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Abstract Background Gait ability can be objectively assessed using gait analysis. Three-dimensional gait analysis, the most commonly used analytical method, has limitations, such as a prolonged examination, high system costs, and inconsistently reported gait symmetry in patients with knee osteoarthritis (OA). Therefore, we aimed to evaluate the gait symmetry and changes before and after unilateral total knee arthroplasty (TKA) using the Walkway analyzer, a sheet-type gait analyzer. Methods The healthy group included 38 participants from the Locomotor Frailty and Sarcopenia Registry study with lower limb pain or Kellgren–Lawrence classification grade 3 or 4 OA. The OA group included 34 participants from the registry study who underwent unilateral TKA. The walking speed, step length, step width, cadence, stride time, stance time, swing phase time, double-limb support phase time, stride, step length, and step width were analyzed per side using the Walkway gait analyzer. Results No significant differences between the right and left sides were observed in the healthy group. In the OA group, the time indices and stance phase (p = 0.011) and the double-limb support phase time (p = 0.039) were longer on the contralateral side and the swing phase was longer on the affected side (p = 0.004) pre-operatively. However, these differences disappeared post-operatively. There were no significant differences in the spatial indices. Thus, this study revealed that patients undergoing unilateral TKA had an asymmetric gait pre-operatively, with a time index compensating for the painful side, and an improved symmetric gait post-operatively. Conclusions The Walkway analyzer employs a simple test that requires only walking; hence, it is expected to be used for objective evaluation in actual clinical practice.

Abstract Because hepatic stellate cells (HSCs) play a major role in fibrosis, we focused on HSCs as a potential target for the treatment of liver fibrosis. In this study, we attempted to identify drug candidates to inactivate HSCs and found that several proteasome inhibitors (PIs) reduced HSC viability. Our data showed that a second-generation PI, carfilzomib (CZM), suppressed the expression of fibrotic markers in primary murine HSCs at low concentrations of 5 or 10 nM. Since CZM was not toxic to HSCs up to a concentration of 12.5 nM, we examined its antifibrotic effects further. CZM achieved a clear reduction in liver fibrosis in the carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis without worsening of liver injury. Mechanistically, RNA sequence analysis of primary HSCs revealed that CZM inhibits mitosis in HSCs. In the CCl4-injured liver, amphiregulin, which is known to activate mitogenic signaling pathways and fibrogenic activity and is upregulated in murine and human metabolic dysfunction-associated steatohepatitis (MASH), was downregulated by CZM administration, leading to inhibition of mitosis in HSCs. Thus, CZM and next-generation PIs in development could be potential therapeutic agents for the treatment of liver fibrosis via inactivation of HSCs without liver injury.

Abstract Objective To reveal the clinical features and assess risk factors linked to brain fog and its societal implications, including labor productivity, providing valuable insights for the future care of individuals who have experienced coronavirus disease 2019 (COVID‐19). Methods We analyzed a comprehensive cohort dataset comprising 1,009 patients with COVID‐19 admitted to Japanese hospitals. To assess brain fog, we analyzed patients who responded to a questionnaire indicating symptoms such as memory impairment and poor concentration. Results The prevalence of brain fog symptoms decreased 3 months posthospitalization but remained stable up to 12 months. Neurological symptoms such as taste and smell disorders and numbness at hospitalization correlated with a higher frequency of identifying brain fog as a long COVID manifestation. Our findings indicated that advanced age, female sex, a high body mass index, oxygen required during hospitalization, chronic obstructive pulmonary disease, asthma, and elevated C‐reactive protein and elevated D‐dimer levels were risk factors in patients exhibiting brain fog. Additionally, we demonstrated the negative impact of brain fog on labor productivity by presenteeism scores. Interpretations This study clarified the clinical characteristics of patients experiencing brain fog as a long COVID manifestation, specifically emphasizing neurological symptoms during hospitalization and their correlation with brain fog. Additionally, the study identified associated risk factors for its onset and revealed that the emergence of brain fog was linked to a decline in labor productivity.

