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Abstract We use the Magnetospheric Multiscale mission (MMS) to study electron acceleration at Earth's quasi‐perpendicular bow shock to address the long‐standing electron injection problem. The observations are compared to the predictions of the stochastic shock drift acceleration (SSDA) theory. Recent studies based on SSDA predict electron distribution being a power law with a cutoff energy that scales with upstream parameters. This scaling law has been successfully tested for a single Earth's bow shock crossing by MMS. Here we extend this study and test the prediction of the scaling law for seven MMS Earth's bow shock crossings with different upstream parameters. A goodness‐of‐fit test shows good agreement between observations and SSDA theoretical predictions, thus supporting SSDA as one of the most promising candidates for solving the electron injection problem.

Acute lymphoblastic leukemia (ALL) is a challenging disease with a growing genetic landscape, even though there is substantial gap between developed and non-developed countries when it comes to availability of such new technologies. This manuscript reports a 5-year retrospective cohort of newly diagnosed ALL patients and their genetic findings and outcomes. An expanded genetic evaluation by using FISH and RT–PCR was implemented, aiming to identify Ph-like alterations. Patients were treated according to our local protocol, which allocated patients according to age and Philadelphia-chromosome status. A total of 104 patients was included, with median age of 37.5 years. Philadelphia chromosome was detected in 33 cases of B-lineage. Among 45 Ph-negative B-lineage, after excluding KMT2A or TCF3-PBX1 cases, we identified 9 cases with Ph-like fusion. Ph-positive and Ph-like patients had higher initial WBC (p = 0.06). Out of 104 cases, two cases did not start chemotherapy and an early death rate of 10.8% was found. Allogeneic transplantation was performed in 18 cases, being ten performed in first CR. Three-year overall survival (OS) and 3-year event-free survival were 42.8% and 30.8%, respectively. For patients treated with a pediatric regimen, 3-year OS was 52.5%. Extramedullary disease (HR 0.42) and platelet counts (HR 0.9) were independently associated with OS. We still face excessive non-relapse mortality that compromises our results. Alternative strategies implementing FISH and RT–PCR are feasible and able to identify Ph-like fusions. Delays in allogeneic transplantation, as well as the unavailability of new agents, impact long-term survival. Measures to decrease early infection are desirable.

Excitation of whistler-mode waves by cyclotron instability is considered as the likely generation process of the waves. Here, the authors show direct observational evidence for locally ongoing secular energy transfer from the resonant electrons to the whistler-mode waves in Earth’s magnetosheath.

Background: In the resting conditions, narrowing the window of coronary pressure measurements from the whole cardiac cycle to diastole improves diagnostic performance of coronary pressure–derived physiological index. However, whether this also applies to the hyperemic conditions has not yet been thoroughly evaluated. Objectives: The purpose of this study was to assess whether diastolic fractional flow reserve (diastolic FFR) has better diagnostic performance in identifying ischemia-causing coronary lesions than conventional FFR in a prospective, multicenter, and independent core laboratory–based environment. Methods: In this prospective multicenter registry at 29 Japanese centers, we compared the diagnostic performance of FFR, diastolic FFR, resting distal to aortic coronary pressure (Pd/Pa), and diastolic pressure ratio (dPR) using myocardial perfusion scintigraphy (MPS) as the reference standard in 378 patients with single-vessel coronary disease. Results: Inducible myocardial ischemia was found on MPS in the relevant myocardial territory of the target vessel in 85 patients (22%). In the receiver-operating curve analyses, diastolic FFR had comparable area under the curve (AUC) compared with FFR (AUCdiastolic FFR: 0.66; 95% confidence interval [CI]: 0.58-0.73, vs AUCFFR: 0.66; 95% CI: 0.58-0.74, P = 0.624). FFR and diastolic FFR showed significantly larger AUCs than resting Pd/Pa (0.62; 95% CI: 0.54-0.70; P = 0.033 and P = 0.046) but did not show significantly larger AUCs than dPR (0.62; 95% CI: 0.55-0.70; P = 0.102 and P = 0.113). Conclusions: Diastolic FFR showed a similar diagnostic performance to FFR as compared with MPS. This result reaffirms the use of FFR as the most accurate invasive physiological lesion assessment. (Diagnostic accuracy of diastolic fractional flow reserve (d-FFR) for functional evaluation of coronary stenosis; UMIN000015906)

In a honeycomb-lattice spin-orbit assisted Mott insulator α-RuCl_{3}, ultrafast magnetization is induced by circularly polarized excitation below the Mott gap. Photocarriers play an important role, which are generated by turning down the synergy of the onsite Coulomb interaction and the spin-orbit interaction realizing the insulator state. An ultrafast 6 fs measurement of photocarrier dynamics and a quantum mechanical analysis clarify the mechanism, according to which the magnetization emerges from a coherent charge motion between different t_{2g} orbitals (d_{yz}-d_{xz}-d_{xy}) of Ru^{3+} ions. This ultrafast magnetization is weakened in the antiferromagnetic (AFM) phase, which is opposite to the general tendency that the inverse Faraday effect is larger in AFM compounds than in paramagnetic ones. This temperature dependence indicates that the interorbital charge motion is affected by pseudospin rotational symmetry breaking in the AFM phase.

Background The role of antithrombotic chemoprophylaxis in prevention of venous thromboembolism (VTE) in laparoscopic surgery for gastric and colorectal malignancies is unknown. This study compared the addition of enoxaparin following intermittent pneumatic compression (IPC) with IPC alone in patients undergoing laparoscopic surgery for gastrointestinal malignancy. Methods In this multicentre RCT, eligible patients were older than 40 years and had a WHO performance status of 0 or 1. Exclusion criteria were prescription of antiplatelet or anticoagulant drugs and history of VTE. Patients were allocated to IPC or to ICP with enoxaparin in a 1 : 1 ratio. Stratification factors included sex, location of cancer, age 61 years and over, and institution. Enoxaparin was administered on days 1–7 after surgery. Primary outcome was VTE, evaluated by multidetector CT on day 7. Results Of 448 patients randomized, 208 in the IPC group and 182 in the IPC with enoxaparin group were evaluated. VTE occurred in ten patients (4·8 per cent) in the IPC group and six (3·3 per cent) in the IPC with enoxaparin group (P = 0·453). Proximal deep vein thrombosis and/or pulmonary embolism occurred in seven patients (3·4 per cent) in the IPC group and one patient (0·5 per cent) in the IPC with enoxaparin group (P = 0·050). All VTE events were asymptomatic and non‐fatal. Bleeding occurred in 11 of 202 patients in the IPC with enoxaparin group, and one patient needed a transfusion. All bleeding events were managed by discontinuation of the drug. Conclusion IPC with enoxaparin after laparoscopic surgery for gastric and colorectal malignancies did not reduce the rate of VTE. Registration number: UMIN000011667 ( https://www.umin.ac.jp/).

Here the authors show second harmonic generation (SHG) from a centrosymmetric organic superconductor κ-(BEDT-TTF)2Cu[N(CN)2]Br. They find unusual temperature dependence and CEP-sensitive nature of the SHG which are explained in terms of nonlinear current.

Abstract Background NUT midline carcinoma is a rare and aggressive subset of squamous cell carcinoma, which is characterized by the translocation of nuclear protein in testis gene that is mostly fused with bromodomain and extraterminal family proteins. We describe here the first Brazilian case of NUT midline carcinoma with BRD4-NUT fusion detected in a next-generation sequencing panel and we present the clinical evolution of this patient. Case presentation A 42-year-old Caucasian man was diagnosed with poorly differentiated squamous cell carcinoma of the left maxillary sinus, with negative in situ hybridization for Epstein–Barr encoding region and human papillomavirus genotyping. He received induction therapy, chemoradiotherapy with weekly systemic chemotherapy, and, concurrently, weekly intra-arterial chemotherapy. New imaging evaluation, 1 month after the end of the last treatment, revealed a good partial response in the primary lesion. However, positron emission tomography-computed tomography showed multiple suspicious lesions in his bones and lungs, which were histologically confirmed. He died exactly 2 months after metastatic disease was diagnosed. Conclusions NUT midline carcinoma is usually very aggressive. Currently, there is no standard of care for treatment of NUT midline carcinoma. The definitive diagnosis must be by demonstration of NUTM1 rearrangement. Immunohistochemical staining of greater than 50% of tumor nuclei on formalin-fixed paraffin-embedded tissue using the monoclonal rabbit antibody to NUT (clone C52B1), has a specificity of 100%, and sensitivity of 87% for the diagnosis of NUT midline carcinoma. Our case is the first Brazilian case of NUT midline carcinoma with BRD4-NUT fusion.

