Deviated binding of anti-HBV nucleoside analog E-CFCP-TP to the reverse transcriptase active site attenuates the effect of drug-resistant mutations.

While certain human hepatitis B virus-targeting nucleoside analogs (NAs) serve as crucial anti-HBV drugs, HBV yet remains to be a major global health threat. E-CFCP is a 4'-modified and fluoromethylenated NA that exhibits potent antiviral activity against both wild-type and drug-resistant HBVs but less potent against human immunodeficiency virus type-1 (HIV-1). Here, we show that HIV-1 with HBV-associated amino acid substitutions introduced into the RT's dNTP-binding site (N-site) is highly susceptible to E-CFCP. We determined the X-ray structures of HBV-associated HIV-1 RT mutants complexed with DNA:E-CFCP-triphosphate (E-CFCP-TP). The structures revealed that exocyclic fluoromethylene pushes the Met184 sidechain backward, and the resultant enlarged hydrophobic pocket accommodates both the fluoromethylene and 4'-cyano moiety of E-CFCP. Structural comparison with the DNA:dGTP/entecavir-triphosphate complex also indicated that the cyclopentene moiety of the bound E-CFCP-TP is slightly skewed and deviated. This positioning partly corresponds to that of the bound dNTP observed in the HIV-1 RT mutant with drug-resistant mutations F160M/M184V, resulting in the attenuation of the structural effects of F160M/M184V substitutions. These results expand our knowledge of the interactions between NAs and the RT N-site and should help further design antiviral NAs against both HIV-1 and HBV.

Favorite Parts of a Single Leaf for Giant Flying Squirrels to Eat in Three Species of Food Trees.

To examine the effect of leaf chemical composition on selective herbivory by the Japanese giant flying squirrels (Petaurista leucogenys), we measured and compared the total phenolic, glucose, and water contents of leaves among their main food tree species, deciduous Quercus acutissima, and evergreen Q. sessilifolia and Phonitia serratifolia. Leaves of these three tree species were available in the warm season (April to October), but the flying squirrels mostly preferred the leaves of Q. acutissima, having higher glucose and water contents than those of the other two tree species. In the cold season (November to the next March), the two evergreen tree species were available, and the flying squirrels used both leaves without any apparent influence of the chemical compositions. On the other hand, the favorite parts of a single leaf differed among the three tree species. Flying squirrels dropped the individual leaves after partial consumption. Their feeding marks on the dropped leaves were distinguished into four types: apical, basal, central, and marginal parts of consumption. The basal parts of consumption were most frequent in Q. acutissima leaves in which more water was contained at the basal part, and the central part consumption followed, which may be related to a lower phenolic content and more glucose and water at the leaf center than its margin. In contrast, the apically consumed leaves dominated in Q. sessilifolia, with relatively homogeneous leaf chemical distribution except for more water at the center. In P. serratifolia, leaves consumed at the center were frequent, but those with marginal consumption were also observed, which may be related to its specific chemical distribution with less phenolics and more glucose at the leaf margin. Thus, the chemical distributions within the single leaf differ among tree species, and the flying squirrel's selectivity of the tree species and the part of each leaf depends partly on the relative compositions of preferable glucose and water and unpreferable phenolics.

Academic Activities of Female Neurosurgeons in All Branch Meetings of the Japan Neurosurgical Society.

This study aims to evaluate the academic activities of female neurosurgeons at all branch meetings of the Japan Neurosurgical Society and identify related issues they encountered. The programs of all seven branch meetings of the Japan Neurosurgical Society (Hokkaido, Tohoku, Kanto, Chubu, Kinki, Chugoku/Shikoku, and Kyushu) were used to determine the number of presentations and chairpersons by sex. The covered period was from January 2008 to December 2020, which was available for viewing during the survey. Of note, only the Kinki branch used data from January 2008 to December 2019. The Neurologia Medico-chirurgica (NMC), the journal of the Japan Neurosurgical Society, was also reviewed to identify publication achievements during the same period. In all seven branches, the percentage of presentations given by female physicians increased from 7.9% in 2008 to 9.6% in 2020 (p < 0.05).Conversely, the percentage of female chairpersons in all branch meetings did not change over time and it was significantly lower (1.1%) than that of female presenters (7.9%) for all branch meetings combined in over 13 years (p < 0.01). In the NMC, the number of articles with female physicians as first authors did not increase or decrease over the years. We conclude that efforts to smoothly promote female neurosurgeons as chairpersons and increase the number of female first authors are necessary to facilitate their academic activities.