Abstract A simple method for determining the anaerobic threshold in patients with heart failure (HF) is needed. This prospective clinical trial (LacS-001) aimed to investigate the safety of a sweat lactate-monitoring sensor and the correlation between lactate threshold in sweat (sLT) and ventilatory threshold (VT). To this end, we recruited 50 patients with HF and New York Heart Association functional classification I–II (mean age: 63.5 years, interquartile range: 58.0–72.0). Incremental exercise tests were conducted while monitoring sweat lactate levels using our sensor. sLT was defined as the first steep increase in lactate levels from baseline. Primary outcome measures were a correlation coefficient of ≥ 0.6 between sLT and VT, similarities as assessed by the Bland–Altman analysis, and standard deviation of the difference within 15 W. A correlation coefficient of 0.651 (95% confidence interval, 0.391–0.815) was achieved in 32/50 cases. The difference between sLT and VT was −4.9 ± 15.0 W. No comparative error was noted in the Bland–Altman plot. No device-related adverse events were reported among the registered patients. Our sweat lactate sensor is safe and accurate for detecting VT in patients with HF in clinical settings, thereby offering valuable additional information for treatment.

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35–74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women’s health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

Background: Uremic toxin indoxyl sulfate (IS) induces vascular inflammation, a crucial event in renal failure, and vascular complications in patients with chronic kidney disease (CKD). In endothelial cells, IS increases the production of inflammatory cytokines partially via the activation of the aryl hydrocarbon receptor (AhR), and several food flavonoids have been reported to act as antagonists of AhR. Objective: This study aimed to investigate whether antagonistic flavonoids can attenuate IS-induced inflammatory responses in vascular endothelial cells in vitro and renal failure in vivo. Design: Human umbilical vein endothelial cells (HUVECs) pretreated with the flavones apigenin, chrysin, or luteolin were stimulated with IS. Expression levels of genes involved in AhR signaling, inflammatory cytokine production, and reactive oxygen species (ROS) production were analyzed. Uninephrectomized mice were orally administered chrysin and received daily intraperitoneal injections of IS for 4 weeks. Results: In HUVECs, IS upregulated the mRNA expression of AhR-targeted genes (CYP1A1 and AhRR), and genes involved in inflammation (NOX4, MCP-1, IL-6, and COX2) and monocyte invasion/adhesion (ICAM1). All three flavones attenuated the IS-induced increase in the expression of these mRNAs. They also suppressed the IS-induced nuclear translocation of AhR and intracellular ROS production. Furthermore, IS-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was inhibited by treatment with these flavones. The results of in-vivo experiments showed that administration with chrysin attenuated the elevation of blood urea nitrogen levels and AhR-target gene expression and the pathological impairment of renal tissues in mice, regardless of higher serum levels of IS. Conclusions: Natural food flavones antagonizing AhR exerted protective effects against IS-induced inflammation through the inhibition of the AhR–STAT3 pathway in HUVECs. Moreover, chrysin ameliorated IS-induced renal dysfunction in a mouse model of CKD. These flavonoids could be a therapeutic strategy for vascular inflammation in CKD.

Abstract Possible local influence of an extreme marine heatwave is investigated on unprecedentedly hot summer around northern Japan in 2023. Sea-surface temperatures (SSTs) and subsurface ocean temperatures around northern Japan were also unprecedentedly high in the summer. This was especially the case off the east coast of Japan, where cool Oyashio water was replaced with much warmer water due to a striking poleward meander of the Kuroshio Extension persistent from the spring. Particularly amplified near-surface air temperature anomalies and even stronger warm anomalies in the subsurface ocean suggest that the marine heatwave acted to sustain the atmospheric heatwave. Anomalous upward of latent and sensible heat fluxes from the warmed sea surface are indicative of local oceanic impact. The warm SST anomalies reduced the lower-tropospheric stratification to maintain unfavourable condition for low-level cloud formation, which in turn led to increased surface insolation for further SST warming as positive feedback. The increased moisture in the warmed lower troposphere contributed to the enhanced surface downward longwave radiation. This enhanced greenhouse effect acted not only as positive feedback on the warm SST anomalies that increased evaporation but also as a contributor for the extreme warmth over northern Japan landmass.

