Pembrolizumab is an FDA-approved therapeutic antibody that targets the programmed cell death-1 (PD-1) to block the immune checkpoint pathway for the treatment of various types of cancer. It receives ...remarkable attention due to the high degree of efficacy. Very recently, the crystal structure of the Fab fragment of pembrolizumab (PemFab) in complex with the extracellular domain of human PD-1 (PD-1
) was reported at a resolution of 2.9 Å. However, this relatively low-resolution structural data fails to provide sufficient information on interfacial water molecules at the binding interface that substantially contribute to affinity and specificity between the therapeutic antibody and target. Here, we present the independently determined crystal structure of the Fv fragment of pembrolizumab (PemFv) in complex with the PD-1
at a resolution of 2.15 Å. This high-resolution structure allows the accurate mapping of the interaction including water-mediated hydrogen bonds and provides, for the first time, a coherent explanation of PD-1 antagonism by pembrolizumab. Our structural data also provides new insights into the rational design of improved anti-PD-1 therapeutics.
The altered activity of the fructose transporter GLUT5, an isoform of the facilitated-diffusion glucose transporter family, has been linked to disorders such as type 2 diabetes and obesity. GLUT5 is ...also overexpressed in certain tumour cells, and inhibitors are potential drugs for these conditions. Here we describe the crystal structures of GLUT5 from Rattus norvegicus and Bos taurus in open outward- and open inward-facing conformations, respectively. GLUT5 has a major facilitator superfamily fold like other homologous monosaccharide transporters. On the basis of a comparison of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, we show that a single point mutation is enough to switch the substrate-binding preference of GLUT5 from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of Escherichia coli XylE suggests that, in addition to global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices TM7 and TM10 underlie a 'gated-pore' transport mechanism in such monosaccharide transporters.
Background: Although right ventricular (RV) enlargement may affect RV diastolic dysfunction assessed by end-diastolic forward flow (EDFF) in patients with repaired tetralogy of Fallot (TOF), EDFF may ...also be modified by left ventricular (LV) hemodynamics. We hypothesized that EDFF is affected by LV hemodynamics, not limited to RV diastolic stiffening.Methods and Results: Among 145 consecutive patients with repaired TOF who underwent catheterization, hemodynamic properties in 47 with consistent EDFF and 75 without EDFF were analyzed. Compared with patients without EDFF, those with EDFF had a large RV volume with a high regurgitant fraction. Although cardiac index and central venous pressure (CVP) were similar, contrast injection augmented CVP and LV end-diastolic pressure (EDP) in patients with vs. those without EDFF, suggesting compromised diastolic reserve. In patients with EDFF, the velocity–time integral (VTI) of EDFF was positively correlated with LVEDP and systemic vascular resistance, in addition to RV EDP. EDFF-VTI was correlated with hepatic venous wedge pressure and markers of hepatic dysfunction. Subanalysis of the older (≥6 years) half of the study cohort revealed that EDFF was associated with bi-atrial enlargement independent of RV volume, highlighting the pronounced role of EDFF on the diastolic property in the aged cohort.Conclusions: EDFF-VTI in patients with repaired TOF reflects RV diastolic dysfunction, affected by the left heart system. EDFF-VTI indicates blood stagnation, which may be attributed to end-organ damage.
Zirconia restorations are becoming increasingly common. However, zirconia reduces the polymerization of dual-cured resin cement owing to light attenuation, resulting in residual resin monomers. This ...study investigated the effects of dual-cured resin cement, with incomplete polymerization owing to attenuated light through zirconia, on the inflammatory response in vitro. The dual-cured resin cement (SA Luting Multi, Kuraray) was light-irradiated through zirconia with three thickness diameters (1.0, 1.5, and 2.0 mm). The light transmittance and the degree of conversion (DC) of the resin cement significantly decreased with increasing zirconia thickness. The dual-cured resin cement in 1.5 mm and 2.0 mm zirconia and no-irradiation groups showed significantly higher amounts of hydroxyethylmethacrylate and triethyleneglycol dimethacrylate elution and upregulated gene expression of proinflammatory cytokines
and
from human gingival fibroblasts (hGFs) and
from human monocytic cells, compared with that of the 0 mm group. Dual-cured resin cement with lower DC enhanced intracellular reactive oxygen species (ROS) levels and activated mitogen-activated protein (MAP) kinases in hGFs and monocytic cells. This study suggests that dual-cured resin cement with incomplete polymerization induces inflammatory responses in hGFs and monocytic cells by intracellular ROS generation and MAP kinase activation.