Teenagers generally present mild to no symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present report, we present the case of a 14-year-old boy with Angelman syndrome (AS) who presented with severe COVID-19 symptoms. He spent 20 days in the ICU with elevated inflammatory biomarkers (C-reactive protein and D-dimer) and increased peaks of neutrophil-to-lymphocyte ratio, which is uncommon for teenagers diagnosed with COVID-19. Although he showed physiological instability, he was able to produce neutralizing antibodies, suggesting a functional immune response. The literature concerning the immune response to infections in patients with AS is still poor, and to our knowledge, this was the first report of a patient with AS diagnosed with COVID-19. As such, the present study may alert other patients with AS or other rare diseases that they lack a competent immune response and could suffer severe consequences of SARS-CoV-2 infection.

Abstract Storm time Pc5 waves are considered to be excited through the drift‐bounce resonance by ring current ions associated with the injection from the magnetotail. Using the Geospace Environment Modeling System for Integrated Studies–Ring Current simulation, a drift‐kinetic and self‐consistent model for ring current particles, we investigate the excitation mechanism of these waves in the inner magnetosphere. The power spectra of electromagnetic field fluctuations show the excitation of both poloidal and toroidal mode waves in Pc5 frequency range. It is found that these waves are fundamental mode waves with the azimuthal wave number m~ − 20 and excited through the drift resonance with the drifting ions with energies of 80–120 keV. The simulation indicates that global distribution of wave power coincides with the positive local growth rate mainly contributed by the positive phase space density gradient in energy.

Background: The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. Methods and results: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012–2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P

Leptospirosis is considered one of the most important zoonosis worldwide. The activation of the Complement System is important to control dissemination of several pathogens in the host. Only a few studies have employed murine models to investigate leptospiral infection and our aim in this work was to investigate the role of murine C5 during in vivo infection, comparing wild type C57BL/6 (B6 C5+/+) and congenic C57BL/6 (B6 C5−/−, C5 deficient) mice during the first days of infection. All animals from both groups survived for at least 8 days post-infection with pathogenic Leptospira interrogans serovar Kennewicki strain Fromm (LPF). At the third day of infection, we observed greater numbers of LPF in the liver of B6 C5−/− mice when compared to B6 C5+/+ mice. Later, on the sixth day of infection, the LPF population fell to undetectable levels in the livers of both groups of mice. On the third day, the inflammatory score was higher in the liver of B6 C5+/+ mice than in B6 C5−/− mice, and returned to normal on the sixth day of infection in both groups. No significant histopathological differences were observed in the lung, kidney and spleen from both infected B6 C5+/+ than B6 C5−/− mice. Likewise, the total number of circulating leukocytes was not affected by the absence of C5. The liver levels of IL-10 on the sixth day of infection was lower in the absence of C5 when compared to wild type mice. No significant differences were observed in the levels of several inflammatory cytokines when B6 C5+/+ and B6 C5−/− were compared. In conclusion, C5 may contribute to the direct killing of LPF in the first days of infection in C57BL/6 mice. On the other hand, other effector immune mechanisms probably compensate Complement impairment since the mice survival was not affected by the absence of C5 and its activated fragments, at least in the early stage of this infection.

Mesenchymal stromal cells (MSCs) are multipotent cells with abilities to exert immunosuppressive response promoting tissue repair. Studies have shown that MSCs can secrete extracellular vesicles (MVs-MSCs) with similar regulatory functions to the parental cells. Furthermore, strong evidence suggesting that MVs-MSCs can modulate several immune cells (i.e., Th1, Th17, and Foxp3+ T cells). However, their precise effect on macrophages (Mϕs) remains unexplored. We investigated the immunoregulatory effect of MVs-MSCs on activated M1-Mϕs in vitro and in vivo using differentiated bone marrow Mϕs and an acute experimental model of thioglycollate-induced peritonitis, respectively. We observed that MVs-MSCs shared surface molecules with MSCs (CD44, CD105, CD90, CD73) and expressed classical microvesicle markers (Annexin V and CD9). The in vitro treatment with MVs-MSCs exerted a regulatory-like phenotype in M1-Mϕs, which showed higher CD206 level and reduced CCR7 expression. This was associated with decreased levels of inflammatory molecules (IL-1β, IL-6, nitric oxide) and increased immunoregulatory markers (IL-10 and Arginase) in M1-Mϕs. In addition, we detected that MVs-MSCs promoted the downregulation of inflammatory miRNAs (miR-155 and miR-21), as well as, upregulated its predicted target gene SOCS3 in activated M1-Mϕs. In vivo MVs-MSCs treatment reduced the Mϕs infiltrate in the peritoneal cavity inducing a M2-like regulatory phenotype in peritoneal Mϕs (higher arginase activity and reduced expression of CD86, iNOS, IFN-γ, IL-1β, TNF-α, IL-1α, and IL-6 molecules). This in vivo immunomodulatory effect of MVs-MSCs on M1-Mϕs was partially associated with the upregulation of CX3CR1 in F4/80+/Ly6C+/CCR2+ Mϕs subsets. In summary, our findings indicate that MVs-MSCs can modulate an internal program in activated Mϕs establishing an alternative regulatory-like phenotype.

Abstract.Objective and Design:??The role of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, was tested using a mouse asthma model.Materials:??One hundred and four male BALB/c mice were used in this study.Treatment:??Mice were actively sensitized with an intraperitoneal injection of ovalbumin (OVA) and challenged with repeated nebulization of 1 w/v% OVA. Polyclonal anti-MIF antibody was intraperitoneally injected at 10 mg/kg during the antigen challenge period.Methods:??Bronchoalveolar lavage (BAL) was performed 8 h after the last challenge. Airway hyperresponsiveness to inhaled methacholine was measured 24 h after the last challenge.Results:??Antigen challenge to immunized mice induced increase in inflammatory cells and concentration of Th2 cytokines in BAL fluid (BALF), and caused the development of airway hyperresponsiveness. Anti-MIF antibody significantly decreased the numbers of inflammatory cells including macrophages, eosinophils, lymphocytes and neutrophils in BALF from OVA-challenged mice. Prednisolone decreased the numbers of eosinophils, lymphocytes and neutrophils but not macrophages. Anti-MIF antibody reduced airway hyperresponsiveness. Anti-MIF antibody affected neither the cytokine levels in BALF nor the IgE levels in serum.Conclusion:??MIF was involved in the antigen-induced inflammatory cell accumulation in the lung and airway hyperresponsiveness without affecting immune responses. [ABSTRACT FROM AUTHOR]

We fabricated a GaAlAs-GaAs thermally tunable vertical-cavity filter with a thermal strain control layer and heating element on a micromachined cantilever structure. We achieved a large negative temperature dependence of -0.79 nm/K for the vertical-cavity filter by loading a GaAs strain control layer. The tuning voltage is as low as 4.9 V for wavelength tuning of 18.1 nm. We examined the dynamic response of the thermally tunable micromachined GaAlAs-GaAs filter, exhibiting both rise time and fall time of below 100 μs. [ABSTRACT FROM PUBLISHER]