Background: Dupilumab has clinical effects in patients with moderate-to-severe asthma. When considering interleukin (IL)-4 and IL-13 signaling, effects of dupilumab on airway mucus hypersecretion and airway remodeling are expected, but they have been reported in only a few short-term studies. Its efficacy for airway hyperresponsiveness (AHR) remains unknown. We comprehensively assessed the efficacy of dupilumab, especially for subjective and objective measures of airway mucus hypersecretion and airway dimensions in moderate-to-severe asthmatic patients. Methods: In 28 adult patients with moderate-to-severe uncontrolled asthma, the comprehensive efficacy of 48-week dupilumab treatment, including the Cough and Sputum Assessment Questionnaire (CASA-Q), radiological mucus scores and airway dimensions on computed tomography (CT), was assessed prospectively. Treatment responsiveness to dupilumab was analyzed. Results: With 48-week dupilumab treatment, all four cough and sputum domain scores of CASA-Q improved significantly. Radiological mucus scores and airway wall thickening on CT were significantly decreased. The decreases in mucus scores were significantly associated with improvements in Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire (AQLQ) overall scores, airway obstruction, and airway type 2 inflammation. When defined by > 0.5 improvement in AQLQ overall scores, 18 patients (64%) were identified as responders. Conclusions: Dupilumab reversed subjective and objective measures of airway mucus hypersecretion and some aspects of airway remodeling in patients with moderate-to-severe uncontrolled asthma.

Introduction: From the late 1960s to the present, physicians’ dress codes have been actively studied in Western countries. Until the early 21st century, patients tended to prefer a conservative dress style, such as “shirt and tie or skirt” with white coats for physicians. However, as attitudes toward dress codes have changed, knowledge regarding this issue needs to be updated. A variety of colours of scrubs are currently commonly used by medical professionals, but it is not known whether all colours are acceptable to patients. The current study sought to investigate the acceptability of various dress codes for physicians from the patients’ perspective, to inform medical education. Methods: Outpatients and their family members at a university hospital and a small-to-medium-sized hospital were surveyed. We inquired about which of the different styles of white coats and different colours of scrubs were most desirable for male and female physicians. We used Scheffe’s paired comparison method to determine rankings. Results: Patients and their family members expected their physicians to wear white coats rather than scrubs. Furthermore, a more traditional and formal dress code was preferred. The least preferred colour of scrubs was yellow. Conclusion: The current results indicated that patients’ preference for a traditional, conservative appearance has not changed over time. This finding does not match current perspectives on infection prevention. Both patient preferences and infection prevention are important for informing education and gaining patient trust.

Abstract Background Following an acute myocardial infarction (AMI), surgery for left ventricular free wall rupture (LVFWR) and ventricular septal rupture (VSR) has a high in-hospital mortality rate, which has not improved significantly over time. Unloading the LV is critical to preventing excessive stress on the repair site and avoiding problems such as bleeding, leaks, patch dehiscence, and recurrence of LVFWR and VSR because the tissue is so fragile. We present two cases of patients who used Impella 5.5 for LV unloading following emergency surgery for AMI mechanical complications. Case presentation A 76-year-old male STEMI patient underwent fibrinolysis of the distal right coronary artery. Three days later, he passed out and went into shock. Echocardiography revealed a cardiac tamponade. We found an oozing-type LVFWR on the posterolateral wall and treated it with a non-suture technique using TachoSil. Before the patient was taken off CPB, Impella 5.5 was inserted into the LV via a 10 mm synthetic graft connected to the right axillary artery. We kept the flow rate above 4.0 to 4.5 L/min until POD 3 to reduce LV wall tension while minimizing pulsatility. On POD 6, we weaned the patient from Impella 5.5. A postoperative cardiac CT scan showed no contrast leakage from the LV. However, a cerebral hemorrhage on POD 4 during heparin administration complicated his hospitalization. Case 2: A diagnosis of cardiogenic shock caused by STEMI occurred in an 84-year-old male patient, who underwent PCI of the LAD with IABP support. Three days after PCI, echocardiography revealed VSR, and the patient underwent emergency VSR repair with two separate patches and BioGlue applied to the suture line between them. Before weaning from CPB, we implanted Impella 5.5 in the LV and added venoarterial extracorporeal membrane oxygenation (VA-ECMO) support for right heart failure. The postoperative echocardiography revealed no residual shunt. Conclusions Patients undergoing emergency surgery for mechanical complications of AMI may find Impella 5.5 to be an effective tool for LV unloading. The use of VA-ECMO in conjunction with Impella may be an effective strategy for managing VSR associated with concurrent right-sided heart failure.