Gamma Knife Thalamotomy for Essential Tremor: A Retrospective Analysis.

BACKGROUND: Gamma knife (GK) thalamotomy has been used as a treatment option for essential tremor (ET). Numerous studies on GK use in ET treatment have reported more varied responses and complication rates. METHODS: Data from 27 patients with ET who underwent GK thalamotomy were retrospectively analyzed. The Fahn-Tolosa-Marin Clinical Rating Scale for Tremor, handwriting, and spiral drawing were evaluated. Postoperative adverse events and magnetic resonance imaging findings were also evaluated. RESULTS: The mean age at GK thalamotomy was 78.1 ± 4.2 years. The mean follow-up period was 32.5 ± 19.4 months. The preoperative postural tremor, handwriting, and spiral drawing scores were 3.4 ± 0.6, 3.3 ± 1.0, and 3.2 ± 0.8, respectively, all of which showed significant improvements to 1.5 ± 1.2 (55.9% improvement, P < 0.001), 1.4 ± 1.1 (57.6% improvement, P < 0.001), and 1.6 ± 1.3 (50% improvement, P < 0.001), respectively, at the available final follow-up evaluations. Three patients presented with no improvement in tremor. Six patients presented with adverse effects, including complete hemiparesis, foot weakness, dysarthria, dysphagia, lip numbness, and finger numbness, at the final follow-up period. Two patients presented with serious complications, including complete hemiparesis due to massive widespread edema and chronic encapsulated expanding hematoma. One patient died of aspiration pneumonia following severe dysphagia secondary to chronic encapsulated expanding hematoma. CONCLUSIONS: GK thalamotomy is an efficient procedure for treating ET. Careful treatment planning is necessary to reduce complication rates. The prediction of radiation complications will increase the safety and effectiveness of GK treatment.

Development of Genetic Markers for Sex and Individual Identification of the Japanese Giant Flying Squirrel (Petaurista leucogenys) by an Efficient Method Using High-Throughput DNA Sequencing.

DNA markers that detect differences in the number of microsatellite repeats can be highly effective for genotyping individuals that lack differences in external morphology. However, isolation of sequences with different microsatellite repeat numbers between individuals has been a time-consuming process in the development of DNA markers. Individual identification of Japanese giant flying squirrels (Petaurista leucogenys) has been challenging because this species is arboreal and nocturnal and exhibits little to no morphological variation between individuals. In this study, we developed DNA markers for sex and individual identification of this species by an efficient method using high-throughput DNA sequence data. Paired-end 5 Gb (2 × 250 bp) and 15 Gb (2 × 150 bp) genome sequences were determined from a female and a male Japanese giant flying squirrel, respectively. We searched SRY and XIST genes located on Y and X chromosomes, respectively, from high-throughput sequence data and designed primers to amplify these genes. Using these primer sets, we succeeded to identify the sex of individuals. In addition, we selected 12 loci containing microsatellites with different numbers of repeats between two individuals from the same data set, and designed primers to amplify these sequences. Twenty individuals from nine different locations were discriminated using these primer sets. Furthermore, both sex and microsatellite markers were amplified from DNA extracted non-invasively from single fecal pellet samples. Based on our results for flying squirrels, we expect our efficient method for developing non-invasive high-resolution individual- and sex-specific genotyping to be applicable to a diversity of mammalian species.

Group multi-component programme based on cognitive behavioural therapy and positive psychology for family caregivers of people with dementia: a randomised controlled study (3C study).