We report extragalactic observations of two fluorine-bearing species, hydrogen fluoride (HF) and fluoronium (H2F+), in the z = 0.89 absorber in front of the lensed blazar PKS 1830−211 with the Atacama Large Millimeter/submillimeter Array. HF was detected toward both southwest and northeast images of the blazar, with column densities >3.4 × 1014 cm−2 and 0.18 × 1014 cm−2, respectively. H2F+ was not detected, down to an upper limit (3σ) of 8.8 × 1011 cm−2 and an abundance ratio of [H2F+]/[HF] 1/386. We also searched for H2F+ toward the Galactic sources NGC 6334 I and W51C, and toward Galactic center clouds with the Herschel HIFI spectrometer.6 The upper limit on the column density was derived to be 2.5 × 1011 cm−2 in NGC 6334 I, which is 1/68 of that for H2Cl+. In constrast, the ortho transition of H2Cl+ is detected toward PKS 1830–211. To understand the small abundance of interstellar H2F+, we carried out laboratory experiments to determine the rate constants for the ion–electron recombination reaction by infrared time-resolved spectroscopy. The constants determined are ke(209 K) = cm3 s−1 and cm3 s−1 for H2F+ and H2Cl+, respectively. The difference in the dissociative recombination rates between H2F+ and H2Cl+ by a factor ∼2 and the cosmic abundance ratio [F]/[Cl] ≈ 1/6 are not enough to explain the much smaller abundance of H2F+. The difference in the formation mechanism of H2F+ and H2Cl+ in interstellar space would be a major factor in the small abundance of H2F+. [ABSTRACT FROM AUTHOR]

Perturbation of circadian rhythm is believed to be detrimental to the physiology of organs, including the mammalian ovary. However, the molecular mechanisms that are regulated by circadian rhythm in the ovary have not been identified. To identify the molecular mechanisms that are regulated by circadian rhythm and to speculate on the physiologies that are likely to be damaged by perturbation of circadian rhythm in the ovary, we searched for genes in which the amount of transcripts oscillates every 24 h in the mouse ovary. To achieve this, expression profiles of circadian genes (per1, per2, and bmal1) that code transcription-regulation factors for which transcription activities are known to oscillate every 24 h in almost all organs, and wee1, the transcription activity of which circadian genes regulate and which is known to elongate the G2 phase in the cell cycle, were analyzed in this study. Six-week-old female ICR mice were kept individually under a lighting schedule with lights on for 14 h followed by lights off for 10 h. A vaginal smear of each mouse was collected every day to determine its estrous cycle. Ovaries of 3 mice were collected continuously every 4 h over a 4-day period from the start of the light period on the day of proestrus. Total RNA was extracted from each ovary, and 500 ng each was used for cDNA synthesis. Transcripts of each gene and of tbp were quantified by real-time PCR, and the amount of the transcripts of each gene in each sample was divided by the amount of tbp transcripts. The obtained relative values in each sample were used as the representative data of the amount of transcripts of each gene. The amounts of per1, per2, and bmal1 clearly oscillated every 24 h. The maximum and minimum values of per1 and per2 were observed at 16 and 4 h, respectively, after onset of the light period each day. The maximum and minimum values of bmal1 were observed at the time of onset of the light period and at 12 h after onset of the light period each day. Averages of the maximum values of per1, per2, and bmal1 each day were significantly greater than averages of the minimum values (per1, 3.60 0.10 and 1.38 0.09; per2, 0.82 0.08 and 0.27 0.06; bmal1, 0.61 0.05 and 0.17 0.01; P < 0.05). The cyclicity in the oscillation of the amount of wee1 transcripts was weaker than that observed in circadian genes, but the average of values that were obtained from 12 to 20 h after onset of the light period each day was significantly greater than that obtained from 0 to 8 h (0.29 0.02 and 0.22 0.01; P < 0.05). Our results suggested that the cell cycle of ovarian cells is regulated in a circadian manner through wee1 transcription, which is regulated by circadian genes of which the amounts of transcripts oscillate every 24 h. Because an abnormal cell cycle seems to trigger the development of tumors or follicular cysts, perturbation of circadian rhythm may cause those ovarian diseases. [ABSTRACT FROM AUTHOR]

Histone acetylation is one of the major mechanisms of epigenetic reprogramming of gamete genomes after fertilization or of transferred cell genomes after nuclear transfer to establish a totipotent state for normal development. In the fertilization of bovine oocytes, asynchronous histone acetylation occurs during pronuclear formation in the manner that modification of the paternal genome precedes that of the maternal genome (Wee et al. 2006 J. Biol. Chem. 281, 6048–6057). In the present study, the effects of trichostatin A (TSA), an inhibitor of histone deacetylase, during in vitro fertilization (IVF) of bovine oocytes on subsequent embryonic development were investigated. Cumulus-enclosed oocytes obtained from slaughterhouse ovaries were in vitro-matured (IVM) for 21 h in TCM-199 supplemented with 5% v/v FCS, 0.5 mM sodium pyruvate, 0.02 AU mL-1 FSH, and 1 g mL-1 estradiol-17? at 39C under 5% CO2 in air. After IVM, the oocytes were subjected to IVF with 3 106 mL-1 of Percoll gradient-selected sperm in a defined medium (Brackett and Oliphant 1975 Biol. Reprod. 12, 260–274) supplemented with 0 (control), 5, 50, and 500 nM TSA for 18 h. After IVF, presumptive zygotes were freed from cumulus cells and cultured in mSOF medium until 168 h post-insemination (hpi) at 39C under 5% CO2, 5% O2, and 90% N2 with high humidity. Cleavage and blastocyst development were assessed at 48 and 168 hpi, respectively. Inner cell mass (ICM) and trophectoderm (TE) of blastocysts were differentially stained by the method of Thouas et al. (2001 Reprod. Biomed. Online 3, 25–29) to assess cell number and ICM/TE ratio. Experiments were replicated 3 times. Data are presented as means SEM and statistically analyzed by multiple comparison with the Holm method. Rates of cleavage (0 nM: 71.0 7%, n = 102; 5 nM: 75.5 5%, n = 106; 50 nM: 68.8 6%, n = 105; and 500 nM: 71.7 4%, n = 98) and blastocyst formation (21.4 5%, 22.3 6%, 17.8 2%, and 18.2 2%, respectively) were similar among the groups. However, 500 nM TSA significantly (P < 0.05) increased ICM and total cell numbers (59.8 4 and 143.5 7, respectively, n = 31) compared with the control (43.1 3 and 120.9 7, n = 31). In addition, ICM/TE ratios were higher in the 50 nM (0.81 0.08, n = 29) and 500 nM (0.92 0.2, n = 31) groups than in the control (0.59 0.04, P < 0.05). These results suggest that TSA treatment during IVF of bovine oocytes does not affect the blastocyst rate but alters the cell numbers and their allocation to ICM and TE. Overriding epigenetic modification of the genome during fertilization may have a carryover effect on cell proliferation and differentiation in pre-implantation embryos.This study was supported by a grant from Wakayama Prefecture Collaboration of Regional Entities for the Advancement of Technological Excellence, JST. [ABSTRACT FROM AUTHOR]

Maternal transcripts that accumulate during oocyte growth are involved in the meiotic maturation, the initiation of the first mitosis, and the later pre-implantation development. Although the conserved E-box sequences in promoter region of some maternal genes (for example, Zp3 and Gdf-9), which are important in regulating gene transcripts as binding sites of transcriptional factors, may play a role in the oocyte-specific expression in ovary, the molecular mechanism that regulates the expression of the maternal genes is still not known. In this study, we have focused on the transcriptional activity of promoter regions to clarify the molecular mechanism of transcriptional regulation of these maternal genes [Histone H1oo (H1oo), Nucleoplasmin 2 (Npm2), and Zygote arrest 1 (Zar1)]. First, we observed the expression of firefly luciferase expression vectors under promoter regions of 3 maternal genes in oocytes isolated from 10- to 12-day-old mice, which is mainly NSN-type, transcriptionally active form (Bouniol-Baly et al. 1999 Biol. Reprod. 60, 580–587). Transcriptional activities of H1oo (-3975), Npm2 (-2610), and Zar1 (-5187) promoters were detected in oocytes, the relative luciferase activities being an average of 70, 130, and 12, respectively. On the other hand, these promoter activities were not detected in embryos at the 2-cell stage. Furthermore, deletion analysis of promoter elements (E-boxes) of H1oo and Npm2 was done by microinjecting deletion constructs into oocytes. In the H1oo promoter, deletion of sequences between -3975 and -72 bp from the transcription start site resulted in one-third of the level obtained in the full H1oo (-3975) promoter. In addition, deletion of sequence -68 bp resulted in no detection of luciferase activity. These findings indicate that the putative distal promoter sequences exist at the 52-flanking region (-3975 to -759) of the H1oo gene and that the region (-314 to -68) including the E-box region (-72) may be required for high-level transcriptional activity of the H1oo promoter. In the Npm2 promoter, deletion of sequences between -2610 and -180 bp from the transcription start site resulted in one-third of the level of wild-type activity of the Npm2 (-2610) promoter. In addition, deletion of sequence -101 bp resulted in no detection of luciferase activity. These findings also indicate that 3 putative distal promoter sequences exist at the 52-flanking region (-2610 to -210) of the Npm2 gene and that the region (-210 to -101) that includes the E-box region (-180) is crucial for high-level transcriptional activity of the Npm2 promoter. In conclusion, the E-box may be a key regulatory region for the expression of two of the maternal genes (H1oo and Npm2) examined. Currently, we are attempting to identify the transcriptional factor binding sites by DNase I footprint analysis and gel mobility shift assay. [ABSTRACT FROM AUTHOR]