General circulation models' (GCMs) estimates of the liquid water path adjustment to anthropogenic aerosol emissions differ in sign from other lines of evidence. This reduces confidence in estimates of the effective radiative forcing of the climate by aerosol–cloud interactions (ERFaci). The discrepancy is thought to stem in part from GCMs' inability to represent the turbulence–microphysics interactions in cloud-top entrainment, a mechanism that leads to a reduction in liquid water in response to an anthropogenic increase in aerosols. In the real atmosphere, enhanced cloud-top entrainment is thought to be the dominant adjustment mechanism for liquid water path, weakening the overall ERFaci. We show that the latest generation of GCMs includes models that produce a negative correlation between the present-day cloud droplet number and liquid water path, a key piece of observational evidence supporting liquid water path reduction by anthropogenic aerosols and one that earlier-generation GCMs could not reproduce. However, even in GCMs with this negative correlation, the increase in anthropogenic aerosols from preindustrial to present-day values still leads to an increase in the simulated liquid water path due to the parameterized precipitation suppression mechanism. This adds to the evidence that correlations in the present-day climate are not necessarily causal. We investigate sources of confounding to explain the noncausal correlation between liquid water path and droplet number. These results are a reminder that assessments of climate parameters based on multiple lines of evidence must carefully consider the complementary strengths of different lines when the lines disagree.

Earth system models (ESMs) participating in the latest Coupled Model Intercomparison Project Phase 6 (CMIP6) simulate various components of fine particulate matter (PM2.5) as major climate forcers. Yet the model performance for PM2.5 components remains little evaluated due in part to a lack of observational data. Here, we evaluate near-surface concentrations of PM2.5 and its five main components over China as simulated by 14 CMIP6 models, including organic carbon (OC; available in 14 models), black carbon (BC; 14 models), sulfate (14 models), nitrate (4 models), and ammonium (5 models). For this purpose, we collect observational data between 2000 and 2014 from a satellite-based dataset for total PM2.5 and from 2469 measurement records in the literature for PM2.5 components. Seven models output total PM2.5 concentrations, and they all underestimate the observed total PM2.5 over eastern China, with GFDL-ESM4 (−1.5 %) and MPI-ESM-1-2-HAM (−1.1 %) exhibiting the smallest biases averaged over the whole country. The other seven models, for which we recalculate total PM2.5 from the available component output, underestimate the total PM2.5 concentrations partly because of the missing model representations of nitrate and ammonium. Concentrations of the five individual components are underestimated in almost all models, except that sulfate is overestimated in MPI-ESM-1-2-HAM by 12.6 % and in MRI-ESM2-0 by 24.5 %. The underestimation is the largest for OC (by −71.2 % to −37.8 % across the 14 models) and the smallest for BC (−47.9 % to −12.1 %). The multi-model mean (MMM) reproduces the observed spatial pattern for OC (R = 0.51), sulfate (R = 0.57), nitrate (R = 0.70) and ammonium (R = 0.74) fairly well, yet the agreement is poorer for BC (R = 0.39). The varying performances of ESMs on total PM2.5 and its components have important implications for the modeled magnitude and spatial pattern of aerosol radiative forcing.

Abstract The experimental findings from the Large Helical Device have demonstrated a fast, nondiffusive behavior during the propagation of heat pulses, with an observed increase in speed with reduction in their temporal width. Concurrent propagation of the temperature gradient and turbulence, in a timeframe spanning from a few milliseconds to tens of milliseconds, aligned with the avalanche model. These results indicate that the more spatiotemporally localized the heat and turbulence pulses are, the greater the deviation of the plasma from its equilibrium state, coupled with faster propagation velocity. This insight is pivotal for future fusion reactors, which necessitate the maintenance of a steady-state, non-equilibrium condition.

