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We reconstructed surface mass balance (SMB) around Dome Fuji, Antarctica, over the last 5000 years using the data from 15 shallow ice cores and seven snow pits. The depth–age relationships for the ice cores were determined by synchronizing them with a layer-counted ice core from West Antarctica (WAIS Divide ice core) using volcanic signals. The reconstructed SMB records for the last 4000 years show spatial patterns that may be affected by their locations relative to the ice divides around Dome Fuji, proximity to the ocean, and wind direction. The SMB records from the individual ice cores and snow pits were stacked to reconstruct the SMB history in the Dome Fuji area. The stacked record exhibits a long-term decreasing trend at -0.037±0.005 kg m−2 per century over the last 5000 years in the preindustrial period. The decreasing trend may be the result of long-term surface cooling over East Antarctica and the Southern Ocean and sea ice expansion in the water vapor source areas. The multidecadal to centennial variations of the Dome Fuji SMB after detrending the record shows four distinct periods during the last millennium: a mostly negative period before 1300 CE, a slightly positive period from 1300 to 1450 CE, a slightly negative period from 1450 to 1850 CE with a weak maximum around 1600 CE, and a strong increase after 1850 CE. These variations are consistent with those of previously reconstructed SMB records in the East Antarctic plateau. The low accumulation rate periods tend to coincide with the combination of strong volcanic forcings and solar minima for the last 1000 years, but the correspondence is not clear for the older periods, possibly because of the lack of coincidence of volcanic and solar forcings or the deterioration of the SMB record due to a smaller number of stacked cores.

The retrieval of continuous ice core records of more than 1 Myr is an important challenge in palaeo-climatology. For identifying suitable sites for drilling such ice, knowledge of the subglacial topography and englacial layering is crucial. For this purpose, extensive ground-based ice radar surveys were carried out over Dome Fuji in the East Antarctic plateau during the 2017/18 and 2018/19 austral summers by the Japanese Antarctic Research Expedition, on the basis of ground-based radar surveys conducted over the previous ∼ 30 years. High-gain Yagi antennae were used to improve the antenna beam directivity, thereby significantly decreasing hyperbolic features of unfocused along-track diffraction hyperbolae in the echoes from mountainous ice–bedrock interfaces. We combined the new ice thickness data with the previous ground-based data, recorded since the 1980s, to generate an accurate high-spatial-resolution (up to 0.5 km between survey lines) ice thickness map. This map revealed a complex landscape composed of networks of subglacial valleys and highlands. Based on the new map, we examined the roughness of the ice–bed interface, the bed surface slope, the driving stress of ice and the subglacial hydrological condition. These new products and analyses set substantial constraints on identifying possible locations for new drilling. In addition, our map was compared with a few bed maps compiled by earlier independent efforts based on airborne radar data to examine the difference in features between datasets. Our analysis suggests that widely available bed topography products should be validated with in situ observations where possible.

The crystal orientation fabric (COF) of a polar ice sheet has a significant effect on the rheology of the ice sheet. With the aim of better understanding the deformation regime of ice sheets, the work presented here investigates the COF in the upper 80 % of the Dome Fuji Station ice core in East Antarctica. Dielectric anisotropy (Δε) data were acquired as a novel indicator of the vertical clustering of COF resulting from vertical compressional strain within the dome. The Δε values were found to exhibit a general increase with depth, but with fluctuations over distances in the order of 10–102 m. In addition, significant decreases in Δε were found to be associated with depths corresponding to three major glacial to interglacial transitions. These changes in Δε are ascribed to variations in the deformational history caused by dislocation motion occurring from near-surface depths to deeper layers. Fluctuations in Δε over distances of less than 0.5 m exhibited a strong inverse correlation with Δε at depths greater than approximately 1200 m, indicating that they were enhanced during the glacial-interglacial transitions. The Δε data also exhibited a positive correlation with the concentration of chloride ions and an inverse correlation with the amount of dust particles in the ice core at greater depths corresponding to decreases in the degree of c axis clustering. Finally, we found that fluctuations in Δε persisted to approximately 80 % of the total depth of the ice sheet. These data suggest that the factors determining the deformation of ice include the concentration of chloride ions and the amount of dust particles, and that the layered contrast associated with the COF is preserved all the way from the near-surface to a depth corresponding to approximately 80 % of the thickness of the ice sheet. These findings provide important implications regarding further development of the COF under the various stress-strain configurations that the ice will experience in the deepest region, approximately 20 % of the total depth from the ice/bed interface.

The degradation of permafrost is a large source of uncertainty in understanding the behaviour and projecting the future impacts of Earth's climate system. The spatial distributions of soil organic carbon (SOC) and ground ice (ICE) provide essential information for the assessment and projection of risks and impacts of permafrost degradation. However, uncertainties regarding the geographical distribution and estimated range of the total amount of stored carbon and ice are still substantial. A numerical soil organic carbon–ground ice budget model, SOC-ICE-v1.0, that considers essential aspects of carbon and hydrological processes in above-ground and subsurface environments and permanently frozen ground (permafrost) and land cover changes (ice sheets and coastlines) was developed to calculate the long-term evolution of local SOC and ICE. The model was integrated to cover the last 125 kyr – from the last interglacial to date for areas north of 50∘ N at 1∘ resolution – to simulate the balance between accumulation and dissipation of SOC and ICE. Model performance was compared with observation-based data and evaluated to assess allogenic (external) impacts on soil carbon dynamics in the circum-Arctic region on a glacial–interglacial timescale. Despite the limitation of forcing climate data being constructed on the basis of a single Greenland ice core dataset, the simulated results successfully reproduced temporal changes in northern SOC and ICE, consist with current knowledge. The simulation also captured regional differences in different geographical and climatic characteristics within the circum-Arctic region. The model quantitatively demonstrated allogenic controls on soil carbon evolution represented by a key parameter that reflects climatological and topo-geographical factors. The resulting circum-Arctic set of simulated time series can be compiled to produce snapshot maps of SOC and ICE distributions for past and present assessments or future projection simulations. Examples of 1∘ resolution maps for the Last Glacial Maximum and mid-Holocene periods were provided. Despite a simple modelling framework, SOC-ICE-v1.0 provided substantial information on the temporal evolution and spatial distribution of circum-Arctic SOC and ICE. Model improvements in terms of forcing climate data, improvement of SOC and ICE dynamics, and choice of initial values are, however, required for future research.

