of mNTCP. Superposing on the human NTCP (hNTCP)-preS1 complex structure shows that Arg158 of mNTCP causes steric clash to prevent preS1 from embedding onto the bile acid tunnel of NTCP. Cell-based mutation analysis confirms that only Gly158 permitted preS1 binding, in contrast to robust bile acid transport among mutations. As the second determinant, Asn86 on the extracellular surface of mNTCP shows less capacity to restrain preS1 from dynamic fluctuation than Lys86 of hNTCP, resulting in unstable preS1 binding. Additionally, presence of long-chain conjugated-bile acids in the tunnel induces steric hindrance with preS1 through their tailed-chain. This study presents structural basis in which multiple sites in mNTCP constitute a molecular barrier to strictly restrict HBV., (© 2024. The Author(s).)

Patients on hemodialysis (HD) are at a very high risk of stroke, especially hemorrhagic stroke, with worse outcomes than the general population. We have determined the indications for urgent neurosurgery for intracerebral hemorrhage (ICH) based on the hematoma volume and neurological severity, regardless of HD status. This study aimed to evaluate the neurosurgical outcomes of ICH in patients undergoing HD. We retrospectively reviewed 38 cases of surgical removal of ICH performed in patients on HD. Patients were categorized into poor or better (0-4) and very poor (5 or 6) groups according to their modified Rankin Scale (mRS) score at discharge. Patient demographics, clinical characteristics, and operative records were retrospectively analyzed. The median Glasgow Coma Scale (GCS) score and hematoma volume were 6 and 99 mL, respectively. A total of 30 patients (78.9%) had very poor outcomes at discharge. Significant differences were observed in GCS score (13 vs. 6) and hematoma volume (53 vs. 114 mL) between the poor or better and very poor groups. The receiver operating characteristic curve analysis showed the cut-off values were 9 for GCS (AUC = 0.821) and 63.3 mL for hematoma volume (AUC = 0.812). The most common complication was rebleeding (10.5%), followed by seizures (7.9%), infection (7.9%), and cerebral edema (7.9%). In conclusion, neurosurgical outcomes of ICH in patients undergoing HD remain poor, but 21.1% of these patients achieved an mRS ≤ 4. ICH patients on HD with a GCS score > 9 or hematoma volume < 63 mL are more likely to demonstrate mRS ≤ 4 after surgical evacuation. The postoperative management of patients on HD should be performed considering specific risks, such as seizures and rebleeding.