BACKGROUND: Caregivers of people with dementia frequently experience an elevated level of psychological distress and burden. This study aimed to examine the effectiveness of a group-format multi-component programme which is based on cognitive behavioural therapy and positive psychology. METHODS: Family caregivers of dementia were allocated (1:1) to the intervention group and the wait-list control group, stratified by age (<65 years, ≥65 years) and care status (at home or in an institution). The intervention group received a six-session, 10-week, group-format programme. The primary outcome was the Hospital Anxiety Depression Scale (HADS). Secondary outcomes were the short-version of the Zarit Burden Interview (personal strain and role strain), Neuropsychiatric Inventory Questionnaire, Dementia Caregiver Positive Feeling Scale, and Self-Compassionate Reactions Inventory. The evaluations were conducted at baseline, 10 weeks (post-intervention), and 14 weeks (follow-up). RESULTS: The analyses were performed with 64 registered participants. In the whole sample, no significant effect was observed on HADS. There was medium effect on role strain (P = 0.04, partial η2  = 0.08). Positive feelings of caregiving increased after the intervention but were not maintained at follow-up. In the subgroup analysis of caregivers under 65 years of age, a statistically significant effect was observed for personal strain (P = 0.03, partial η2 = 0.16). An interaction effect was also found for the total score of positive feelings of caregiving (P < 0.05, partial η2 = 0.02) and the meaning of caregiving (P = 0.02, partial η2 = 0.10). CONCLUSIONS: This programme did not show significant improvement in depression and anxiety of caregivers of dementia; however, it reduced the burden of their role conflict (role strain) and yielded favourable short-term effects on the positive feelings and the meaning of caregiving among the participants. Also, the programme effectively reduced the personal strain of caregivers under 65 years.

Impact of continued mindfulness practice on resilience and well-being in mindfulness-based intervention graduates during the COVID-19 pandemic: A cross-sectional study.

Aim: The coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented stress. Mindfulness-based interventions (MBIs) are known to be effective in reducing stress. However, it is unclear how long-term outcomes differ between those who continue mindfulness practice after MBIs and those who do not. In this study, we hypothesized that those who continued mindfulness practice would have higher stress tolerance, and we examined this hypothesis through a survey of MBI graduates. In this study, we examined the association between the continuation of mindfulness practice among MBI completers and individual stress during the COVID-19 epidemic. Methods: A cross-sectional survey of MBI graduates was conducted. The physical and mental health states were compared between those who established a habit of mindfulness practice (practice group) and those who did not (no practice group). Results: The data were collected from 95 participants (response rate: 53.7%). Of the total respondents, 66 (69.5%) practiced mindfulness. Although the degree of perceived stress due to the COVID-19 pandemic was not statistically different between the practice and no practice groups, the practice group showed significantly lower levels of depression (p = 0.007), higher levels of resilience (p = 0.006), higher levels of overall health (p = 0.006), and higher levels of mental health (p = 0.039). The effect of mindfulness practice on reducing depression was fully mediated by resilience. Conclusion: Among MBI graduates, those who regularly practiced mindfulness had lower levels of depression and higher levels of physical and mental health. Thus, the continuation of mindfulness practice increases resilience, buffers against new stressors such as the COVID-19 pandemic, and has the potential to prevent depression.

Contributing role of mitochondrial energy metabolism on platelet adhesion, activation and thrombus formation under blood flow conditions.

Platelets have an active energy metabolism mediated by mitochondria. However, the role of mitochondria in platelet adhesion, activation, and thrombus formation under blood flow conditions remains to be elucidated. Blood specimens were obtained from healthy adult volunteers. The consumption of glucose molecules by platelets was measured after 24 hours. Platelet adhesion, activation, and thrombus formation on collagen fibrils and immobilized von Willebrand factor (VWF) at a wall shear rate of 1,500 s-1 were detected by fluorescence microscopy with an ultrafast laser confocal unit in the presence or absence of mitochondrial functional inhibitors of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), antimycin A, and oligomycin. Consumption of glucose molecules within the first 24 h of 4.21 × 10-15 ± 4.46 x 10-15 (n = 6) increased to 13.82 × 10-15 ± 3.46 x 10-15 (n = 4) in the presence of FCCP, 12.11 × 10-15 ± 2.33 x 10-15 (n = 4) in the presence of antimycin A, and 11.87 × 10-15 ± 3.56 x 10-15 (n = 4) in the presence of oligomycin (p < .05). These mitochondrial functional blockers did not influence both surface area coverage by platelets and the 3-dimensional size of platelet thrombi formed on the collagen fibrils. However, a rapid increase in the intracellular calcium ion concentration ([Ca2+]i) upon adhering on immobilized VWF decreased significantly from 405.5 ± 86.2 nM in control to 198.0 ± 79.2 nM in the presence of FCCP (p < .005). A similar decrease in the rapid increase in ([Ca2+]i) was observed in the presence of antimycin A and oligomycin. Mitochondrial function is necessary for platelet activation represented by a rapid increase in [Ca2+]i after platelet adhesion on VWF. However, the influence could not be detected as changes in platelet adhesion or 3-dimensional growth of platelet thrombi on collagen fibrils.