To establish a noninvasive selection system of human embryos with a high implantation potential before transferring.
Cohort study.
Independent IVF clinics.
One hundred sixty-four patients, with 791 ...embryos fertilized, checked, and recorded.
Embryos were divided into nine groups according to the number of cells they contained and the extent of their fragmentation during the first and second divisions. We examined the effects of the cell division pattern and division time of embryos on subsequent development in vitro and in vivo using a time-lapse incubator.
Rates of blastocyst formation, high-quality blastocyst formation, and pregnancy.
The rates of embryos developed into blastocysts and blastocysts in which both the inner cell mass and trophectoderm grades were scored B or higher (good-quality blastocysts) were high in groups that formed two cells during the first division and four cells during the second division, regardless of the presence or absence of fragmentation. In these groups the first and second division times (25.90 and 37.88 hours after culture, respectively) of embryos developed into good-quality blastocysts were significantly shorter than those of other embryos. Although embryo selection based on the first and second division times did not affect the pregnancy rates after transfer at day 2 or 3 of culture, it improved the pregnancy rates after blastocyst transfer at day 5.
Transfer of blastocysts derived from embryos that completed first and second divisions within 25.90 and 37.88 hours after culture, respectively, brings about high pregnancy rates.
Background: Long-term and prolonged piano performance does not provide essential skeletal muscle training benefits while increasing the risk of injury to the upper extremities. Unlike high-intensity ...exercise training, moderate blood flow restriction (BFR) training has been found to improve neuromuscular mechanisms with a variety of physical exercises (machine, elastic band, walking, electrical stimulation, and body weight).Aim and methods: We investigated the physiological and perceptual responses related to piano performance with or without BFR based on acute responses of neuromuscular mechanisms. Student or professional pianists (n=7) performed the "Revolutionary Etude" on the piano with (Piano-BFR) and without (Piano-Ctrl) BFR. During the Piano-BFR performance, 150-180 mmHg of cuff pressure was applied around the most proximal region of both arms as a moderate BFR.Results: Changes in upper limb girth, muscle thickness, and hand grip strength were measured before and immediately after the performance. After the performance, perceptual and other responses were recorded. Immediately after the performance, the Piano-BFR condition induced greater changes in girth (forearm and upper arm), muscle thickness (forearm), and handgrip strength than the Piano-Ctrl condition. Piano-BFR was (p<0.01) higher than Piano-Ctrl on eight questions regarding perceptual response (upper arm fatigue and difficulty playing the piano). Piano performance with BFR was revealed to increase upper extremity muscle size and fatigue in pianists after playing.Conclusion: Piano performance with BFR was revealed to increase upper extremity muscle size and fatigue in pianists after playing. The effect of BFR on neuromuscular mechanisms on piano performance was greater in the forearm than in the upper arm.
Purpose We investigated whether blood flow-restricted training known as KAATSU training, was effective for rehabilitation of a pianist with residual neurological symptoms in the upper limbs. ...Participant and Methods A pianist with residual neurological symptoms in the upper body played “Revolutionary Etude” under two conditions: piano performance with (Piano-blood flow-restricted) and without (Piano-control) the restriction of blood flow to the upper limbs. In the Piano-blood flow-restricted exercise, a pressure of 130–170 mmHg was applied around the most proximal portion of both arms. The changes in upper limb circumference and muscle strength were measured before, immediately after, and 15 min after the performance. The impression of the piano performance was recorded after the Piano-blood flow-restricted exercise. Results Immediately after the piano performance, the forearm and upper arm circumferences had increased significantly in both arms, and the change was greater in the Piano-blood flow-restricted than in the Piano-control condition. The handgrip strength for the right arm also showed greater changes in the former than the latter. However, there were no significant differences between the two conditions regarding the handgrip strength of the left arm. Conclusion There is a high possibility that blood flow-restricted training is effective for rehabilitation of the pianist with residual neurological symptoms in the upper limbs.