Background: Rising antimicrobial resistance (AMR) in Salmonella Typhi restricts typhoid treatment options, heightening concerns for pan-oral drug-resistant outbreaks. However, lack of long-term temporal surveillance data on AMR in countries with high burden like Bangladesh is scarce. Our study explores the AMR trends of Salmonella Typhi isolates from Bangladesh, drawing comparisons with antibiotic consumption to optimize antibiotic stewardship strategies for the country., Methodology/principal Findings: The typhoid fever surveillance from 1999 to 2022 included two pediatric hospitals and three private clinics in Dhaka, Bangladesh. Blood cultures were performed at treating physicians' discretion; cases were confirmed by microbiological, serological, and biochemical tests. Antibiotic susceptibility was determined following CLSI guidelines. National antibiotic consumption data for cotrimoxazole, ciprofloxacin, and azithromycin was obtained from IQVIA-MIDAS database for comparison. Over the 24 years of surveillance, we recorded 12,435 culture-confirmed typhoid cases and observed declining resistance to first-line drugs (amoxicillin, chloramphenicol, and cotrimoxazole); multidrug resistance (MDR) decreased from 38% in 1999 to 17% in 2022. Cotrimoxazole consumption dropped from 0.8 to 0.1 Daily defined doses (DDD)/1000/day (1999-2020). Ciprofloxacin non-susceptibility persisted at >90% with unchanged consumption (1.1-1.3 DDD/1000/day, 2002-2020). Low ceftriaxone resistance (<1%) was observed, with slightly rising MIC (0.03 to 0.12 mg/L, 1999-2019). Azithromycin consumption increased (0.1 to 3.8 DDD/1000/day, 1999-2020), but resistance remained ≤4%., Conclusion: Our study highlights declining MDR amongst Salmonella Typhi in Bangladesh; first-line antimicrobials could be reintroduced as empirical treatment options for typhoid fever if MDR rates further drops below 5%. The analysis also provides baseline data for monitoring the impact of future interventions like typhoid conjugate vaccines on typhoid burden and associated AMR., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tanmoy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Surgical management of mitral annular calcification remains challenging. Our institution pursued a strategy of total mitral annular calcification resection with pericardial patch reconstruction of the left ventricle when primary atrioventricular groove closure was not possible. We present the short-term outcomes derived after implementing this strategy., Methods: A single-institution retrospective analysis included patients with significant mitral annular calcification undergoing totally endoscopic robotic mitral valve surgery between October 2009 and August 2023. Mitral valve repair was performed in patients with sufficient posterior leaflet length. Patients requiring pericardial patch ventriculoplasty were compared with those in whom primary atrioventricular groove closure was possible (non-pericardial patch ventriculoplasty)., Results: Of 1441 patients who underwent totally endoscopic mitral valve surgery, 217 (15.1%) presented with significant mitral annular calcification. Pericardial patch ventriculoplasty was performed in 69 patients (31.8%). Patients undergoing non-pericardial patch ventriculoplasty were significantly younger than patients undergoing pericardial patch ventriculoplasty (63.4 vs 67.8 years, P  = .01). Mitral valve repair was conducted in 145 patients (98.0%) in the non-pericardial patch ventriculoplasty group versus 56 patients (81.2%) in the pericardial patch ventriculoplasty group ( P  < .01). The median postoperative length of stay was significantly shorter in the non-pericardial patch ventriculoplasty group (3 vs 5 days, P  < .01). There was no significant difference in postoperative stroke (0.7% vs 2.9%, P  = .50) or 30-day mortality (1.4% vs 1.4%, P  = 1.00). Three-year survival was comparable between the groups (97.4% vs 93.7%, P  = .52)., Conclusions: Totally endoscopic robotic mitral valve repair is a safe and feasible technique for the management of mitral annular calcification with promising results at 3 years. Patients who required atrioventricular groove pericardial patch reconstruction had similar outcomes to those in whom primary closure was possible., Competing Interests: E.A.G. and D.F.L. are former proctors for Intuitive Surgical. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

Background and Aim: Anti-aminoacyl-tRNA synthetase (ARS) antibodies form a condition called Antisynthetase syndrome (ASSD). While interstitial lung disease (ILD) is a particularly frequent manifestation of ASSD and is closely associated with morbidity and mortality, few studies have been conducted on its characteristics on high-resolution computed tomography (HRCT). In this study, we clarified the HRCT findings in patients with anti-ARS antibody-positive ILD (ARS-ILD).  Methods: The HRCT findings at the time of the ILD diagnosis in 24 ARS-ILD patients were retrospectively evaluated by 2 pulmonologists and one radiologist. We also assessed the clinical symptoms, physical examination findings, and laboratory data including the type of anti-ARS antibodies. For a further analysis, the data of patients were divided into two groups: the polymyositis (PM)/dermatomyositis (DM) group and the non-PM/DM group., Results: The ratio of men to women was almost 1:1. The median age at the time of the diagnosis was 53 years old. Anti-glycyl (anti-EJ) and anti-histidyl (anti-Jo-1) antibodies were more common than others. An analysis of the HRCT patterns of 23 ARS-ILD patients showed that the most common pattern was the nonspecific interstitial pneumonia (NSIP) pattern. The second most common pattern was the usual interstitial pneumonia (UIP) pattern. Between the PM/DM and non-PM/DM groups, no clear trends were noted in the age, sex ratio, proportion of HRCT patterns, or type of anti-ARS antibodies., Conclusions: This retrospective study demonstrated that ARS-ILD patients, regardless of myositis symptoms, most often showed the NSIP pattern on HRCT, as previously reported. However, unlike previous reports, the UIP pattern on HRCT was not rare.