Konjac Ceramide (kCer)-Mediated Signal Transduction of the Sema3A Pathway Promotes HaCaT Keratinocyte Differentiation.

Histamines suppress epidermal keratinocyte differentiation. Previously, we reported that konjac ceramide (kCer) suppresses histamine-stimulated cell migration of HaCaT keratinocytes. kCer specifically binds to Nrp1 and does not interact with histamine receptors. The signaling mechanism of kCer in HaCaT cells is also controlled by an intracellular signaling cascade activated by the Sema3A-Nrp1 pathway. In the present study, we demonstrated that kCer treatment induced HaCaT keratinocyte differentiation after migration of immature cells. kCer-induced HaCaT cell differentiation was accompanied by some features of keratinocyte differentiation markers. kCer induced activating phosphorylation of p38MAPK and c-Fos, which increased the protein levels of involucrin that was the latter differentiation marker. In addition, we demonstrated that the effects of both kCer and histamines are regulated by an intracellular mechanism of Rac1 activation/RhoA inhibition downstream of the Sema3A/Nrp1 receptor and histamine/GPCR pathways. In summary, the effects of kCer on cell migration and cell differentiation are regulated by cascade crosstalk between downstream Nrp1 and histamine-GPCR pathways in HaCaT cells.

Important Regulatory Roles of Erythrocytes in Platelet Adhesion to the von Willebrand Factor on the Wall under Blood Flow Conditions.

The role of erythrocytes in platelet adhesion to von Willebrand factor (VWF) on the vessel wall through their membrane glycoprotein (GP)Ibα under blood flow conditions has not yet been elucidated. Blood specimens containing fluorescent-labeled platelets and native, biochemically fixed, or artificial erythrocytes at various hematocrits were perfused on the surface of VWF immobilized on the wall at a shear rate of 1,500 s-1. The rates of platelet adhesion were measured under each condition. The computer simulation of platelet adhesion to the VWF on the wall at the same shear rate was conducted by solving the governing equations with a finite-difference method on a K computer. The rates of platelet adhesion were calculated at various hematocrit conditions in the computational domain of 100 µm (x-axis) × 400 µm (y-axis) × 100 µm (z-axis). Biological experiments demonstrated a positive correlation between the rates of platelet adhesion and hematocrit values in native, fixed, and artificial erythrocytes. (r = 0.992, 0.934, and 0.825 respectively, p < 0.05 for all). The computer simulation results supported the hematocrit-dependent increase in platelet adhesion rates on VWF (94.3/second at 10%, 185.2/second at 20%, and 327.9/second at 30%). These results suggest that erythrocytes play an important role in platelet adhesion to VWF. The augmented z-axis fluctuation of flowing platelets caused by the physical presence of erythrocytes is speculated to be the cause of the hematocrit-dependent increase in platelet adhesion.

Predictors and moderators of outcomes in mindfulness-based cognitive therapy intervention for early breast cancer patients.

OBJECTIVES: To deliver mindfulness-based cognitive therapy (MBCT) efficiently, the present study aimed (1) to identify predictors and moderators of patients who benefit from MBCT for psychological distress and (2) to explore the initial treatment reaction to identify the optimal number of sessions that produce a significant clinical effect. METHODS: This is the secondary analysis of a randomized controlled trial of MBCT for breast cancer patients (N = 74). We classified the participants into remitters vs. non-remitters, and responder vs. non-responders, according to the total score of the Hospital Anxiety and Depression Scale at the end of the intervention. We conducted multivariate analyses to explore for predictors of response and remission. We adopted generalized estimating equations to explore the optimal number of sessions. RESULTS: Sociodemographic and clinical backgrounds did not have significant influence on the treatment outcomes of the MBCT. Better program adherence, which was represented as the participants' better attendance to the MBCT program, was a significant predictor of both remission and response [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.25-2.89, p = 0.003, and OR = 1.72, 95% CI 1.12-2.65, p = 0.013, respectively]. It was not until seventh session that the remission rate exceeded 50% and the response rate showed significance. SIGNIFICANCE OF RESULTS: Sociodemographic and clinical characteristics did not significantly influence the treatment outcomes, while homework minutes and class attendance had significant effects on treatment outcomes. This implies that MBCT is recommended to any cancer patient, if he/she is motivated to the program, regardless of their sociodemographic and clinical characteristics. Patients are encouraged to attend a standard MBCT program (eight sessions) and do the assigned homework as intensely as possible. Further studies with larger sample and objective measurements are desired.