Abstract Pear pollination is performed by artificial pollination because the pollination rate through insect pollination is not stable. Pollen must be collected to secure sufficient pollen for artificial pollination. However, recently, collecting sufficient amounts of pollen in Japan has become difficult, resulting in increased imports from overseas. To solve this problem, improving the efficiency of pollen collection and strengthening the domestic supply and demand system is necessary. In this study, we proposed an Artificial Intelligence (AI)-based method to estimate the amount of pear pollen. The proposed method used a deep learning-based object detection algorithm, You Only Look Once (YOLO), to classify and detect flower shapes in five stages, from bud to flowering, and to estimate the pollen amount. In this study, the performance of the proposed method was discussed by analyzing the accuracy and error of classification for multiple flower varieties. Although this study only discussed the performance of estimating the amount of pollen collected, in the future, we aim to establish a technique for estimating the time of maximum pollen collection using the method proposed in this study.

Abstract Background Recent studies have indicated the importance of muscle quality in addition to muscle quantity in sarcopenia pathophysiology. Intramuscular adipose tissue (IMAT), which originates from mesenchymal progenitors (MPs) in adult skeletal muscle, is a key factor affecting muscle quality in older adults, suggesting that controlling IMAT formation is a promising therapeutic strategy for sarcopenia. However, the molecular mechanism underlying IMAT formation in older adults has not been clarified. We recently found that the vitamin D receptor (VDR) is highly expressed in MPs in comparison to myotubes (P = 0.028, N = 3), indicating a potential role of vitamin D signalling in MPs. In this study, we aimed to clarify the role of vitamin D signalling in MP kinetics, with a focus on adipogenesis. Methods MPs isolated from mouse skeletal muscles were subjected to adipogenic differentiation conditions with or without vitamin D (1α,25(OH)2D3, 100 nM) for 7 days, and adipogenicity was evaluated based on adipogenic marker expression. For in vivo analysis, tamoxifen‐inducible MP‐specific VDR‐deficient (VdrMPcKO) mice were newly developed to investigate whether lack of vitamin D signalling in MPs is involved in IMAT formation. To induce muscle atrophy, VdrMPcKO male mice were subjected to tenotomy of the gastrocnemius muscle, and then muscle weight, myofibre cross‐sectional area, adipogenic marker expression, and fatty infiltration into the muscle were evaluated at 3 weeks after operation (N = 3–4). In addition, a vitamin D‐deficient diet was provided to wild‐type male mice (3 and 20 months of age, N = 5) for 3 months to investigate whether vitamin D deficiency causes IMAT formation. Results Vitamin D treatment nearly completely inhibited adipogenesis of MPs through Runx1‐mediated transcriptional modifications of early adipogenic factors such as PPARγ (P = 0.0031) and C/EBPα (P = 0.0027), whereas VDR‐deficient MPs derived from VdrMPcKO mice differentiated into adipocytes even in the presence of vitamin D (P = 0.0044, Oil‐Red O+ area). In consistency with in‐vitro findings, VdrMPcKO mice and mice fed a vitamin D‐deficient diet exhibited fat deposition in atrophied (P = 0.0311) and aged (P = 0.0216) skeletal muscle, respectively. Conclusions Vitamin D signalling is important to prevent fate decision of MPs towards the adipogenic lineage. As vitamin D levels decline with age, our data indicate that decreased vitamin D levels may be one of the causes of IMAT formation in older adults, and vitamin D signalling may be a novel therapeutic target for sarcopenia.

Background: Human dental pulp-derived stem cells (hDPSCs) have emerged as a promising source for adult stem cell-based regenerative medicine. Stage-specific embryonic antigen 3 (SSEA3) is a cell surface marker associated with Multilineage-differentiating stress-enduring (Muse) cells, a subpopulation of human bone marrow-derived stem cells (hBMSCs), known for their potent regenerative potential and safety profile. In this study, we investigated the influence of the prolonged culture period and the number of culture passages on the regenerative capacity of hDPSCs and explored the association between SSEA3 expression and their regenerative abilities. Methods: hDPSCs were isolated and cultured for up to 20 passages. Cell proliferation, migration, and osteogenic, adipogenic and neurogenic differentiation potential were assessed at passages 5, 10, and 20. Flow cytometry and immunofluorescence were employed to analyze SSEA3 expression. RNA sequencing (RNA-seq) was performed on SSEA3-positive and SSEA3-negative hDPSCs to identify differentially expressed genes and associated pathways. Results: Our findings demonstrated a progressive decline in hDPSCs proliferation and migration capacity with increasing passage number. Conversely, cell size exhibited a positive correlation with passage number. Early passage hDPSCs displayed superior osteogenic and adipogenic differentiation potential. Notably, SSEA3 expression exhibited a significant negative correlation with passage numbers, reflecting the observed decline in differentiation capacity. RNA-seq analysis revealed distinct transcriptional profiles between SSEA3-positive and SSEA3-negative hDPSCs. SSEA3-positive cells displayed upregulation of genes associated with ectodermal differentiation and downregulation of genes involved in cell adhesion. Conclusions: This study elucidates the impact of passaging on hDPSC behavior and suggests SSEA3 as a valuable biomarker for evaluating stemness and regenerative potential. SSEA3-positive hDPSCs, functionally analogous to Muse cells, represent a promising cell population for developing targeted regenerative therapies with potentially improved clinical outcomes.