Cerebral infarction due to post-traumatic cerebral vasospasm is rare. Although some modalities are recommended to detect post-traumatic cerebral vasospasm, its diagnosis remains controversial and challenging. Therefore, in this report, we will use a case report to highlight challenges and to delineate the characteristics of post-traumatic cerebral vasospasm in pediatric patients, including the diagnostic and treatment options. A 12-year-old female was admitted to our hospital following a motor vehicle collision. Her consciousness was severely impaired. Initial computed tomography (CT) revealed an acute subdural hematoma along the tentorium, and a focal subarachnoid hemorrhage was observed in the Sylvian fissure. The patient underwent the insertion of an intracranial pressure sensor and received therapy for increased intracranial pressure (ICP) control under sedation. On the second day, CT angiography (CTA) revealed no signs of arterial abnormality. A patient who is comatose or under sedation has masked neurological symptoms. Thus, new neurological events could only be detected via an intracranial pressure sensor. Her ICP increased on the seventh day, and a CT scan showed a new cerebral infarction in the right middle cerebral artery (MCA) region. We performed decompressive craniectomy to reduce ICP. Postoperative CTA confirmed severe vasospasm in the right MCA. The severe cerebral vasospasm induced the cerebral infarction. Our review suggests that physicians in trauma departments should frequently perform vascular evaluations by CTA, magnetic resonance angiography (MRA), transcranial Doppler ultrasound, or digital subtraction angiography (DSA), especially within two weeks from onset, to detect post-traumatic cerebral vasospasm., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Tanikawa et al.)

Hepatitis B virus (HBV), a leading cause of developing hepatocellular carcinoma affecting more than 290 million people worldwide, is an enveloped DNA virus specifically infecting hepatocytes. Myristoylated preS1 domain of the HBV large surface protein binds to the host receptor sodium-taurocholate cotransporting polypeptide (NTCP), a hepatocellular bile acid transporter, to initiate viral entry. Here, we report the cryogenic-electron microscopy structure of the myristoylated preS1 (residues 2-48) peptide bound to human NTCP. The unexpectedly folded N-terminal half of the peptide embeds deeply into the outward-facing tunnel of NTCP, whereas the C-terminal half formed extensive contacts on the extracellular surface. Our findings reveal an unprecedented induced-fit mechanism for establishing high-affinity virus-host attachment and provide a blueprint for the rational design of anti-HBV drugs targeting virus entry., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce G i/o signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with lipolytic and atherogenic activity, and neuroinflammation. Although many reports have elucidated the function of HCAR2 and its potential as a therapeutic target for treating not only dyslipidemia but also neuroimmune disorders such as multiple sclerosis and Parkinson's disease, the structural basis of ligand recognition and ligand-induced G i -coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2-G i signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. All three agonists are held in a deep pocket lined by residues that are not conserved in HCAR1 and HCAR3. A distinct hairpin loop at the HCAR2 N-terminus and extra-cellular loop 2 (ECL2) completely enclose the ligand. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation., (© 2023. The Author(s).)