It has been reported that activity of Rho, one of the GTPases, is essential for division of nuclei and cytoplasm of fertilized mouse eggs. Since it has been reported that alteration of activities of GTPases modifies their ability to attach to each of their effector proteins in somatic cells, effector proteins seem to be able to control not only progression but also repression of cell division by changing their cellular localizations through activities of GTPases. For this reason, Rhophilin-2, one of the effector proteins of Rho, seems to be involved in the decision of progression of division of fertilized mouse eggs. To examine whether this involvement works in fertilized mouse eggs, cellular localization of Rho and Rhophilin-2 in fertilized mouse eggs that were treated with Rho inhibitor were analyzed. Moreover, cellular localization of GABA A receptor association protein (GABARAP), which was identified in our previous study (Matsuoka et al. 2006 Reprod. Fertil. Dev. 18, 176–177) as a protein that interacts with Rhophilin-2, was also analyzed. Fertilized mouse eggs were obtained from in vitro fertilization technique. One group of fertilized eggs was obtained at 24 h after insemination as experimental control. To obtain the mouse eggs in which Rho activities were inhibited, Clostridium botulinum C3 exoenzyme (C3-CB), an inhibitor of Rho activity, was injected into the other group of fertilized mouse eggs at 12 h after insemination, and were collected after 12 h of subsequent culture. Cellular localization of Rho (n = 100), Rhophilin-2 (n = 10). and GABARAP (n = 10) in the collected oocytes was analyzed by using immunofluorescence. Our results showed that Rho and Rhophilin-2 were co-localized at the midbody microtubule, which is an important device for cytoplasmic division in control eggs. However, the inhibition of Rho activity did not modify the co-localization of Rho and Rhophilin-2. On the other hand, localization of GABARAP was modified by the inhibition of Rho activity, and GABARAP was detected around the nuclei of fertilized eggs in which Rho activity was inhibited. In the next experiment, we examined whether interaction of Rhophilin-2 and GABARAP was modified by the inhibition of Rho activity by using a co-immunoprecipitation assay (co-IP) (n = 100). The interaction of Rhophilin-2 and GABARAP was found to disappear after inhibition of Rho activity. These results suggest that activity of Rho seems to regulate cytoplasmic division through Rhophilin-2 modification. Moreover, Rho seem to modulate the nuclear division of fertilized mouse eggs by regulating the interaction between Rhophilin-2 and GABARAP.This study was supported by a Grant-in-Aid for the 21st Century COE Program of the Japan Mext and by a grant for the Wakayama Prefecture Collaboration of Regional Entities for the Advancement of Technology Excellence of the JST. [ABSTRACT FROM AUTHOR]

Cloning by adult somatic cell nuclear transfer (SCNT) has proven to be successful for the production of clones from many species (Keith 2004 Cytogenet. Genome Res. 105, 285). However, somatic cloning is currently highly inefficient. One of the reasons for this is that SCNT is believed to be associated with epigenetic errors including abnormal DNA methylation of the reconstructed embryo. The Oct-3/4 gene, a member of the POU transcription factor family, is expressed throughout the pre-implantation embryo. Abnormal expression of the Oct-3/4 gene in the nuclear-transferred embryo is either directly or indirectly caused by nuclear transfer and is suggested to be indicative of a general failure to reset the genetic program (Boiani et al. 2002 Genes Dev. 16, 1209). In this study, we investigated the DNA methylation profiles of the Oct-3/4 gene in the genome of SCNT embryos, using bisulfite sequencing analysis. Then, we observed the detailed subcellular localization of Oct-3/4 proteins in SCNT embryos using immunocytochemical (ICC) analysis. Nuclear transfer of cumulus cell nuclei was carried out as previously described (Wakayama et al. 1998 Nature 394, 369). After nuclear transfer, embryos were subsequently cultured in KSOM media to the morula and blastocyst stages. We compared the methylation profiles of 3 transcriptional control elements (distal enhancer, DE; proximal enhancer, PE; and promoter) of the upstream region of the Oct-3/4 gene with the genome of in vitro fertilization (IVF) and SCNT embryos. The methylation rate of CpG sites in the DE and promoter regions of both IVF and SCNT embryos was low at both the morula and the blastocyst stages. What''s interesting is that there was a significant difference in the methylation level on CpG sites in the PE element between IVF and SCNT embryos. At the morula stage, the methylation level on CpG sites in the PE element was very low in the IVF embryo and moderately high in the SCNT embryo (0.9% and 26.3%). Conversely, at the blastocyst stage, CpG sites in the PE element showed high methylation in the IVF embryo and low methylation in the SCNT embryo (55.2% and 10.5%). CpG sites in the PE element were lightly methylated (3.0%) in the inner cell mass (ICM) of the IVF embryo. This means that the main portion of methylation in the IVF blastocyst embryo occurred at the trophectoderm (TE). On the other hand, in ICM of the SCNT embryo, the methylation level of each embryonic cell was almost the same in the whole blastocyst embryo (9.8% and 10.5%). As a result, it is highly possible that the CpG sites in the PE element of ICM were methylated as in the TE. ICC analysis revealed that some SCNT embryos showed aberrant Oct-3/4 expression in the TE. These results indicate that the methylation of CpG sites in the Oct-3/4 PE element may be related to expression of Oct-3/4 in the mouse IVF and SCNT embryos. These differences in methylation level between IVF and SCNT embryos were reflected as abnormal expressions of Oct-3/4 on SCNT embryos.This study was supported by the 21st COE Program of MEST. M.K. is a JSPS Research Fellow and supported by Grant-in Aid for Scientific Research (No. 1751132) of JSPS. [ABSTRACT FROM AUTHOR]

Zygotic gene activation (ZGA) starts at the G2 phase at the 1-cell stage in the mouse. However, the molecular mechanism of ZGA has not been completely elucidated. We have investigated the molecular functions of many gene clusters, DD clones obtained by differential display assays for ovulated eggs at the M II stage and 1-cell stage embryos at the G2 phase. As a result, we have identified a functionally unknown gene, whose sequence did not match a known transcript in the gene bank DD2-2 gene. Here, we report the expression profile and knockdown analysis of the DD2-2 gene in mouse pre-implantation embryos. Nucleotide sequence analysis of the DD2-2 cDNA revealed that the open reading frame of 1056 bp encodes a protein of 351 amino acids with a predicted molecular mass of 41.5 kDa. The deduced amino acid sequence indicated that DD2-2 protein might be a soluble protein without a signal peptide. We first investigated the expression profiles of DD2-2 in pre-implantation embryos by quantitative real-time PCR using an ABI PRISM 7300 Sequence Detection System (Applied Biosystems, Foster City, CA, USA). To investigate the effect of knockdown of the DD2-2 gene on the development of pre-implantation embryos, we injected p?-act/antisenseDD2-2/IRES/EGFP into male pronuclei of embryos at 7 to 9 h after insemination (hpi) and observed the development of embryos that showed EGFP expression at 24 hpi. Real-time PCR analysis of pre-implantation embryos showed that maternal DD2-2 mRNA at a low level significantly increased up to the early 2-cell stage, and significantly decreased by the 4-cell stage and later, suggesting that DD2-2 gene specifically expresses at major ZGA. In the knockdown analysis, EGFP-positive embryos with p?-act/antisenseDD2-2/IRES/EGFP showed a lower rate of development to the 4-cell stage and later, compared with that of EGFP-positive embryos with p?-act/luc+/IRES/EGFP [72% (94/130) vs. 54% (71/131); P < 0.05], indicating that the knockdown of DD2-2 by antisense RNA resulted in a inhibition of pre-implantation development. In conclusion, the DD2-2 gene, a functionally unknown gene, may play an important role in pre-implantation development.This study was supported by a Grant-in-Aid for the 21st Century COE Program of the Japan Mext and by a grant for the Wakayama Prefecture Collaboration of Regional Entities for the Advancement of Technology Excellence of the JST. [ABSTRACT FROM AUTHOR]