Malnutrition-inflammation-atherosclerosis (MIA) syndrome is a significant risk factor for mortality in patients undergoing hemodialysis. This study aimed to investigate the association between MIA syndrome and oral health status in hemodialysis patients. A cross-sectional study was conducted on 254 hemodialysis patients. Comprehensive medical and dental examinations were performed. Three components were included to define MIA syndrome: Geriatric Nutritional Risk Index, serum high-sensitivity C-reactive protein, and history of cardiovascular events as indicators of malnutrition, inflammation, and atherosclerosis, respectively. The association of MIA syndrome components with periodontitis and occlusal support was examined by multiple-ordered logistic regression analysis. Of 254 participants, 188 (74.0%) had at least one component of MIA syndrome. After adjusting for possible confounding factors, severe periodontitis was significantly associated with presence of more components of MIA syndrome (odds ratio [OR]: 2.64, 95% confidence interval [CI], 1.44-4.84, p = 0.002) and inflammation and malnutrition components (OR: 2.47 and 3.46, 95% CI 1.16-5.28 and 1.70-7.05, p = 0.020 and 0.001). On the other hand, occlusal support, evaluated by Eichner index, was not significantly associated with MIA syndrome or any of its components. In conclusion, periodontitis is associated with MIA syndrome, particularly with inflammation and malnutrition in hemodialysis patients, independent of occlusal support.

Macaques are representative animal models in translational research. However, the distinct shape and location of the brain regions between macaques and humans prevents us from comparing the brain structure directly. Here, we calculated structural connectivity (SC) with multi-scale hierarchical regions of interest (ROIs) to parcel out human and macaque brain into 8 (level 1 ROIs), 28 (level 2 ROIs), or 46 (level 3 ROIs) regions, which consist of anatomically and functionally defined level 4 ROIs (around 100 parcellation of the brain). The SC with the level 1 ROIs showed lower individual and interspecies variation in macaques and humans. SC with level 2 and 3 ROIs shows that the several regions in frontal, temporal and parietal lobe show distinct connectivity between macaques and humans. Lateral frontal cortex, motor cortex and auditory cortex were shown to be important areas for interspecies differences. These results provide insights to use macaques as animal models for translational study.

Abstract Since the 5th Assessment Report of the Intergovernmental Panel on Climate Change (AR5) an extended concept of the energetic analysis of climate change including forcings, feedbacks and adjustment processes has become widely adopted. Adjustments are defined as processes that occur in response to the introduction of a climate forcing agent, but that are independent of global‐mean surface temperature changes. Most considered are the adjustments that impact the Earth energy budget and strengthen or weaken the instantaneous radiative forcing due to the forcing agent. Some adjustment mechanisms also impact other aspects of climate not related to the Earth radiation budget. Since AR5 and a following description by Sherwood et al. (2015, https://doi.org/10.1175/bams‐d‐13‐00167.1), much research on adjustments has been performed and is reviewed here. We classify the adjustment mechanisms into six main categories, and discuss methods of quantifying these adjustments in terms of their potentials, shortcomings and practicality. We furthermore describe aspects of adjustments that act beyond the energetic framework, and we propose new ideas to observe adjustments or to make use of observations to constrain their representation in models. Altogether, the problem of adjustments is now on a robust scientific footing, and better quantification and observational constraint is possible. This allows for improvements in understanding and quantifying climate change.