Bipolar disorder (BP) is characterized by cognitive decline. Individual differences exist in maintaining cognitive function due to daily physical activity and sleep. We examined the relationship between leisure experiences as proxies for cognitive reserve (CR) and cognitive function in patients with bipolar disorder after adjusting for daily physical activity and sleep. The CR of patients with BP (n = 24) and healthy study controls (HC) (n = 24) was assessed using premorbid IQ, years of education, and leisure activity history. Performance-based neuropsychological tests were performed to evaluate cognitive function. A self-reported scale was used to assess resilience. Physical activity and sleep were measured using an activity meter. Verbal fluency, story memory, and verbal memory were significantly positively correlated with the kinds of leisure experiences in patients with BP. A hierarchical regression analysis accounting for confounding factors showed that verbal fluency and memory were associated with the kinds of leisure experiences. Neither years of education nor resilience were significantly associated with neuropsychological scores. Various leisure experiences in patients with BP are associated with higher language-related cognitive functioning. Engaging in various leisure experiences may affect higher cognitive functions related to language., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Neutrophil granulocytes play key roles in innate immunity and shaping adaptive immune responses. They are attracted by chemokines to sites of infection and tissue damage, where they kill and phagocytose bacteria. The chemokine CXCL8 (also known as interleukin-8, abbreviated IL-8) and its G-protein-coupled receptors CXCR1 and CXCR2 are crucial elements in this process, and also the development of many cancers. These GPCRs have therefore been the target of many drug development campaigns and structural studies. Here, we solve the structure of CXCR1 complexed with CXCL8 and cognate G-proteins using cryo-EM, showing the detailed interactions between the receptor, the chemokine and Gαi protein. Unlike the closely related CXCR2, CXCR1 strongly prefers to bind CXCL8 in its monomeric form. The model shows that steric clashes would form between dimeric CXCL8 and extracellular loop 2 (ECL2) of CXCR1. Consistently, transplanting ECL2 of CXCR2 onto CXCR1 abolishes the selectivity for the monomeric chemokine. Our model and functional analysis of various CXCR1 mutants will assist efforts in structure-based drug design targeting specific CXC chemokine receptor subtypes., (© 2023. The Author(s).)

The selective transformation of a less reactive carbonyl moiety in the presence of more reactive ones can realize straightforward and environmentally benign chemical processes. However, such a transformation is highly challenging because the reactivity of carbonyl compounds, one of the most important functionalities in organic chemistry, depends on the substituents on the carbon atom. Herein, we report an Ir catalyst for the selective hydrogenolysis of urea derivatives, which are the least reactive carbonyl compounds, affording formamides and amines. Although formamide, as well as ester, amide, and carbamate substituents, are considered to be more reactive than urea, the proposed Ir catalyst tolerated these carbonyl groups and reacted with urea in a highly chemoselective manner. The proposed chemo- and regioselective hydrogenolysis allows the development of a strategy for the chemical recycling of polyurea resins., (© 2023. The Author(s).)

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with few effective therapeutic options. Recently, drug repositioning, which involves identifying novel therapeutic potentials for existing drugs, has been popularized as a new approach for the development of novel therapeutic reagents. However, this approach has not yet been fully utilized in the field of pulmonary fibrosis., Methods: The present study identified novel therapeutic options for pulmonary fibrosis using a systematic computational approach for drug repositioning based on integration of public gene expression signatures of drug and diseases (in silico screening approach)., Results: Among the top compounds predicted to be therapeutic for IPF by the in silico approach, we selected BI2536, a polo-like kinase (PLK) 1/2 inhibitor, as a candidate for treating pulmonary fibrosis using an in silico analysis. However, BI2536 accelerated mortality and weight loss rate in an experimental mouse model of pulmonary fibrosis. Because immunofluorescence staining revealed that PLK1 expression was dominant in myofibroblasts while PLK2 expression was dominant in lung epithelial cells, we next focused on the anti-fibrotic effect of the selective PLK1 inhibitor GSK461364. Consequently, GSK461364 attenuated pulmonary fibrosis with acceptable mortality and weight loss in mice., Conclusions: These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies., (© 2023. The Author(s).)

Carbonate apatite (CO 3 Ap) granules are useful as a bone substitute because they can be remodeled to new natural bone in a manner that conforms to the bone remodeling process. However, reconstructing large bone defects using CO 3 Ap granules is difficult because of their granular shape. Therefore, we fabricated CO 3 Ap honeycomb blocks (HCBs) with continuous unidirectional pores. We aimed to elucidate the tissue response and availability of CO 3 Ap HCBs in the reconstruction of rabbit mandibular bone defects after marginal mandibulectomy. The percentages of the remaining CO 3 Ap area and calcified bone area (newly formed bone) were estimated from the histological images. CO 3 Ap area was 49.1 ± 4.9%, 30.3 ± 3.5%, and 25.5 ± 8.8%, whereas newly formed bone area was 3.0 ± 0.6%, 24.3 ± 3.3%, and 34.7 ± 4.8% at 4, 8, and 12 weeks, respectively, after implantation. Thus, CO 3 Ap HCBs were gradually resorbed and replaced by new bone. The newly formed bone penetrated most of the pores in the CO 3 Ap HCBs at 12 weeks after implantation. By contrast, the granulation tissue scarcely invaded the CO 3 Ap HCBs. Some osteoclasts invaded the wall of CO 3 Ap HCBs, making resorption pits. Furthermore, many osteoblasts were found on the newly formed bone, indicating ongoing bone remodeling. Blood vessels were also formed inside most of the pores in the CO 3 Ap HCBs. These findings suggest that CO 3 Ap HCBs have good osteoconductivity and can be used for the reconstruction of large mandibular bone defects. The CO 3 Ap HCB were gradually resorbed and replaced by newly formed bone., (© 2022. The Author(s).)