Antiferromagnets (AFMs) are prospective for future spintronic devices, owing to their speed and insensitivity to perturbations. Using a combination of electronic and magnetic dichroism measurements, the authors demonstrate reversible current-induced switching of the Néel vector in AFM PtMn.

During the occurrence of floods, the government generally tries to determine the extent of the continuously changing inundation (water) area as a disaster response for planning evacuations and designing drainage systems. One of the most common methods to identify this area during the daytime involves the interpretation of aerial optical images and videos that are obtained using an airplane, helicopter, or satellite. However, these aerial approach methods have not been established convincingly for their use during the night time. Therefore, to identify the water area at night, two hand-held optical sensors were used in this study, namely: an ultrasensitive camera (Sony SL camera α7S), and a thermal infrared camera (Optris thermography PI640). The night-time aerial performance was evaluated using a helicopter, along with a supplementary night-time examination on the ground. Herein, we targeted river water areas during normal conditions. As a result, it was determined that the water area could be identified clearly with an ultrasensitive camera that has an ISO sensitivity between 51200 and 102400. The thermal infrared camera was able to identify the water area to have a higher temperature than that of the surrounding area. However, in some cases, the water area boundaries were not clear. Thus, as the thermal infrared camera was susceptible to varying conditions, supplemental use of an ultrasensitive camera was determined to be effective for the identification of inundation (water) areas at night. The significance of this study is established by the fact that the studied sensors can be easily transported in a helicopter or mounted on a UAV for night-time applications.

We present results for pseudo-critical temperatures of QCD chiral crossovers at zero and non-zero values of baryon (B), strangeness (S), electric charge (Q), and isospin (I) chemical potentials μX=B,Q,S,I. The results were obtained using lattice QCD calculations carried out with two degenerate up and down dynamical quarks and a dynamical strange quark, with quark masses corresponding to physical values of pion and kaon masses in the continuum limit. By parameterizing pseudo-critical temperatures as Tc(μX)=Tc(0)[1−κ2X(μX/Tc(0))2−κ4X(μX/Tc(0))4], we determined κ2X and κ4X from Taylor expansions of chiral observables in μX. We obtained a precise result for Tc(0)=(156.5±1.5) MeV. For analogous thermal conditions at the chemical freeze-out of relativistic heavy-ion collisions, i.e., μS(T,μB) and μQ(T,μB) fixed from strangeness-neutrality and isospin-imbalance, we found κ2B=0.012(4) and κ4B=0.000(4). For μB≲300 MeV, the chemical freeze-out takes place in the vicinity of the QCD phase boundary, which coincides with the lines of constant energy density of 0.42(6)GeV/fm3 and constant entropy density of 3.7(5)fm−3.

The thermal stability impedes the application of nanoscale magnetic tunnel junctions in electronic and spintronics devices. Here the authors achieved current-induced magnetization switching in magnetic tunnel junctions smaller than 10 nm with sufficient thermal stability due to the shape anisotropy without adding new material systems.

Abstract The pseudoscalar correlator is an ideal lattice probe for thermal modifications to quarkonium spectra, given that it is not compromised by a contribution from a large transport peak. We construct a perturbative spectral function incorporating resummed thermal effects around the threshold and vacuum asymptotics above the threshold, and compare the corresponding imaginary-time correlators with continuum-extrapolated lattice data for quenched SU(3) at several temperatures. Modest differences are observed, which may originate from non-perturbative mass shifts or renormalization factors, however no resonance peaks are needed for describing the quenched lattice data for charmonium at and above T ∼ 1.1T c ∼ 350 MeV. For comparison, in the bottomonium case a good description of the lattice data is obtained with a spectral function containing a single thermally broadened resonance peak.

We measure ferromagnetic resonance spectra of sputtered Py (20 nm) on (Bi1-xSbx)2Te3 (∼50 nm, x = 0-1) grown by molecular beam epitaxy. The linewidths of the spectra for Py on (Bi1-xSbx)2Te3 are much broader than that of Py directly deposited on a flat Si/SiO2 substrate. We find that the broadening results from spin pumping as well as inhomogeneity in Py induced by surface roughness of underneath (Bi1-xSbx)2Te3.

We study current-induced magnetization switching properties of a magnetic tunnel junction with junction diameter of 19 nm and resistance-area product of 6 Ωμm2 in the nanosecond regime with and without in-plane magnetic field. At zero field, for both parallel (P)-to-anti-parallel (AP) and AP-to-P switchings, the probability of switching PSW approaches unity with the increase of pulse voltage duration τP. However, under in-plane magnetic field, PSW for P-to-AP switching starts to saturate at a value lower than unity with increasing τP, while AP-to-P switching remains the same as in the absence of in-plane magnetic field. This in-plane field dependence of PSW can be partially explained by the influence of electric-field modulation of magnetic anisotropy.

Creep motion of magnetic domain wall (DW), thermally activated DW dynamics under subthreshold driving forces, is a paradigm to understand the interaction between driven interfaces and applied external forces. Previous investigation has shown that DW in a metallic system interacts differently with current and magnetic field, manifesting itself as different universality classes for the creep motion. In this article, we first review the experimental determination of the universality classes for current- and field-driven DW creeps in a Ta/CoFeB/MgO wire, and then elucidate the underlying factors governing the obtained results. We show that the nature of torque arising from current in association with DW configuration determines universality class for the current-induced creep in this system. We also discuss the correlation between the field-induced DW creep characteristics and structure observed by a transmission electron microscope. The observed results are expected to provide a deeper understanding for physics of DW motion in various magnetic materials.

We investigated properties of perpendicular-anisotropy magnetic tunnel junctions (p-MTJs) with [Co/Pt]-multilayer based synthetic ferrimagnetic reference (SyF) layer at elevated annealing temperature Ta from 350°C to 400°C. Shift field HS defined as center field of minor resistance versus magnetic field curve of the MTJs increased with increase of Ta from 350°C to 400°C. The variation of HS is attributed to the variation of saturation magnetic moment in the SyF reference layer. Cross sectional energy dispersive X-ray spectroscopy analysis revealed that Fe element of CoFeB in the reference layer diffuses to Co/Pt multilayers in the SyF reference layer.