ABSTRACT Streptococcus pneumoniae is one of the major pathogens responsible for bacterial meningitis and neurological sequelae. The present study was conducted to identify a non-hematogenous route used by S. pneumoniae to gain access to brain tissue without causing bacteremia or pneumonia, as well as bacterial and host factors involved in this process. To investigate the molecular mechanisms and dissemination pathways of pneumococcal infection in brain tissue, mice were intranasally inoculated with S. pneumoniae strain EF3030, a clinical isolate from a patient with otitis media. Pneumococci were isolated from the frontal olfactory bulb, caudal cerebrum, and cerebellum, with neither bacteremia nor pneumonia observed in the present model. Immunostaining imaging revealed the presence of S. pneumoniae organisms in olfactory nerve fibers. Knockout of the ply gene encoding pneumolysin (PLY) markedly compromised the ability of the bacterial organisms to disseminate into brain tissue, whereas the dissemination efficiency of the complemented strain was restored to nearly the same level as the wild type. Notably, distinct upregulation of Gli1 and Snail1, which are involved in the transcriptional repression of junctional proteins, along with downregulation of E-cadherin, was detected in nasal lavage samples from mice infected with the wild-type or complemented strain, but not in those from mice infected with the ply mutant. Taken together, the present findings indicate that PLY induces Gli1-Snail1-dependent dysfunction of the nasal epithelial barrier, thus allowing pneumococcal dissemination to brain tissue that occurs in a non-hematogenous manner.IMPORTANCEBacterial meningitis, considered to be caused by bacteremia, can lead to blood–brain barrier disruption and bacterial dissemination into the central nervous system. Despite the availability of intravenously administered antibiotics with cerebrospinal fluid transferability, bacterial meningitis remains associated with high rates of morbidity and mortality. Here, we utilized Streptococcus pneumoniae strain EF3030, clinically isolated from otitis media, for the construction of a murine infection model to investigate the molecular mechanisms by which nasally colonized pneumococci disseminate into brain tissue. The obtained findings indicate that pneumolysin (PLY) induces Gli1-Snail1-dependent dysfunction of the nasal epithelial barrier, which facilitates pneumococcal dissemination to brain tissue in a non-hematogenous manner. Our results support the existence of an alternative route by which S. pneumoniae can reach the central nervous system and indicate the need for the development of novel therapeutic strategies, which would be an important contribution to the clinical management of bacterial meningitis.

The development of reduced models provide efficient methods that can be used to perform short term experimental data analysis or narrow down the parametric range of more sophisticated numerical approaches. Reduced models are derived by simplifying the physics description with the goal of retaining only the essential ingredients required to reproduce the phenomena under study. This is the role of the gyro-fluid code FAR3d, dedicated to analyze the linear and nonlinear stability of Alfvén Eigenmodes (AE), Energetic Particle Modes (EPM) and magnetic-hydrodynamic modes as pressure gradient driven mode (PGDM) and current driven modes (CDM) in nuclear fusion devices. Such analysis is valuable for improving the plasma heating efficiency and confinement; this can enhance the overall device performance. The present review is dedicated to a description of the most important contributions of the FAR3d code in the field of energetic particles (EP) and AE/EPM stability. FAR3d is used to model and characterize the AE/EPM activity measured in fusion devices as LHD, JET, DIII-D, EAST, TJ-II and Heliotron J. In addition, the computational efficiency of FAR3d facilitates performing massive parametric studies leading to the identification of optimization trends with respect to the AE/EPM stability. This can aid in identifying operational regimes where AE/EPM activity is avoided or minimized. This technique is applied to the analysis of optimized configurations with respect to the thermal plasma parameters, magnetic field configuration, external actuators and the effect of multiple EP populations. In addition, the AE/EPM saturation phase is analyzed, taking into account both steady-state phases and bursting activity observed in LHD and DIII-D devices. The nonlinear calculations provide: the induced EP transport, the generation of zonal structures as well as the energy transfer towards the thermal plasma and between different toroidal/helical families. Finally, FAR3d is used to forecast the AE/EPM stability in operational scenarios of future devices as ITER, CFETR, JT60SA and CFQS as well as possible approaches to optimization with respect to variations in the most important plasma parameters.