Background: Lymphocyte-specific protein tyrosine kinase (Lck) is a member of the Src family of tyrosine kinases. The significance of Lck inhibition in lung fibrosis has not yet been fully elucidated, even though lung fibrosis is commonly preceded by inflammation caused by infiltration of T-cells expressing Lck. In this study, we examined the effect of Lck inhibition in an experimental mouse model of lung fibrosis. We also evaluated the effect of Lck inhibition on the expression of TGF-β1, an inhibitory cytokine regulating the immune function, in regulatory T-cells (Tregs)., Methods: Lung fibrosis was induced in mice by intratracheal administration of bleomycin. A-770041, a Lck-specific inhibitor, was administrated daily by gavage. Tregs were isolated from the lung using a CD4+CD25+ Regulatory T-cell Isolation Kit. The expression of Tgfb on Tregs was examined by flow cytometry and quantitative polymerase chain reaction. The concentration of TGF-β in bronchoalveolar lavage fluid (BALF) and cell culture supernatant from Tregs was quantified by an enzyme-linked immunosorbent assay., Results: A-770041 inhibited the phosphorylation of Lck in murine lymphocytes to the same degree as nintedanib. A-770041 attenuated lung fibrosis in bleomycin-treated mice and reduced the concentration of TGF-β in BALF. A flow-cytometry analysis showed that A-770041 reduced the number of Tregs producing TGF-β1 in the lung. In isolated Tregs, Lck inhibition by A-770041 decreased the Tgfb mRNA level as well as the concentration of TGF-β in the supernatant., Conclusions: These results suggest that Lck inhibition attenuated lung fibrosis by suppressing TGF-β production in Tregs and support the role of Tregs in the pathogenesis of lung fibrosis., Competing Interests: The authors have declared that no competing interests exist.

Galanin is a neuropeptide expressed in the central and peripheral nervous systems, where it regulates various processes including neuroendocrine release, cognition, and nerve regeneration. Three G-protein coupled receptors (GPCRs) for galanin have been discovered, which is the focus of efforts to treat diseases including Alzheimer's disease, anxiety, and addiction. To understand the basis of the ligand preferences of the receptors and to assist structure-based drug design, we used cryo-electron microscopy (cryo-EM) to solve the molecular structure of GALR2 bound to galanin and a cognate heterotrimeric G-protein, providing a molecular view of the neuropeptide binding site. Mutant proteins were assayed to help reveal the basis of ligand specificity, and structural comparison between the activated GALR2 and inactive hβ2AR was used to relate galanin binding to the movements of transmembrane (TM) helices and the G-protein interface., Competing Interests: The authors have declared that no competing interests exist.