Aims and objectives
To describe how a health guidance programme provided to one person influences change in their spouse's health behaviours.
Background
Individuals are indirectly affected by the ...health behaviours of those close to them; therefore, it is likely that guidance on the prevention of lifestyle disease modifies the behaviour of targeted individuals and their family members. In a previous study, approximately 30% of families displayed positive health changes because one individual family member received health guidance.
Design
This study used an inductive, exploratory, qualitative design.
Methods
Semi‐structured interviews were conducted with spouses of persons who participated in a health guidance programme for lifestyle‐related disease prevention. Data were analysed from 11 spouses (all women; Mage = 61.0 ± 9.1 years) using a modified grounded theory approach. This study was conducted according to the consolidated criteria for reporting qualitative research (COREQ; see Appendix S1).
Results
The process of change in each spouse was a result of their partner's influence, which changed from a stage of assisting, where the spouse contemplated {I am just a supporter} to the partner, to a stage where the spouse thought {I am also a player}, and she engaged in her own health improvement practices.
Conclusions
For a spouse to change from assisting their partner to becoming a practitioner of their own health improvement, the spouse needed to experience a sense of surprise at the changes in her partner, through calm observation of the partner's attitude. Through the spreading effect of health guidance utilisation, indirect encouragement could be expected, even when people have difficulty accessing healthcare services.
Relevance to clinical practice
This type of spreading effect from one participant to a family member could perhaps assist health guidance provisions so that disease prevention becomes more efficient.
Studies have reported an association between attention deficit hyperactivity disorder (ADHD) and somatic diseases; however, the correlation of mental disorders with the association between ADHD and ...somatic diseases remains uninvestigated. This study investigated and compared the prevalence of somatic diseases among adults with/without ADHD, stratified by the presence or absence of mental disorders.
This cross-sectional study (October 2020-September 2021), using data (June 2013-September 2021) from a Japanese health insurance claims database, included adult participants with a medical record of and receiving medication for ADHD (ADHD group); the control group (matched 1:5 by age/sex) comprised participants without ADHD. The prevalence and odds ratio (OR; ADHD versus control) of type 2 diabetes mellitus (T2DM), diabetes complications, hypertension, cardiovascular disease (CVD), dyslipidemia, gout and hyperuricemia, chronic obstructive pulmonary disease (COPD), non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), and atopic dermatitis were investigated. Pooled ORs for stratified analysis were calculated using the Mantel-Haenszel method.
In the matched analysis sets, the ORs for all somatic diseases were significantly higher for the ADHD group (n=15,028) versus the control group (n=74,796). On stratified analysis, the Mantel-Haenszel ORs were significant for NAFLD/NASH (1.53; 95% confidence interval CI: 1.34, 1.73), diabetes complications (1.39; 95% CI: 1.09, 1.77), and gout and hyperuricemia (1.34; 95% CI: 1.19, 1.51). Furthermore, the stratum-specific ORs for T2DM, hypertension, and dyslipidemia were >1 and <1 in the presence and absence of mental disorders, respectively. The prevalence of all somatic diseases except atopic dermatitis increased with age. For participants aged ≥40 years, the Mantel-Haenszel ORs were significant for all somatic diseases except CVD, COPD, and atopic dermatitis.
The prevalence of several somatic diseases, including chronic disorders, was high among adults with ADHD, particularly in those aged ≥40 years and those with mental disorders.
PDF