Ratios of cumulants of conserved net charge fluctuations are sensitive to the degrees of freedom that are carriers of the corresponding quantum numbers in different phases of strong interaction matter. Using lattice QCD with 2+1 dynamical flavors and quenched charm quarks we calculate second and fourth order cumulants of net charm fluctuations and their correlations with other conserved charges such as net baryon number, electric charge and strangeness. Analyzing appropriate ratios of these cumulants we probe the nature of charmed degrees of freedom in the vicinity of the QCD chiral crossover region. We show that for temperatures above the chiral crossover transition temperature, charmed degrees of freedom can no longer be described by an uncorrelated gas of hadrons. This suggests that the dissociation of open charm hadrons and the emergence of deconfined charm states sets in just near the chiral crossover transition. Till the crossover region we compare these lattice QCD results with two hadron resonance gas models—including only the experimentally established charmed resonances and also including additional states predicted by quark model and lattice QCD calculations. This comparison provides evidence for so far unobserved charmed hadrons that contribute to the thermodynamics in the crossover region.

In this work, we strive to gain insight into thermal modifications of charmonium and bottomonium bound states as well as the heavy quark diffusion coefficient. The desired information is contained in the spectral function which can not be calculated on the lattice directly. Instead, the correlator given by an integration over the spectral function times an integration kernel is obtained. Extracting the spectral function is an ill-posed inversion problem and various different solutions have been proposed. We focus on a comparison to a spectral function obtained from combining perturbative and pNRQCD calculations. In order to get precise results, continuum extrapolated correlators originating from large and fine lattices are used. We first analyze the pseudoscalar channel since the absence of a transport peak simplifies the analysis. The knowledge gained from this is then used to extend the analysis to the vector channel, where information on heavy quark transport is encoded in the low frequency regime of the spectral function. The comparison shows a qualitatively good agreement between perturbative and lattice correlators. Quantitative differences can be explained by systematic uncertainties.

The current-driven magnetization reversal of exchange-biased spin-valve giant magnetoresistive nanopillars with a magnetically pinned ferromagnetic layer is investigated. Current-driven magnetzation reversal of a ferromagnetic layer is found to take place even when the layer is pinned by the exchange bias induced by an antiferromagnet.

The protein μ1B is a member of the medium chain family of the clathrin-associated adaptor complex and is expressed exclusively in epithelial cells. We determined the genomic structure of previously cloned murine genes for μ1B (Ap1m2) and its closely related homolog, μ1A (Ap1m1). Comparison of their genomic structures revealed that the positions of introns are identical between these two genes, except for the insertion of an additional intron in Ap1m1 (intron 4). By contrast, these structures are different from that of the more distantly related Ap2m1 gene encoding μ2. Taken together with the similarity of amino acid sequences among these genes, the data presented in this study suggest that Ap1m1/2 and Ap2m1 diverged long before the separation of Ap1m1 and Ap1m2, which most likely resulted from a relatively recent gene duplication. We also mapped AP1M2 to human chromosome 19p13.2 and Ap1m2 to the proximal region of mouse chromosome 9. The results are consistent with the fact that these regions are syntenic. Copyright © 1999 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We deposit 30 nm thick Cr2MnSb films on a MgO(0 0 1) substrate by magnetron sputtering. X-ray diffraction reveals that the annealing promotes the crystallization of Cr2MnSb from amorphous at as-deposited state to partially crystallized phase, and that the crystallinity improves by raising the annealing temperature. The crystallized phase exhibits full B2 and partial L21 ordering after the annealing above 300 °C. The magnetic and magneto-transport properties reveal that the annealed Cr2MnSb shows magnetic ordering up to ~350 K with small magnetic moment, 0.3µB/formula unit for the sample annealed at 300 °C. We adopt Cr2MnSb as one of the electrodes in magnetic tunnel junctions (MTJs), and observe the switching of junction resistance, when the magnetization direction is reversed by sweeping an external magnetic field. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction plays an important role in the development of podocyte injury in diabetic nephropathy (DN). Tunnelling nanotubes (TNTs) are long channels that connect cells and allow organelle exchange. Mesenchymal stromal cells (MSCs) can transfer mitochondria to other cells through the M-Sec-TNTs system. However, it remains unexplored whether MSCs can form heterotypic TNTs with podocytes, thereby enabling the replacement of diabetes-damaged mitochondria. In this study, we analysed TNT formation, mitochondrial transfer, and markers of cell injury in podocytes that were pre-exposed to diabetes-related insults and then co-cultured with diabetic or non-diabetic MSCs. Furthermore, to assess the in vivo relevance, we treated DN mice with exogenous MSCs, either expressing or lacking M-Sec, carrying fluorescent-tagged mitochondria. MSCs formed heterotypic TNTs with podocytes, allowing mitochondrial transfer, via a M-Sec-dependent mechanism. This ameliorated mitochondrial function, nephrin expression, and reduced apoptosis in recipient podocytes. However, MSCs isolated from diabetic mice failed to confer cytoprotection due to Miro-1 down-regulation. In experimental DN, treatment with exogenous MSCs significantly improved DN, but no benefit was observed in mice treated with MSCs lacking M-Sec. Mitochondrial transfer from exogenous MSCs to podocytes occurred in vivo in a M-Sec-dependent manner. These findings demonstrate that the M-Sec-TNT-mediated transfer of mitochondria from healthy MSCs to diabetes-injured podocytes can ameliorate podocyte damage. Moreover, M-Sec expression in exogenous MSCs is essential for providing renoprotection in vivo in experimental DN., (© 2024 The Author(s).)

Targeted drug delivery in response to external stimuli is therapeutically desirable, but long-term drug retention at the target site after stimulation is turned off remains a challenge. Herein, we present a targeted-delivery strategy via irreversible aggregation of drug carriers in response to mild external heating. We constructed two types of polymeric micelles, DBCO-TRM and Az-TRM, having a thermo-responsive polymer shell based on N-isopropylacrylamide (NIPAAm) and incorporating alkyne and azide moieties, respectively. Upon heating at 42 °C, the micelles aggregated through hydrophobic interaction between their dehydrated shells. Further, the azide moieties of Az-TRM become exposed on the surface due to the thermally shrinkage of the shells, thereby enabling crosslinking between the two types of micelles via azide-alkyne click chemistry to form irreversible aggregates. These aggregates were efficiently accumulated at tumor sites in mice by local heating after intravenous administration of a mixture of the micelles, and were well retained after cessation of heating due to their increased size. As proof of concept, we show that delivery of doxorubicin in this heat-guided drug delivery system dramatically improved the anti-tumor effect in a mouse model after a single treatment. Our results suggest that this platform could be an efficient tool for on-demand drug delivery., Competing Interests: Competing interests: The authors declare no competing interests, (© 2024. The Author(s).)

Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) and IFNγ reporter mice (Nr4a3-Tocky-Ifnγ-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic tumour infiltrating lymphocytes (TILs) exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced central memory (T CM ) formation. Modelling of T-cell-tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2024. The Author(s).)

Genetic studies in mice have shown that the zinc finger transcription factor BCL11B has an essential role in regulating early T cell development and neurogenesis. A de novo heterozygous missense BCL11B variant, BCL11B N441K , was isolated from a patient with T cell deficiency and neurological disorders. Here, we show that mice harboring the corresponding Bcl11b N440K mutation show the emergence of natural killer (NK)/group 1 innate lymphoid cell (ILC1)-like NKp46 + cells in the thymus and reduction in TBR1 + neurons in the neocortex, which are observed with loss of Bcl11a but not Bcl11b. Thus, the mutant BCL11B-N440K protein interferes with BCL11A function upon heterodimerization. Mechanistically, the Bcl11b N440K mutation dampens the interaction of BCL11B with T cell factor 1 (TCF1) in thymocytes, resulting in weakened antagonism against TCF1 activity that supports the differentiation of NK/ILC1-like cells. Collectively, our results shed new light on the function of BCL11A in suppressing non-T lymphoid developmental potential and uncover the pathogenic mechanism by which BCL11B-N440K interferes with partner BCL11 family proteins., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Sea ice is regarded as a temporal sink and carrier of microplastics (MPs). Nevertheless, knowledge and understanding of MPs in sea ice remain sparse. This study investigated the abundance, composition, size (> 30 μm), and shape of MPs in four sea-ice cores retrieved at the southern end of the Sea of Okhotsk. Nine microplastic (MP) types, mostly with fragmentary shapes, were detected among ice-core sections. Most fragmentary MPs were smaller than 120 μm, but all fiber MPs were in the largest size class (> 210 μm). MP concentrations were 0-60 particles/L, with an average of 21 particles/L. Higher occurrences of MPs observed in the lower ice layers are attributable to heavier MP contamination in the southern part of the sea and/or relocation of MPs in the ice matrix. No significant correlation was found between the distributions of MP and inorganic particle (sediment) abundances, implying difference in their kinetics of suspension freezing. Taken together, these findings suggest important implications for elucidating the nature and distribution of MPs in sea ice., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Human gut microbiota plays a crucial role in health and disease. Infancy is a critical period for gut microbiota maturation and immune system development and has the potential to affect long-term health. Understanding the development of gut microbiota in Japanese children is essential because of regional differences and the long-term health effects of the early gut microbiota. However, while several longitudinal studies in Japan have explored the development of the gut microbiota after birth, more extended follow-up periods are still needed. In this study, we aimed to analyze the gut microbiota of 106 Japanese mother-child pairs from the Chiba Study of Mother and Child Health, Japan, over 3.5 years. The results showed that the alpha diversity of the gut microbiota in children increased with age, and its composition began to resemble that of adults. We identified four distinct clusters of gut microbiota that reflected different maturation stages. The similarity between the maternal and child gut microbiota appeared to follow a bimodal-like distribution, suggesting that the presence of older siblings may enhance this similarity. This study highlights the dynamic nature of gut microbiota development in Japanese children and deepens our understanding of the similarities between maternal and child gut microbiota., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Orbital torque (OT) in magnetic heterostructures has been actively discussed in terms of its actual existence and usefulness in comparison to the spin-orbit torque (SOT) that shows promise for next-generation magnetoresistive random access memories. The objectives of this study are 2-fold: (i) making an apples-to-apples comparison in two representative stacks where OT and SOT are expected to dominate and (ii) examining the potential emergence of OT in archetypal SOT stacks. Cr/CoFeB/MgO and W/CoFeB/MgO are chosen as the OT- and SOT-dominant systems, respectively. Systematic variations in each layer's thicknesses reveal that (i) Cr/CoFeB/MgO exhibits substantial torque comparable to or even exceeding that of the W/CoFeB/MgO stack when Cr and CoFeB layers are especially thick and (ii) the torque in W/CoFeB/MgO changes sign with increasing W and CoFeB thicknesses, suggesting a crossover of the dominant mechanism from SOT to OT. The findings clarify the opportunities and challenges of devices leveraging SOT and OT.

Background: The incidence of pancreatic cancer is on the rise, and its prognosis remains poor. Recent reports have established a link between the gut and oral microbiome and pancreatic cancer. However, the intricacies of this association within the Japanese population remain unclear. In this study, we investigated the gut and oral microbiomes of Japanese patients with pancreatic cancer, comparing them with those of healthy individuals., Methods: We recruited 30 patients with untreated pancreatic cancer and 18 healthy controls at Kyoto University Hospital (2018-2022). We performed a comprehensive 16S rRNA gene sequencing to analyze their gut and oral microbiomes., Results: Analysis revealed that the diversity of the gut and oral microbiomes of patients with pancreatic cancer was reduced compared to that of the healthy controls. Specifically, we observed an increase in the genus Streptococcus in both the gut and oral microbiomes and a significant decrease in several butyrate-producing bacteria in fecal samples. Moreover, bacteria such as Streptococcus mitis and Holdemanella biformis were present in pancreatic cancer tissues, suggesting that they might influence the carcinogenesis and progression of pancreatic cancer., Conclusions: The gut and oral microbiome differed between patients with pancreatic cancer and healthy controls, with a notable decrease in butyrate-producing bacteria in the gut microbiome of the patients. This suggests that there may be a distinct microbial signature associated with pancreatic cancer in the Japanese population. Further studies are required to elucidate the microbiome's causal role in this cancer and help develop prognostic markers or targeted therapies., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Surgical treatment of pheochromocytomas is associated with circulatory dynamics instability, necessitating systemic management of the patient in the intensive care unit after surgery. Early mobilization after pheochromocytoma surgery is not described in the guidelines, and to our knowledge, no reports have specifically focused on circulatory dynamics during early mobilization after surgery., Case Presentation: A 31-year-old Japanese woman was diagnosed with bilateral pheochromocytoma and underwent a second-stage adrenalectomy for bilateral pheochromocytoma at our hospital. We evaluated circulatory dynamics during a passive upright posture on postoperative days 1 and 4. She was placed on a tilt bed in the supine position (0° head) for 15 min, passive upright posture (60°) for 15 min, and supine position again for 10 min. In the passive upright posture, both systolic and diastolic blood pressure decreased, and the heart rate increased by 10 bpm over approximately 10 minutes. After the postural change from the passive upright posture to the supine position, the heart rate decreased to a level lower than in the supine prior to the passive upright posture. The same measurements were taken on postoperative day 4. Systolic blood pressure decreased in the passive upright posture, but diastolic blood pressure remained unchanged. The heart rate also increased earlier after passive upright posture compared with that on the day after surgery. When the patient returned to the supine position from the passive upright posture, the heart rate decreased even further compared with its level prior to the passive upright posture, as observed on the day after surgery., Conclusion: Circulatory dynamics may fluctuate after surgery for pheochromocytoma due to a relative decrease in epinephrine and norepinephrine secretion. In this case, the patient's response may be close to normal by the fourth postoperative day, but circulatory dynamics fluctuations were noted on both the first and fourth postoperative days when the patient was supine after passive upright posture. Although the substantial variability of perioperative circulatory dynamics in patients with pheochromocytoma has improved considerably with the development of perioperative management guidelines, circulatory dynamics should be carefully monitored during early mobilization and after its completion., (© 2024. The Author(s).)