The assessment of adrenergic modulation of sweating as assessed via pharmacologic administration of α- and β-adrenergic receptor blockers during exercise has yielded mixed findings. However, the underlying mechanisms for this disparity remain unresolved. We investigated the effects of separate and combined blockade of α- and β-adrenergic receptors on forearm sweating induced by a 30-min moderate-intensity exercise bout ( n = 17, protocol 1 ) and the administration of adrenergic agonists epinephrine and norepinephrine ( n = 16, protocol 2 ) in the heat. Adrenergic receptor blockade was induced via the separate and combined iontophoretic administration of terazosin (α-adrenergic receptor antagonist) and propranolol (β-adrenergic receptor antagonist) on forearm skin. Bretylium, a noradrenergic sympathetic nerve inhibitor, was also administered separately in protocol 1 . In protocol 1 , relative to the separate administration of propranolol, terazosin alone or in combination with propranolol attenuated exercise sweating to a similar extent (both P ≤ 0.037), although the effect was reduced relative to that observed with bretylium treatment ( P < 0.001). In protocol 2 , administration of propranolol increased norepinephrine- ( P = 0.029) but not epinephrine-induced sweat rate. The combined administration of terazosin reversed this response, attenuating sweating ( P < 0.001) to a greater extent than terazosin treatment alone ( P = 0.030). Altogether, we showed that although β-adrenergic receptors may interact with α-adrenergic receptors pharmacologically, it does not appear to modulate exercise-induced sweating on the forearm. Furthermore, α- but not β-adrenergic receptors independently modulate the regulation of forearm sweating during exercise in the heat. Finally, the bretylium-induced reduction in forearm sweat rate during exercise likely occurs independently of α- and β-adrenergic receptors. NEW & NOTEWORTHY Pharmacological stimulation of α- and β-adrenergic receptors produces sweating in vivo. Still, the separate and interactive roles of these adrenergic receptors during exercise and pharmacological adrenergic stimulation in the heat remain unknown. We showed that β-adrenergic receptors may interact with α-adrenergic receptors pharmacologically, but it does not modulate exercise-induced sweating. The α-adrenergic receptors independently modulate sweating during exercise in the heat. We provide important new insights into our understanding of the mechanisms regulating human sweating.

As a low-energy method to increase the data rate of optical links in data centers, we propose self-homodyne Nyquist optical time division multiplexing (OTDM). In Nyquist OTDM, spectrally efficient high-baud rate signals can be generated exceeding the limit of electronic signal processing. However, full integration of OTDM systems has not been reported, mainly because of the complicated signal detection scheme, which involves demultiplexing and clock recovery. In our proposal, the Nyquist pulse train is transmitted to the receiver as a local oscillator (LO) to leverage self-homodyne detection, which allows using large linewidth lasers and a simplified digital signal processing (DSP) algorithm. As the transmitted pulse train serves as an optical clock, demultiplexing and detection of the OTDM signal can be performed without using power-intensive high-bandwidth electronics and DSP. In this method, the LO pulse train needs to enter the coherent detector in exact synchronization with the OTDM signal for detecting the individual tributary correctly. For this purpose, we present a pulse delay control method suitable for photonic integration. A Nyquist pulse train with m carriers enables m -time multiplexing of optical signals. We explain and demonstrate the proposed concept in the case of m  = 2, as it is the most feasible implementation. In the O-band where the chromatic dispersion (CD) is negligible, DSP-free operation can be achieved using the QPSK format. At the band edges where CD is non-negligible, it can be compensated by the DSP as in the conventional coherent detection. We verify this numerically and in an experiment involving the transmission of a 64-Gbaud QPSK signal at 1550 nm over a single-mode fiber. In terms of low energy, self-homodyne Nyquist OTDM is advantageous in wavelength division multiplexing (WDM). Taking it into consideration, we perform 4-channel WDM transmission of the 64-Gbaud QPSK signal over a 1-km dispersion shifted fiber without CD compensation. The results demonstrate a data rate of 512 Gb/s with a BER of <1 × 10 -10 .

Purpose: Corneal dysmorphologies (CDs) are typically classified as either regressive degenerative corneal dystrophies (CDtrs) or defective growth and differentiation-driven corneal dysplasias (CDyps). Both eye disorders have multifactorial etiologies. While previous work has elucidated many aspects of CDs, such as presenting symptoms, epidemiology, and pathophysiology, the genetic mechanisms remain incompletely understood. The purpose of this study was to analyze phenotype data from 8,707 knockout mouse lines to identify new genes associated with the development of CDs in humans., Methods: 8,707 knockout mouse lines phenotyped by the International Mouse Phenotyping Consortium were queried for genes associated with statistically significant (P < 0.0001) abnormal cornea morphology to identify candidate CD genes. Corneal abnormalities were investigated by histopathology. A literature search was used to determine the proportion of candidate genes previously associated with CDs in mice and humans. Phenotypes of human orthologues of mouse candidate genes were compared with known human CD genes to identify protein-protein interactions and molecular pathways using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), Protein Analysis Through Evolutionary Relationships (PANTHER), and Kyoto Encyclopedia of Genes and Genomes., Results: Analysis of data from 8,707 knockout mouse lines identified 213 candidate CD genes. Of these, 37 (17%) genes were previously known to be associated with CD, including 14 in the mouse, 16 in humans, and 7 in both. The remaining 176 (83%) genes have not been previously implicated in CD. We also searched publicly available RNAseq data and found that 131 of the total 213 (61.5%) were expressed in adult human corneal tissue. STRING analysis showed several interactions within and between candidate and established CD proteins. All cellular pathways of the established genes were found in the PANTHER analysis of the candidate genes. Several of the candidate genes were implicated in corneal disease, such as TGF-ß signaling. We also identified other possible underappreciated mechanisms relevant to the human cornea., Conclusions: We identified 213 mouse genes that resulted in statistically significant abnormal corneal phenotypes in knockout mice, many of which have not previously been implicated in corneal pathology. Bioinformatic analyses implicated candidate genes in several signaling pathways which are potential therapeutic targets., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures at each IMPC center adhered to local, state, and national regulatory guidelines, based on the standards of Animal Research: Reporting of In Vivo Experiments guidelines, a list of recommendations to standardize and improve the quality and reproducibility of animal research. A Housing and Husbandry protocol was also followed, which contains a collection of mandatory and optional procedures to be used during international mouse experimentation.4,5 Guidelines can be accessed at https://www.mousephenotype.org/about-impc/animal-welfare/ . All procedures on live animals were reviewed and approved by associated institutional animal care and use committees (IACUC), animal care committees (ACC), or equivalent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Tamoxifen, a common adjuvant therapy for hormone receptor-positive breast cancer, is associated with an increased risk of endometrial pathologies, such as hyperplasia, polyps, and carcinoma. This study investigates rapamycin, an mTOR inhibitor, as a potential novel strategy for preventing tamoxifen-induced endometrial proliferation. This in vitro study utilised endometrial stromal cells isolated from infertile women. The cells were treated with tamoxifen alone or in combination with rapamycin, and proliferation was assessed using the CCK-8 assay. The activation of the mTOR pathway, as well as apoptosis and cell cycle markers, was evaluated by Western blotting to elucidate the molecular mechanisms underlying these effects. The study design emphasised simulating clinically relevant exposure levels. Tamoxifen significantly increased endometrial cell proliferation in a dose-dependent manner. Rapamycin effectively inhibited this proliferation, even at concentrations lower than those typically observed in clinical settings. Quantitative analysis by Western blotting showed activation of the mTOR pathway and cell cycle in the tamoxifen group, and inhibition of these pathways in the tamoxifen plus rapamycin combination group, whereas there was no change in apoptosis. In conclusion, rapamycin shows promise as a prophylactic agent against tamoxifen-induced endometrial pathologies, with potential implications for fertility preservation and endometrial protection in breast cancer patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare cardiovascular disorder caused by defective intracellular lipolysis of triglyceride, resulting in heart failure and diffuse narrowing atherosclerosis. Recently, the registry of TGCV patients in Japan revealed that the 3-year overall survival rate was 80.1% and the 5-year overall survival rate was 71.8%. In this study, the effect on mortality of chronic kidney disease (CKD), diabetes malleus (DM), hypertension (HT), and dyslipidemia (DL) was analyzed using this retrospective registry of TGCV patients. The 3-year survival rate was 71.3% in the CKD group and 91.7% in the non-CKD group, and the 5-year survival rate was 61.8% in CKD group and 84.4% in the non-CKD group. The Kaplan-Meier analysis revealed that CKD is a risk factor for mortality in TGCV patients (p = 0.006). Although TGCV patients with CKD were older than those without CKD, Cox proportional hazard model analyses including age indicated that CKD has a significant association of the prognosis of TGCV patients (hazard ratio 2.33 [1.12-4.86], p = 0.024). DM, HT, and DL did not increase mortality in TGCV patients, although these risk factors were established in the general population. TGCV might cause cardiac disorders and kidney disease at the same time, because podocyte foot process disorder in the glomeruli might be caused by TGCV itself, while CKD should be a risk factor for mortality in TGCV patients as is true in the general population. In conclusion, CKD is a major risk factor for mortality in TGCV patients and thus should be paid attention to in these patients., (© 2025. The Author(s).)