Around 250 million people are infected with hepatitis B virus (HBV) worldwide 1 , and 15 million may also carry the satellite virus hepatitis D virus (HDV), which confers even greater risk of severe liver disease 2 . The HBV receptor has been identified as sodium taurocholate co-transporting polypeptide (NTCP), which interacts directly with the first 48 amino acid residues of the N-myristoylated N-terminal preS1 domain of the viral large protein 3 . Despite the pressing need for therapeutic agents to counter HBV, the structure of NTCP remains unsolved. This 349-residue protein is closely related to human apical sodium-dependent bile acid transporter (ASBT), another member of the solute carrier family SLC10. Crystal structures have been reported of similar bile acid transporters from bacteria 4,5 , and these models are believed to resemble closely both NTCP and ASBT. Here we have used cryo-electron microscopy to solve the structure of NTCP bound to an antibody, clearly showing that the transporter has no equivalent of the first transmembrane helix found in other SLC10 proteins, and that the N terminus is exposed on the extracellular face. Comparison of our structure with those of related proteins indicates a common mechanism of bile acid transport, but the NTCP structure displays an additional pocket formed by residues that are known to interact with preS1, presenting new opportunities for structure-based drug design., (© 2022. The Author(s).)

Supporting cells of oocytes, i.e., cumulus cells, control oocyte quality, which determines fertilization success. Therefore, the transformation of mature and immature cumulus cells (MCCs and ICCs, respectively) into dysmature cumulus cells (DCCs) with dead characteristics deteriorates oocyte quality. However, the molecular basis for this transformation remains unclear. Here, we explored the link between autophagic decline and cumulus transformation using cumulus cells from patients with infertility, female mice, and human granulosa cell-derived KGN cell lines. When human cumulus cells were labeled with LysoTracker probes, fluorescence corresponding to lysosomes was enhanced in DCCs compared to that in MCCs and ICCs. Similarly, treatment with the autophagy inhibitor chloroquine elevated LysoTracker fluorescence in both mouse cumulus cells and KGN cells, subsequently suppressing ovulation in female mice. Electron microscopy analysis revealed the proliferation of abnormal lysosomes in chloroquine-treated KGN cells. Conversely, the addition of an autophagy inducer, trehalose, suppressed chloroquine-driven problematic lysosomal anomalies and ameliorated ovulation problems. Our results suggest that autophagy maintains the healthy state of the supporting cells of human oocytes by suppressing the formation of lysosomes. Thus, our results provide insights into the therapeutic effects of trehalose on female fertility.

Somatostatin is a peptide hormone that regulates endocrine systems by binding to G-protein-coupled somatostatin receptors. Somatostatin receptor 2 (SSTR2) is a human somatostatin receptor and is highly implicated in hormone disorders, cancers, and neurological diseases. Here, we report the high-resolution cryo-EM structure of full-length human SSTR2 bound to the agonist somatostatin (SST-14) in complex with inhibitory G (G i ) proteins. Our structural and mutagenesis analyses show that seven transmembrane helices form a deep pocket for ligand binding and that SSTR2 recognizes the highly conserved Trp-Lys motif of SST-14 at the bottom of the pocket. Furthermore, our sequence analysis combined with AlphaFold modeled structures of other SSTR isoforms provide a structural basis for the mechanism by which SSTR family proteins specifically interact with their cognate ligands. This work provides the first glimpse into the molecular recognition mechanism of somatostatin receptors and a crucial resource to develop therapeutics targeting somatostatin receptors., Competing Interests: YH, EY, YJ, NI, HW, SP No competing interests declared, JY is an employee at PCG-Biotech and holds a research director position, JS, WL is a co-founder of PCG-Biotech, (© 2022, Heo et al.)

Introduction: Alzheimer's disease (AD) affects multiple neural pathways and regions, resulting in various visual impairments such as motion perception. Generally, gamma-band activities during visual motion perception have been thought to reflect ongoing cognitive processes. Nevertheless, few studies have specifically examined induced gamma band activity during visual motion perception in AD patients. Therefore, after performing magnetoencephalography (MEG) recording during apparent motion (AM) stimulation for the left hemi-visual field in patients diagnosed as having AD in the early stage, we compared the results with findings of cognitive performance., Methods: Seventeen AD patients in the early stage and 17 controls matched for age, sex, and educational attainment participated in this study. For each participant, memory performance was assessed with the Mini-Mental State Examination (MMSE) and the Wechsler Memory Scale-Revised (WMS-R). For MEG analysis, we examined power changes induced in a higher frequency range (20-100 Hz) after AM stimuli., Results: The power of induced gamma band activities was significantly higher in AD patients. The power of induced gamma band activities was associated with higher performance on both MMSE and WMS-R tests for attention and concentration in AD patients., Conclusions: Given that neuronal dysfunction in AD is associated with excitotoxic neurodegeneration, and given that subsequent development of compensatory inhibitory mechanisms also contributes to pathology in AD patients, elevated gamma band oscillations might reflect an imbalance of inhibitory and excitatory activity in AD patients. Moreover, positive correlation between induced gamma activity and cognitive performance might signify a compensating mechanism of inhibitory neurons which preserve the pyramidal neuron from excitotoxicity in a posterior association area., Competing Interests: The authors have declared that no competing interests exist.