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells abundant in human tissues that play a significant role in defense against bacterial and viral infections and in tissue repair. MAIT cells are activated by recognizing microbial-derived small-molecule ligands presented by the MHC class I related-1 protein. Although several MAIT cell modulators have been identified in the past decade, potent and chemically stable ligands remain limited. Herein, we carried out a structure-activity relationship study of ribityllumazine derivatives and found a chemically stable MAIT cell ligand with a pteridine core and a 2-oxopropyl group as the Lys-reactive group. The ligand showed high potency in a cocultivation assay using model cell lines of antigen-presenting cells and MAIT cells. The X-ray crystallographic analysis revealed the binding mode of the ligand to MR1 and the T cell receptor, indicating that it forms a covalent bond with MR1 via Schiff base formation. Furthermore, we found that the ligand stimulated proliferation of human MAIT cells in human peripheral blood mononuclear cells and showed an adjuvant effect in mice. Our developed ligand is one of the most potent among chemically stable MAIT cell ligands, contributing to accelerating therapeutic applications of MAIT cells.

To establish protection against harmful foreign antigens, the small intestine harbors guardian sites called Peyer's patches (PPs). PPs take up antigens through microfold (M) cells and transfer them to the sub-epithelial dome (SED), which contains a high density of mononuclear phagocytes (MPs), for T cell-priming. Accumulating evidence indicates that SED-MPs have unique functions other than T cell-priming to facilitate mucosal immune responses; however, the crucial factors regulating the functions of SED-MPs have not been determined. Here we performed transcriptome analysis, and identified the gene signatures of SED-MPs. Further data interpretation with transcription factor (TF) enrichment analysis estimated TFs responsible for the functions of SED-MPs. Among them, we found that RelB and C/EBPα were preferentially activated in SED-MPs. RelB-deficiency silenced the expression of IL-22BP and S100A4 by SED-MPs. On the other hand, C/EBPα-deficiency decreased the expression of lysozyme by SED-MPs, resulting the increased invasion of orally administered pathogenic bacteria into PPs and mesenteric lymph nodes. Our findings thus demonstrate that RelB and C/EBPα are essential to regulate the functions of SED-MPs., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2024. Published by Elsevier Inc.)

Intraepithelial lymphocytes (IELs) reside in the epithelial layer and protect against foreign pathogens, maintaining the epithelial barrier function in the intestine. Interactions between IEL and epithelial cells are required for IELs to function effectively; however, the underlying molecular machinery remains to be elucidated. In this study, we found that intestinal epithelium-specific deficiency of the clathrin adaptor protein (AP)-1B, which regulates basolateral protein sorting, led to a massive reduction in IELs. Quantitative proteomics demonstrated that dozens of proteins, including known IEL-interacting proteins (E-cadherin, butyrophilin-like 2, and plexin B2), were decreased in the basolateral membrane of AP-1B-deficient epithelial cells. Among these proteins, CD166 interacted with CD6 on the surface of induced IEL. CD166 knockdown, using shRNA in intestinal organoid cultures, significantly inhibited IEL recruitment to the epithelial layer. These findings highlight the essential role of AP-1B-mediated basolateral sorting in IEL maintenance and survival within the epithelial layer. This study reveals a novel function of AP-1B in the intestinal immune system., (© 2024. The Author(s).)

Background: Histiocytic sarcoma (HS) is a rare disease characterized by the presence of neoplastic histiocytes. We herein report an unusual case of HS that caused massive tumor embolism-related transmural necrosis of the small intestine., Case Presentation: A 64-year-old man presented with multiple nodules in the lungs, bone, mediastinum, and subcutaneous tissues that were incidentally detected on preoperative computed tomography for early transverse colon cancer. Approximately two months later, the patient presented with signs of peritoneal irritation suggestive of small intestinal necrosis. Emergency surgery was performed and the necrotic small intestine was resected. Pathological examination revealed small bowel necrosis due to multifocal HS embolism. The postoperative course was uneventful. The patient was unsuccessfully treated with chemotherapy for HS and died 122 days postoperatively., Conclusions: HS can cause massive enteric necrosis due to tumor embolism. Clinicians should be aware of this rare presentation of HS., (© 2024. The Author(s).)

Block copolymers are recognized as a valuable platform for creating nanostructured materials. Morphologies formed by block copolymer self-assembly can be transferred into a wide range of inorganic materials, enabling applications including energy storage and metamaterials. However, imaging of the underlying, often complex, nanostructures in large volumes has remained a challenge, limiting progress in materials development. Taking advantage of recent advances in X-ray nanotomography, we noninvasively imaged exceptionally large volumes of nanostructured hybrid materials at high resolution, revealing a single-diamond morphology in a triblock terpolymer-gold composite network. This morphology, which is ubiquitous in nature, has so far remained elusive in block copolymer-derived materials, despite its potential to create materials with large photonic bandgaps. The discovery was made possible by the precise analysis of distortions in a large volume of the self-assembled diamond network, which are difficult to unambiguously assess using traditional characterization tools. We anticipate that high-resolution X-ray nanotomography, which allows imaging of much larger sample volumes than electron-based tomography, will become a powerful tool for the quantitative analysis of complex nanostructures and that structures such as the triblock terpolymer-directed single diamond will enable the generation of advanced multicomponent composites with hitherto unknown property profiles.