Background: Limited large-scale, real-world data exist on the prevalence and clinical impact of discordance between fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs)., Methods: The J-PRIDE registry (Clinical Outcomes of Japanese Patients With Coronary Artery Disease Assessed by Resting Indices and Fractional Flow Reserve: A Prospective Multicenter Registry) prospectively enrolled 4304 lesions in 3200 patients from 20 Japanese centers. The lesions were classified into FFR+/NHPR-, FFR-/NHPR+, FFR+/NHPR+, or FFR-/NHPR groups according to cutoff values of 0.89 for NHPRs and 0.80 for FFR. The primary study end point was the cumulative 1-year incidence of target vessel failure (a composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization) on a lesion basis., Results: An NHPR cutoff value of 0.89, determined using online software, predicted an FFR of 0.80 across various NHPR types. Discordance between FFR and NHPRs was observed in 20% of lesions (FFR+/NHPR-, 11.2%; FFR-/NHPRs+, 8.8%). Revascularization was deferred in 42.9% and 88.4% of the FFR+/NHPR- and FFR-/NHPR+ groups, respectively. In deferred vessels, the FFR+/NHPR- and FFR-/NHPR+ groups showed a higher 1-year incidence of target vessel failure compared with the FFR-/NHPR- group (7.9% versus 5.5% versus 1.7%; for FFR+/NHPR-, adjusted hazard ratio [aHR], 4.89 [95% CI, 2.68-8.91]; P <0.001; for FFR-/NHPR+, aHR, 2.64 [95% CI, 1.49-4.69]; P <0.001). In revascularized vessels, the 1-year target vessel failure rate was numerically higher in the FFR-/NHPR+ group than in the FFR+/NHPR+ group (9.6% versus 3.4%; aHR, 2.27 [95% CI, 0.70-7.34]; P =0.17), although with similar outcomes between the FFR+/NHPR- and FFR+/NHPR+ groups (2.3% versus 3.4%; aHR, 0.96 [95% CI, 0.37-2.38]; P =0.93). The FFR+/NHPR- group benefited from revascularization compared with medical treatment (aHR, 0.26 [95% CI, 0.08-0.86]; P =0.027); the FFR-/NHPR+ group did not (aHR, 2.39 [95% CI, 0.62-9.21]; P =0.20)., Conclusions: Discordance between FFR and NHPRs was noted in 20% of lesions, and discordant deferred lesions resulted in worse outcomes than concordant negative lesions. Although the outcomes after deferring revascularization were comparable between the FFR+/NHPR- and FFR-/NHPR+ lesions, only FFR+/NHPR- lesions showed a benefit from revascularization compared with medical treatment, suggesting that an FFR-guided strategy is superior to an NHPR-guided strategy in discordant lesions., Registration: URL: https://www.umin.ac.jp; Unique identifier: UMIN000038403.

There is insufficient evidence comparing the outcomes of tacrolimus-based remission induction therapy with infliximab in refractory ulcerative colitis (UC) and evidence regarding optimal strategies after tacrolimus-based remission induction therapy. We conducted a multi-institutional retrospective study of patients with UC treated with tacrolimus or infliximab between January 2010 and March 2019. The proportion of clinical remission at week 8 and cumulative colectomy-free rate were examined using propensity score matching analysis. The predictors for colectomy after tacrolimus induction were also investigated. Ninety patients in the tacrolimus group and 151 in the infliximab group were enrolled. The proportion of patients in clinical remission at week 8 was 65.2% in the matched tacrolimus group and 37.3% in the matched infliximab group (P = 0.0016), and the long-term colectomy-free rate was lower in the matched tacrolimus group than in the matched infliximab group (P = 0.0003). After clinical remission with tacrolimus, a serum albumin level of ≤ 3.5 g/dL at week 8 was extracted as a factor predicting colectomy (area under the curve: 0.94). Tacrolimus showed a higher remission induction effect for UC compared to infliximab. However, a high rate of colectomy after transition to maintenance treatment was found to be a concern for tacrolimus therapy., Competing Interests: Competing interests: Takeo Yoshihara received lecture fees from EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Nippon Kayaku Co., Ltd. Takahiro Amano received lecture fees from Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation. Shinichiro Shinzaki received personal fees from AbbVie Inc., EA Pharma Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Nippon Kayaku Co., Ltd., and scholarship grants from AbbVie Inc., EA Pharma Co., Ltd., and Nippon Kayaku Co., Ltd. Satoshi Egawa received lecture fees from Mitsubishi Tanabe Pharma Corporation and Janssen Pharmaceutical K.K. Satoshi Hiyama1 received lecture fees from Mitsubishi Tanabe Pharma Corporation and AbbVie Inc. Hideki Iijima received lecture fees from AbbVie Inc., Janssen Pharmaceutical K.K., EA Pharma Co., Ltd., Eisai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Mochida Pharmaceutical Co., Ltd. Yoshito Hayashi received lecture fees from EA Pharma Co., Ltd and Nippon Kayaku Co., Ltd. Tetsuo Takehara received lecture fees from AbbVie Inc.,consigned/joint research expenses from AbbVie Inc., Janssen Pharmaceutical K.K., and Mitsubishi Tanabe Pharma Corporation, and scholarship donations from AbbVie Inc., EA Pharma Co., Ltd., Nippon Kayaku Co., Ltd. and Mitsubishi Tanabe Pharma Corporation. None of the disclosures mentioned above are related to this study. The remaining authors do not have any conflicts of interest to disclose. Ethics approval: This study was approved by the Ethics Committee of Osaka University Hospital and by the Ethics Committees of the respective institutions (the ethics approval number: 18208). Patient consent: The requirement for written informed consent was waived by allowing the participants to opt out because of the study’s retrospective nature., (© 2024. The Author(s).)