Lenvatinib is a multi-targeted tyrosine kinase inhibitor available for the treatment of unresectable hepatocellular carcinoma (HCC). We herein report an 84-year-old-man with interstitial pneumonia caused by lenvatinib. Four months after the start of lenvatinib administration for HCC, chest computed tomography revealed bilateral ground-glass opacity. However, he continued to take lenvatinib for four more months until he complained of dyspnea on exertion. This is a case of lenvatinib-induced interstitial pneumonia that progressed relatively slowly with a long asymptomatic period despite the appearance of pneumonia on image findings.

Background: Although endoscopic ventriculo-cysto-cisternostomy is considered to be effective for suprasellar arachnoid cysts, we encountered a giant suprasellar arachnoid cyst that recurred despite surgery using this technique., Case Description: The patient was a 9-month-old boy. Magnetic resonance imaging revealed a huge suprasellar arachnoid cyst extending from the suprasellar region to the anterior skull base and both middle cranial fossa. First, an endoscopic procedure was performed to open the cyst wall between the right ventricle and the cyst and between the cyst and the prepontine cistern. Although the cyst initially shrank, it recurred over the next 2 months, and hence, we performed another endoscopic surgery. At the second surgery, both the previously opened stomas were found to be occluded. To reopen the cyst wall between the ventricle and the cyst, multiple holes were made with monopolar electrodes, and forceps were used to connect the holes by grasping and twisting the cyst wall so that the stoma was much larger than at the previous surgery. Postoperatively, the cyst shrank and the patient's head circumference stopped expanding., Conclusion: Following the treatment of large cysts, the stoma might become narrower as the cyst shrinks, resulting in obstruction. Using the technique reported here might prevent occlusion of large arachnoid cysts., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Surgical Neurology International.)

Measuring whole brain networks is a promising approach to extract features of autism spectrum disorder (ASD), a brain disorder of widespread regions. Objectives of this study were to evaluate properties of resting-state functional brain networks in children with and without ASD and to evaluate their relation with social impairment severity. Magnetoencephalographic (MEG) data were recorded for 21 children with ASD (7 girls, 60-89 months old) and for 25 typically developing (TD) control children (10 girls, 60-91 months old) in a resting state while gazing at a fixation cross. After signal sources were localized onto the Desikan-Killiany brain atlas, statistical relations between localized activities were found and evaluated in terms of the phase lag index. After brain networks were constructed and after matching with intelligence using a coarsened exact matching algorithm, ASD and TD graph theoretical measures were compared. We measured autism symptoms severity using the Social Responsiveness Scale and investigated its relation with altered small-worldness using linear regression models. Children with ASD were found to have significantly lower small-worldness in the beta band ( p = 0.007) than TD children had. Lower small-worldness in the beta band of children with ASD was associated with higher Social Responsiveness Scale total t -scores ( p = 0.047). Significant relations were also inferred for the Social Awareness ( p = 0.008) and Social Cognition ( p = 0.015) sub-scales. Results obtained using graph theory demonstrate a difference between children with and without ASD in MEG-derived resting-state functional brain networks, and the relation of that difference with social impairment. Combining graph theory and MEG might be a promising approach to establish a biological marker for ASD., 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., (Copyright © 2021 Soma, Hirosawa, Hasegawa, An, Kameya, Hino, Yoshimura, Nobukawa, Iwasaki, Tanaka, Yaoi, Sano, Shiota, Naito and Kikuchi.)