Topological defects-extended lattice deformations that are robust against local defects and annealing-have been exploited to engineer novel properties in both hard and soft materials. Yet, their formation kinetics and nanoscale three-dimensional structure are poorly understood, impeding their benefits for nanofabrication. We describe the fabrication of a pair of topological defects in the volume of a single-diamond network (space group Fd 3 ¯ m) templated into gold from a triblock terpolymer crystal. Using X-ray nanotomography, we resolve the three-dimensional structure of nearly 70,000 individual single-diamond unit cells with a spatial resolution of 11.2 nm, allowing analysis of the long-range order of the network. The defects observed morphologically resemble the comet and trefoil patterns of equal and opposite half-integer topological charges observed in liquid crystals. Yet our analysis of strain in the network suggests typical hard matter behaviour. Our analysis approach does not require a priori knowledge of the expected positions of the nodes in three-dimensional nanostructured systems, allowing the identification of distorted morphologies and defects in large samples., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Food components suppressing small intestinal tumorigenesis are not well-defined partly because of the rarity of this tumor type compared to colorectal tumors. Using Apc min/+ mice, a mouse model for intestinal tumorigenesis, and antigen-free diet, we report here that food antigens serve this function in the small intestine. By depleting Peyer's patches (PPs), immune inductive sites in the small intestine, we found that PPs have a role in the suppression of small intestinal tumors and are important for the induction of small intestinal T cells by food antigens. On the follicle-associated epithelium (FAE) of PPs, microfold (M) cells pass food antigens from lumen to the dendritic cells to induce T cells. Single-cell RNA-seq (scRNA-seq) analysis of immune cells in PPs revealed a significant impact of food antigens on the induction of the PP T cells and the antigen presentation capacity of dendritic cells. These data demonstrate the role of food antigens in the suppression of small intestinal tumorigenesis by PP-mediated immune cell induction., 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 © 2024 Sasaki, Ota, Takikawa, Terrooatea, Kanaya, Takahashi, Taguchi-Atarashi, Tachibana, Yabukami, Surh, Minoda, Kim and Ohno.)

Objective Atrial fibrillation (AF) is the most common cause of tachycardia-induced cardiomyopathy (TIC). However, which patients with AF are prone to developing TIC remains unclear. In this study, we investigated the clinical features of AF patients with TIC. Methods This single-center study included 722 patients with AF (average age, 63.1±10.2 years old; 191 women) who underwent radiofrequency catheter ablation. We defined TIC as an initial left ventricular ejection fraction (LVEF) of <40% and a >20% recovery of the LVEF after successful AF ablation and compared the clinical characteristics between the TIC and control groups. Results The proportions of type 2 diabetes (30.5% vs. 14.7%), renal dysfunction (34.2% vs. 23.8%), hypertension (67.1% vs. 54.8%), and persistent AF (62.2% vs. 32.2%) were significantly higher in the TIC group (n=82) than in the control group (n=640). The atrioventricular nodal effective refractory period (AVNERP) (303±72 ms vs. 332±86 ms; p=0.017) was significantly shorter in the TIC group than in the control group. A multivariable analysis found that persistent AF [odds ratio (OR), 3.19; 95% confidence interval (CI), 1.94-5.24], renal dysfunction (OR, 1.87; 95% CI, 1.06-3.32), and type 2 diabetes (OR, 2.30; 95% CI, 1.31-4.05) were significantly associated with TIC. Conclusion Comorbid renal dysfunction and type 2 diabetes were clinical features of AF patients with TIC. Persistent AF, and short AVNERP may be involved in the development of TIC.

Context: In recent studies of childhood cancer survivors, diabetes has been considered a late effect associated with high therapeutic doses of radiation therapy. Our recent study of atomic bomb (A-bomb) survivors also suggested an association between radiation dose and diabetes incidence, with exposure city and age at exposure as radiation dose effect modifiers. Insulin resistance mediated by systemic inflammation and abnormal body composition has been suggested as a possible primary mechanism for the incidence of diabetes after total body irradiation, however, no studies have examined low-to- moderate radiation exposure (<4 Gy) and insulin resistance in A-bomb survivors., Objectives: To examine the association between radiation dose and markers of inflammation and insulin resistance., Methods: This study investigated 3,152 survivors who underwent a health examination between 2008 and 2012 and who were younger than 15 years at exposure. Multivariate linear regression analyses were used to evaluate the radiation effects on levels of markers of inflammation and insulin resistance., Results: Radiation dose was significantly and positively associated with levels of CRP, triglycerides, homeostasis model assessment of β-cell function (HOMA-β), and HOMA of insulin resistance (HOMA-IR) after adjustment for relevant covariates including sex, city, and age at exposure. Adiponectin and HDL cholesterol levels were also associated significantly and negatively with radiation dose. However, city was not a dose modifier of the radiation response on these markers of inflammation and insulin resistance., Conclusions: Insulin resistance might be a possible factor in the radiation related diabetes incidence in the A-bomb survivors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Aim: This study aimed to analyze two cases of marked hypo-high-density lipoprotein (HDL) cholesterolemia to identify mutations in ATP-binding cassette transporter A1 (ABCA1) and elucidate the molecular mechanism by which these novel pathological mutations contribute to hypo-HDL cholesterolemia in Tangier disease., Methods: Wild type and mutant expression plasmids containing a FLAG tag inserted at the C-terminus of the human ABCA1 gene were generated and transfected into HEK293T cells. ABCA1 protein expression and cholesterol efflux were evaluated via Western blotting and efflux assay. The difference in the rate of change in protein expression was evaluated when proteolytic and protein-producing systems were inhibited., Results: In case 1, a 20-year-old woman presented with a chief complaint of gait disturbance. Her HDL-C level was only 6.2 mg/dL. Tangier disease was suspected because of muscle weakness, decreased nerve conduction velocity, and splenomegaly. Whole-exome analysis showed compound heterozygosity for a W484* nonsense mutation and S1343I missense mutation, which confirmed Tangier disease. Cholesterol efflux decreased by a mixture of W484* and S1343I mutations. The S1343I mutation decreased the protein production rate but increased the degradation rate, decreasing the protein levels. This patient also had Krabbe disease. The endogenous ABCA1 protein level of macrophage cell decreased by knocking down its internal galactocerebrosidase. Case 2, a 51-year-old woman who underwent tonsillectomy presented with peripheral neuropathy, corneal opacity, and HDL-C of 3.4 mg/dL. Whole-exome analysis revealed compound heterozygosity for R579* and R1572* nonsense mutations, which confirmed Tangier disease., Conclusion: Case 1 is a new ABCA1 mutation with complex pathogenicity, namely, a W484*/S1343I compound heterozygote with marked hypo-HDL cholesterolemia. Analyses of the compound heterozygous mutations indicated that decreases in ABCA1 protein levels and cholesterol efflux activity caused by the novel S1343I mutation combined with loss of W484* protein activity could lead to marked hypo-HDL cholesterolemia. Galactocerebrosidase dysfunction could also be a potential confounding factor for ABCA1 protein function.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by a polyarticular synovitis. In recent years, elderly onset rheumatoid arthritis (EORA) has been increasing. Treg cells in RA have been reported to be dysfunctional, but the relationship between aging and their functional changes is unclear. Here, we found that Treg cells from EORA patients had increased percentages, but decreased activity compared to those from younger onset RA (YORA) patients. In experiments using arthritis model mice, decreased suppressive function and oxygen consumption rate (OCR) were observed in Treg cells only from old arthritic mice. Furthermore, type I interferon (IFN) signaling was upregulated in Treg cells from old GIA mice, and IFN-β decreased the suppressive function of Treg cells. Our findings demonstrate that increased type I IFN signaling in old Treg cells is induced only in the arthritic environment and relates to decreased suppressive function of Treg cells, gets involved in EORA., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gut bacteria are linked to neurodegenerative diseases but the risk factors beyond microbiota composition are limited. Here we used a pre-clinical model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), to identify microbial risk factors. Mice with different genotypes and complex microbiotas or six combinations of a synthetic human microbiota were analysed, resulting in varying probabilities of severe neuroinflammation. However, the presence or relative abundances of suspected microbial risk factors failed to predict disease severity. Akkermansia muciniphila, often associated with MS, exhibited variable associations with EAE severity depending on the background microbiota. Significant inter-individual disease course variations were observed among mice harbouring the same microbiota. Evaluation of microbial functional characteristics and host immune responses demonstrated that the immunoglobulin A coating index of certain bacteria before disease onset is a robust individualized predictor of disease development. Our study highlights the need to consider microbial community networks and host-specific bidirectional interactions when aiming to predict severity of neuroinflammation., (© 2024. The Author(s).)