Purpose: Precision medicine plays an important role in the treatment of patients with advanced melanoma. Despite its high incidence in White patients, advanced melanoma is rare in Asian countries, hampering prospective clinical trials targeting the Asian population. This retrospective study aimed to elucidate the real-world molecular diagnoses and outcomes of Japanese patients with melanoma using comprehensive genome profiling (CGP)., Materials and Methods: Patients with melanoma who completed standard anticancer medical treatments (including those expected to complete the treatments) underwent CGP, which is covered by the National Health Insurance. We analyzed the results and clinical annotations of 569 patients registered before August 2023 in a national database., Results: Skin, mucosal, and uveal melanomas accounted for 64%, 28%, and 7% of cases, respectively. Patients with BRAF , NRAS , NF1 , and KIT variants represented 25%, 20%, 17%, and 17%, respectively. Eighty-two percent of BRAF , 97% of NRAS , 69% of NF1 , and 54% of KIT were actionable alterations (ie, BRAF classes I, II, and III, NRAS Q61, G12, G13, NF1 loss-of-function, KIT gain-of-function variants). BRAF V600E/K variants occurred in 22% of skin and 2% of mucosal melanomas, but not in uveal melanomas. The mean tumor mutation burden in cutaneous melanomas was 4.2 variants/Mb. Patients previously treated with BRAF-targeted therapy harbored amplifications of BRAF and cell cycle genes more frequently than therapy-naive patients. Thirty-six patients (6.3%) were treated following the molecular tumor board (MTB) recommendations., Conclusion: Actionable gene alterations in BRAF , NRAS , NF1 , and KIT are common in Japanese patients with melanoma. However, few patients were treated according to the MTB recommendations, suggesting that there is an unmet need to increase accessibility to gene-matched clinical trials in Japan.

The process of autophagy is vital in maintaining normal cellular function, especially during exposure to elevated states of physiological stress associated with exercise and hot ambient temperatures. Although prior observations are primarily limited to responses in males, the autophagic response to acute physiological stress in females represents a considerable knowledge gap. Therefore, we assessed autophagy and related pathways of cellular stress in peripheral blood mononuclear cells (PBMCs) from 20 healthy young [ n = 10, mean (SD): aged 23 yr (3)] and older [ n = 10, aged 69 yr (3)] females in response to 30 min of semi-recumbent high-intensity cycling exercise (70% of predetermined maximal oxygen consumption) in temperate (25°C) and hot (40°C) ambient conditions (15% relative humidity). Mean body temperature (rectal and skin) was measured throughout, whereas cellular responses were evaluated before and after exercise, including up to 6 h of seated recovery. Proteins associated with autophagy and related pathways were assessed via Western blot. Mean body temperature was elevated after exercise in both conditions, with significant elevations observed after exercise in the heat (all, P ≤ 0.05). Although young females displayed signs of elevated autophagic activity [elevations in microtubule-associated light chain 3B (LC3)-II and beclin-2] in response to exercise performed in both temperate and hot ambient conditions (all, P ≤ 0.05), responses were attenuated in older females. This was accompanied by elevations in chaperone-mediated autophagy in young but not in older females in response to exercise independent of ambient temperature. Our findings indicate exercise, with and without ambient heat exposure may stimulate the autophagic response in young but not in older females. NEW & NOTEWORTHY We show for the first time that an acute bout (30 min) of high-intensity intensity exercise stimulates autophagy in young females irrespective of ambient heat exposure. However, older females did not display the same increase in autophagy as their younger counterparts when high-intensity exercise was performed in temperate or hot ambient conditions. Consequently, older females may be at an elevated risk of heat-induced cellular damage during exertional heat stress.

Factors explaining individual variations in whole body sweat sodium ion concentration ([Na + ]) during exercise are not fully understood. Galvanic skin conductance (GSC) reflects the electrical properties of the skin influenced by sweat rate (SR) and the presence of ions. Initiation of increases in this response to elevating sweating may reflect exceeding the maximal capacity of sweat ion reabsorption in sweat glands. We investigated whether the SR threshold for increasing GSC, an indirect measure of maximum ion reabsorption rates of sweat glands, explains the variations in whole body sweat [Na + ]. Thirty young healthy males cycled for 90 min at incremental exercise intensities of 30, 45, and 60% peak oxygen uptake (30 min each) in the heat (32°C, 50% relative humidity). Whole body sweat [Na + ] was measured using a whole body washdown technique. The SR threshold for increasing GSC was determined from the relationship between the local SR (ventilated capsule) and GSC on the forearm and chest. The average whole body sweat [Na + ] was 42.8 ± 18.9 (range: 14.4-81.0) mmol L -1 , and the SR threshold for increasing GSC was 0.29 ± 0.20 (range: 0.02-0.62) and 0.35 ± 0.30 (range: 0.01-1.40) mg cm -2 min -1 for the forearm and chest, respectively. Whole body sweat [Na + ] was not correlated with the SR threshold for increasing GSC in the forearm or chest ( r 2 ≤ 0.001, P ≥ 0.921). We conclude that the SR threshold for increasing GSC at the forearm and chest does not explain the individual variation in whole body sweat [Na + ] during exercise in the heat. NEW & NOTEWORTHY Galvanic skin conductance is influenced by sweat rate and sweat ions, and the sweat rate at which this response begins to increase may reflect the exceeding capacity of sweat ion reabsorption in sweat glands. However, we show that this indirect measure of the sweat gland's capacity of ion regulation on the forearm and chest does not correlate with whole body sweat sodium concentration during exercise, excluding its role as a determinant of systemic sweat sodium loss.

Introduction: The abundance of epicardial adipose tissue (EAT) correlates with the extent and severity of coronary artery disease (CAD). If the quantity of EAT varies between diastole and systole during an ECG-synchronized volume scan, it can potentially affect the diagnostic accuracy of CAD. The aim of this study was to compare the EAT volume between the diastolic and systolic phases during an ECG-gated volume scan of patients with or without CAD., Methods: In this study, 47 patients (11 with and 36 without CAD) underwent coronary computed tomography (CT) angiography between September 2022 and August 2023. All patients underwent a second-generation 320-row computed tomography (CT) scan with a retrospective ECG-triggered volume scan. The data volumes obtained at 5 % steps of the R-R interval were automatically analyzed on a Ziostation2 Plus workstation using a CT coronary artery analysis application. Myocardial fat components ranging from -160 to -70 in CT value were extracted to determine fat content. EAT volumes between R-R intervals were compared for 40 % diastolic and 75 % systolic phases in the scans of patients with and without CAD., Results: The median and interquartile range (IQR) of the EAT volumes were 130 (112-183) mL and 98 (67-129) mL for the groups with and without CAD, respectively, indicating a significant difference (p < 0.05). For the ECG-gated scan without CAD, the median and IQR of the EAT volumes were 98 (66-129) and 94 (68-134) mL in the diastolic and systolic phases (p = 0.82), respectively, and for CAD, 166 (129-191) and 158 (113-178) mL (p = 0.56), respectively. Thus, the differences in the EAT volume were not significant between diastolic and systolic phases (p > 0.05)., Conclusion: Differences in EAT volume between patients with and without CAD were significant. However, the EAT volume differences between the diastolic and systolic phases were not significant, irrespective of CAD, during the ECG-gated volume scans., Implications for Practice: The diastolic and systolic cardiac phases did not significantly influence EAT volume measurements., Competing Interests: Conflict of interest statement The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.)

The physiological mechanisms involved in augmented cholinergic agonist-induced sweating in exercise-trained individuals remain unclear. This study hypothesizes that nitric oxide synthase (NOS) contributes to augmented pilocarpine-induced sweating in habitually exercise-trained individuals. Endurance-trained and untrained men ( n  = 15 each) iontophoretically received 1% L-NAME, a NOS inhibitor, and saline (control) in the forearm and then administered 0.001% and 1% pilocarpine to evaluate sweat rate. L-NAME administration attenuated pilocarpine-induced sweating by 10% in the exercise-trained ( P  = 0.004) but not in untrained ( P  = 0.764) groups independent of pilocarpine concentrations. Results indicate that NOS partially contributes to increased cholinergic sweating in exercise-trained men., Competing Interests: The authors declare no conflicts of interest, financial or otherwise. All conflicts of interest declared on the International Committee of Medical Journal Editors (ICMJE) forms.