The fungus Wickerhamiella pararugosa (Candida pararugosa) has been detected in various human organs but has rarely caused bloodstream infections. This report presents a case of central venous catheter-related bloodstream infection (CRBSI) of W. pararugosa in an adult. A female patient in her 80s was admitted to our facility for intestinal obstruction caused by colorectal cancer. The patient's ability to consume food was hindered, necessitating the insertion of a central venous catheter (CVC) into the internal jugular vein. On day 3 after admission, the patient developed a fever, prompting blood and CVC tip cultures to be performed. On day 5, yeast-like fungi were discovered in the blood cultures, and fosfluconazole (fluconazole [FLCZ] pro-drug) treatment was initiated. On day 8, yeast-like fungi were identified in both the blood and CVC tip cultures, leading to a diagnosis of CRBSI. The fungus was identified as W. pararugosa through biochemical and genetic characterization. This finding justified the use of micafungin (MCFG) for combination therapy. On day 17, the minimum inhibitory concentrations (MIC) for FLCZ and MCFG were 4-8 and 0.06 μg/mL, respectively. Accordingly, the treatment was changed to monotherapy with MCFG. After a 21-day treatment regimen, the patient was discharged on day 31. We present a case of CRBSI caused by W. pararugosa in an adult with intestinal obstruction. The notable increase in the MIC of FLCZ necessitated monotherapy with MCFG, which resulted in successful recovery of the patient., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Sulfilimines and their derivatives have garnered considerable interest in both synthetic and medicinal chemistry. Photochemical nitrene transfer to sulfides is known as a conventional synthetic approach to sulfilimines. However, the existing methods have a limited substrate scope stemming from the incompatibility of singlet nitrene intermediates with nucleophilic functional groups. Herein, we report the synthesis of N-sulfonyl sulfilimines via visible-light-mediated energy transfer to sulfonyl azides, uncovering the previously overlooked reactivity of triplet nitrenes with sulfides. This reaction features broad functional group tolerance, water compatibility, and amenability to the late-stage functionalization of drugs. Thus, this work represents an important example of energy transfer chemistry that overcomes challenges in traditional synthetic methods., (© 2024 Wiley-VCH GmbH.)

Weight faltering (WF) has been associated with stunting and with long-term adverse consequences for health and development. Nutritional care for managing WF may consist of giving nutritional advice (NA) and/or provision of oral nutrition supplements (ONSs). In this study, we aimed to evaluate practical management options in the community for infants with WF aged 6-12 months. This nonrandomized clinical trial was conducted in the community of Makassar, South Sulawesi, from March 2022 to March 2023. A total of 1013 infants were enrolled for screening. Anthropometric measures were performed in 913 infants, of which 170 showed WF below the 15th percentile of the WHO weight increment table without stunting. Infants with a weight increment below P5th were assigned to receive NA plus ONS, while infants between P5th and below P15th were assigned to receive only NA. At the second and third months, ONSs were administered to WF infants who were below P15th. One month after the intervention, 87/105 infants in the NA-plus-ONS group (82.8%) and 52/65 infants in the NA-only group (80%) were no longer WF. After 3 months, infants in the NA-plus-ONS group achieved greater weight gain than infants in the NA group (264.1 g vs. 137.4 g, p < 0.001) as well as greater length gain (2.35 cm vs. 2.14 cm, p < 0.001). WF management should be started at below P15th to achieve a better result. Infants with greater nutritional deficits should be assigned to receive the combination of NA plus ONSs to achieve a higher rate of resolution of growth.

Interleukin-6 (IL-6), a multifunctional cytokine, is an attractive therapeutic target for immunological and inflammatory diseases. We investigated the chemical synthesis of IL-6 and its enantiomer (d-IL-6) using a sequential N-to-C native chemical ligation strategy from six peptide segments. Solubilizing Trt-K 10 tags improved the intermediate solubility and served as protecting groups during the metal-free desulfurization to facilitate the synthesis of full-length IL-6 protein. Synthetic l-IL-6 and recombinant IL-6 exhibited nearly identical structural and binding properties. The symmetrical binding property of d-IL-6 was also demonstrated by functional analysis using IL-6-binding peptides. The resulting functional d-IL-6 was employed to screen a phage-displayed antibody fragment library, leading to the identification of several d-IL-6-binding single-domain antibodies. This work will contribute to the development of novel, potent IL-6 inhibitors without the adverse effects of undesired immune activation.