The hyaline-vascular variant of Castleman disease (HVCD) is relatively uncommon and demonstrates no specific clinical or laboratory findings; therefore, its preoperative diagnosis warrants a radiological evaluation. This study aimed to review imaging findings of HVCD, focusing on perilesional fat stranding and fatty proliferation. Patients with a pathologically confirmed HVCD diagnosis who had undergone CT were recruited from five hospitals from January 2000 to March 2023. Three experienced radiologists assessed CT findings, including lesion location, lesion size, calcification, enhanced pattern, feeding vessel visualization, and arterial enhancement. Perilesional fat stranding, fatty proliferation, neighboring fascial thickening, and surrounding lymphadenopathy were the primary targets of analysis. Moreover, the intensities and apparent diffusion coefficient (ADC) values on MRI and the maximum standardized uptake value (SUVmax) on 18 F-fluorodeoxyglucose positron emission tomography (PET) were evaluated. This study enrolled 43 patients (mean age 41.3 years ± 14.6 [standard deviation], 23 women). All lesions were well-defined round masses. Calcification and feeding vessels were detected in 21% (9/43) and 86% (36/43) of the patients, respectively. Perilesional fat stranding and fatty proliferation were observed in 44% (19/43) and 19% (8/43), respectively, with fatty proliferation detected only in retroperitoneal HVCD. Neighboring fascial thickening and surrounding lymphadenopathy were identified in 21% and 60%, respectively. The mean ADC value and SUVmax were 0.884 × 10 -3 mm 2 /s and 5.0, respectively. Retroperitoneal HVCD cases with perilesional fatty proliferation demonstrated a higher visceral fat ratio than those without ( p = 0.046). Perilesional fat stranding and fatty proliferation were new characteristics of HVCD, especially in retroperitoneal cases., Competing Interests: The authors have no conflicts of interest to disclose., (2024, National Center for Global Health and Medicine.)

Language barriers can severely hinder the advance of conservation science and its contribution to addressing the biodiversity crisis. We build a framework for understanding how language barriers can impede the evidence-based conservation of biodiversity in three ways: barriers to (i) the generation of evidence by non-native English speakers; (ii) the global synthesis of evidence scattered across different languages; and (iii) the application of English-language evidence to local decision making. We provide evidence, building on a growing body of literature, that quantifies the three consequences of language barriers in conservation. We also propose a checklist of solutions for reducing language barriers in conservation by addressing language disparities among scientists, promoting linguistic diversity in conservation, and making conservation science and its communication multilingual., Competing Interests: Declaration of interests As members of the Language Accessibility subcommittee of the Society for Conservation Biology’s 32nd International Congress for Conservation Biology (ICCB 2025), T.A. and V. B.-E. are currently working with Writefull and Wordly (both listed in Table 1) as a sponsor and contractor, respectively, to implement language accessibility measures at the conference. We declare that this does not affect the conclusions of this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Mammalian target of rapamycin (mTOR) inhibitors have been used clinically as anticancer and immunosuppressive agents for over 20 years, demonstrating their safety after long-term administration. These inhibitors exhibit various effects, including inhibition of cell proliferation, interaction with the oestrogen and progesterone pathways, immunosuppression, regulation of angiogenesis, and control of autophagy. We evaluated the potential of mTOR inhibitors as therapeutic agents for endometriosis, examined the secondary benefits related to reproductive function, and assessed how their side effects can be managed. We conducted a thorough review of publications on the role of the mTOR pathway and the effectiveness of mTOR inhibitors in endometriosis patients. These results indicate that the mTOR pathway is activated in endometriosis. Additionally, mTOR inhibitors have shown efficacy as monotherapies for endometriosis. They may alleviate resistance to hormonal therapy in endometriosis, suggesting a potential synergistic effect when used in combination with hormonal therapy. The potential reproductive benefits of mTOR inhibitors include decreased miscarriage rates, improved implantation, and prevention of age-related follicular loss and ovarian hyperstimulation syndrome. Activation of the mTOR pathway has also been implicated in the malignant transformation of endometriosis. Preclinical studies suggest that the dosage of mTOR inhibitors needed for treating endometriosis may be lower than that required for anticancer or immunosuppressive therapy, potentially reducing dosage-dependent side effects. In conclusion, while mTOR inhibitors, which allow for pregnancy during oral administration, show potential for clinical use in all stages of endometriosis, current evidence is limited to preclinical studies, and further research is needed to confirm clinical effectiveness., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

We evaluated reactive oxygen species (ROS) modulation of cutaneous vasodilation during local and whole body passive heating in young and older adults. Cutaneous vascular conductance normalized to maximum vasodilation (%CVC max ) was assessed in young and older adults (10/group) using laser-Doppler flowmetry at four dorsal forearm sites treated with 1 ) Ringer solution (control), 2 ) 100 µM apocynin (NADPH oxidase inhibitor), 3 ) 10 µM allopurinol (xanthine oxidase inhibitor), or 4 ) 10 µM tempol (superoxide dismutase mimetic), via intradermal microdialysis during local ( protocol 1 ) and whole body heating ( protocol 2 ). In protocol 1 , forearm skin sites were set at 33°C during baseline and then progressively increased to 39°C and 42°C (30 min each). In protocol 2 , participants were immersed in warm water (35°C, midsternum) with the experimental forearm above water level, and local skin sites were maintained at 34°C. Bath temperature was increased (∼40°C) to clamp core temperature at 38.5°C for 60 min. In protocol 1 , there were significant treatment site by age interactions for the 39°C ( P = 0.015) and 42°C ( P = 0.004) plateaus; however no significant effects were observed after post hoc adjustment. In protocol 2, there was a significant treatment site by age interaction ( P < 0.001), where %CVC max in older adults was 11.0% [7.4, 14.6] higher for apocynin ( P < 0.001), 8.9% [5.3, 12.5] higher for allopurinol ( P < 0.001), and 4.8% [1.3, 8.4] higher for tempol ( P = 0.016) sites relative to the control site. ROS derived from NADPH oxidase and xanthine oxidase attenuate cutaneous vasodilation in older adults during passive whole body heating, but not during local skin heating, with negligible effects on their young counterparts for either heating modality. NEW & NOTEWORTHY We found that local infusion of apocynin or allopurinol improved cutaneous vasodilator responses to passive whole body heating (but not local skin heating) in healthy older adults. These findings indicate that impaired microvascular responses to whole body heating with primary aging are linked to augmented production of reactive oxygen species (ROS) from NADPH oxidase and xanthine oxidase. This study sheds new light on the specific ROS pathways that modulate age-related changes in cutaneous microvascular responses to heating.

Background and Objectives: While recognizing the acknowledged difference in dementia prevalence between Indigenous and non-Indigenous populations, most previous studies were conducted in the Global North. This study aims to examine the relationship between Indigenous ethnic identity and dementia status with a special focus on urban-rural differences among older adults in Ecuador., Research Design and Methods: Data came from Ecuador's Survey of Health, Welfare, and Aging, derived from a probability sample of households in Ecuador. The final sample comprised 4,984 adults aged 60 or older. Dementia status was assessed through 3 indicators: low scores on a cognitive assessment, the number of difficulties in instrumental activities of daily living, and self-reported dementia diagnosis. Logistic regression and multivariate decomposition analyses were utilized., Results: Indigenous participants, even after adjusting for sociodemographic and health-related factors, exhibited a higher likelihood of having dementia compared to their non-Indigenous counterparts. Among Indigenous participants, those residing in rural areas had a higher likelihood of having dementia status, while there was no significant urban-rural difference observed among non-Indigenous participants. Rural residency and covariates explain 91.0% of the observed difference in dementia prevalence between Indigenous and non-Indigenous older adults., Discussion and Implications: Indigenous older adults who are living in rural areas are at particularly high risk of having dementia largely because they have presently recognized modifiable risk factors. These findings underscore the urgent need to prioritize provisions of appropriate and equitable service related to dementia for Indigenous people living in rural areas outside high-income countries., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)