Background: Western guidelines often recommend biguanides as the first-line treatment for diabetes. However, dipeptidyl peptidase-4 (DPP-4) inhibitors, alongside biguanides, are increasingly used as the first-line therapy for type 2 diabetes (T2DM) in Japan. However, there have been few studies comparing the effectiveness of biguanides and DPP-4 inhibitors with respect to diabetes-related complications and cardio-cerebrovascular events over the long term, as well as the costs associated., Objective: We aimed to compare the outcomes of patients with T2DM who initiate treatment with a biguanide versus a DPP-4 inhibitor and the long-term costs associated., Methods: We performed a cohort study between 2012 and 2021 using a new-user design and the Shizuoka Kokuho database. Patients were included if they were diagnosed with T2DM. The primary outcome was the incidence of cardio-cerebrovascular events or mortality from the initial month of treatment; and the secondary outcomes were the incidences of related complications (nephropathy, renal failure, retinopathy, and peripheral neuropathy) and the daily cost of the drugs used. Individuals who had experienced prior events during the preceding year were excluded, and events within 6 months of the start of the study period were censored. Propensity score matching was performed to compare between two groups., Results: The matched 1:5 cohort comprised 529 and 2,116 patients who were initially treated with a biguanide or a DPP-4 inhibitor, respectively. Although there were no significant differences in the incidence of cardio-cerebrovascular events or mortality and T2DM-related complications between the two groups (p = 0.139 and p = 0.595), daily biguanide administration was significantly cheaper (mean daily cost for biguanides, 61.1 JPY; for DPP-4 inhibitors, 122.7 JPY; p<0.001)., Conclusion: In patients with T2DM who initiate pharmacotherapy, there were no differences in the long-term incidences of cardio-cerebrovascular events or complications associated with biguanide or DPP-4 use, but the former was less costly., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nakatani 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.)

Background: Observational studies have reported associations between primary aldosteronism (PA) and cardiovascular outcomes, including coronary artery diseases (CAD), congestive heart failure (CHF), and stroke. However, establishing causality remains a challenge due to the lack of randomized controlled trial data on this topic. We thus aimed to investigate the causal relationship between PA and the risk of developing CAD, CHF, and stroke., Methods and Results: Cross-ancestry meta-analysis of genome-wide association studies combining East Asian and European ancestry (1560 PA cases and 742 139 controls) was conducted to identify single-nucleotide variants that are associated with PA. Then, using the identified genetic variants as instrumental variables, we conducted the 2-sample Mendelian randomization analysis to investigate the causal relationship between PA and incident CAD, CHF, and stroke among both East Asian and European ancestry. Summary association results were extracted from large genome-wide association studies consortia. Our cross-ancestry meta-analysis of East Asian and European populations identified 7 genetic loci significantly associated with the risk of PA, for which the genes nearest to the lead variants were CASZ1 , WNT2B , HOTTIP , LSP1 , TBX3 , RXFP2 , and NDP . Among the East Asian population, the pooled odds ratio estimates using these 7 genetic instruments of PA were 1.07 (95% CI, 1.03-1.11) for CAD, 1.10 (95% CI, 1.01-1.20) for CHF, and 1.13 (95% CI, 1.09-1.18) for stroke. The results were consistent among the European population., Conclusions: Our 2-sample Mendelian randomization study revealed that PA had increased risks of CAD, CHF, and stroke. These findings highlight that early and active screening of PA is critical to prevent future cardiovascular events.

Introduction: Type 2 diabetes (T2D) represents a remarkable disease burden in Japan, and the cost-effectiveness of pharmacotherapy is an important consideration. In this study, we compared the long-term effects of the type of initial medication, as well as the initial frequency of clinic visits, on the occurrence of T2D-related complications. Additionally, we compared the medical costs associated with each treatment pattern., Methods: We analyzed electronic health record data collected from multiple primary care clinics in Japan. Patients were selected based on being primarily prescribed either biguanides (BG) or DPP-4 inhibitors (DPP-4i) during a 3-month baseline period, both of which are commonly used as first-choice medications in Japan. We then followed the onset of T2D-related complications and conducted survival analyses. Additionally, we calculated the accumulated medical costs up to the onset of an event or loss to follow-up, and summarized the annual costs per patient for each treatment pattern., Results: A total of 416 Japanese patients with T2D who initiated treatment between January 2015 and September 2021 were included. The median follow-up period was 2.69 years. The survival analysis showed that the use of DPP-4is and frequent visits from the beginning of treatment did not offer a benefit in suppressing the onset of complications later on. On the other hand, it was found that the annual medical costs for the group using DPP-4i with frequent visits were about 1.9 times higher than for the group using BGs with less frequent visits., Conclusions: The results suggest that for Japanese patients with T2D, the use of BGs along with relatively long follow-up intervals in the beginning of treatment can remarkably reduce medical costs while providing a level of complication suppression equivalent to that of the use of DPP-4is or frequent visits., (© 2024. The Author(s).)

We describe two types of IGH :: BCL2 breakpoints involving the 5' region of BCL2 (5' BCL2 ). One was ins(14;18)(q32;q21q21) observed in 2 follicular lymphoma (FL) cases, in which IGH was cleaved at 3' of IGHD and 5' of IGHJ and BCL2 was cleaved at 5' BCL2 and downstream regions, and a 281- or 201-kilobase pair fragment containing the BCL2 protein-coding sequences was invertedly inserted into IGH . In another type observed in 2 FL and 2 chronic lymphocytic leukemia (CLL) cases, breakage and reunion occurred within the switch region associated with IGHM (Sµ) and 5' BCL2 , creating IGH Sµ::5' BCL2 fusion sequences on der(18)t(14;18)(q32;q21). The former is considered to be mediated by VDJ -recombination, while the latter by the class switch recombination process. There were no particular features in FL or CLL cases with IGH ::5' BCL2 breakpoints compared with those with t(14;18)(q32;q21)/ IGH :: BCL2 involving the 3' breakpoint cluster regions.