Biochemical and Structural Properties of Entecavir-Resistant Hepatitis B Virus Polymerase with L180M/M204V Mutations.

Entecavir (ETV) is a widely used anti-hepatitis B virus (HBV) drug. However, the emergence of resistant mutations in HBV reverse transcriptase (RT) results in treatment failure. To understand the mechanism underlying the development of ETV resistance by HBV RT, we analyzed the L180M, M204V, and L180M/M204V mutants using a combination of biochemical and structural techniques. ETV-triphosphate (ETV-TP) exhibited competitive inhibition with dGTP in both wild-type (wt) RT and M204V RT, as observed using Lineweaver-Burk plots. In contrast, RT L180M or L180M/M204V did not fit either competitive, uncompetitive, noncompetitive, or typical mixed inhibition, although ETV-TP was a competitive inhibitor of dGTP. Crystallography of HIV RTY115F/F116Y/Q151M/F160M/M184V, mimicking HBV RT L180M/M204V, showed that the F115 bulge (F88 in HBV RT) caused by the F160M mutation induced deviated binding of dCTP from its normal tight binding position. Modeling of ETV-TP on the deviated dCTP indicated that a steric clash could occur between ETV-TP methylene and the 3'-end nucleoside ribose. ETV-TP is likely to interact primarily with HBV RT M171 prior to final accommodation at the deoxynucleoside triphosphate (dNTP) binding site (Y. Yasutake, S. Hattori, H. Hayashi, K. Matsuda, et al., Sci Rep 8:1624, 2018, https://doi.org/10.1038/s41598-018-19602-9). Therefore, in HBV RT L180M/M204V, ETV-TP may be stuck at M171, a residue that is conserved in almost all HBV isolates, leading to the strange inhibition pattern observed in the kinetic analysis. Collectively, our results provide novel insights into the mechanism of ETV resistance of HBV RT caused by L180M and M204V mutations. IMPORTANCE HBV infects 257 million people in the world, who suffer from elevated risks of liver cirrhosis and cancer. ETV is one of the most potent anti-HBV drugs, and ETV resistance mutations in HBV RT have been extensively studied. Nevertheless, the mechanisms underlying ETV resistance have remained elusive. We propose an attractive hypothesis to explain ETV resistance and effectiveness using a combination of kinetic and structural analyses. ETV is likely to have an additional interaction site, M171, beside the dNTP pocket of HBV RT; this finding indicates that nucleos(t)ide analogues (NAs) recognizing multiple interaction sites within RT may effectively inhibit the enzyme. Modification of ETV may render it more effective and enable the rational design of efficient NA inhibitors.

Gamma Knife Radiosurgery for Pituitary Adenomas Invading the Cavernous Sinus: Tokyo Women's Medical University Experience.

Total surgical removal of a pituitary adenoma (PA) invading the cavernous sinus (CS) is challenging and carries a significant risk of postoperative complications. As an alternative treatment strategy, after incomplete resection, such tumors may undergo stereotactic radiosurgery-in particular, Gamma Knife surgery (GKS). Treatment planning based on advanced neuroimaging (e.g., thin-slice 3-dimensional postcontrast constructive interference in steady state (CISS) images) allows clear visualization of the target microanatomy, which results in highly conformal and selective radiation delivery to the lesion with preservation of adjacent functionally important neurovascular structures. In the Tokyo Women's Medical University experience of GKS for 43 nonfunctioning and 46 hormone-secreting PA invading the CS, with a minimum follow-up period of 5 years (mean 76 months, range 60-118 months), the tumor control rate has reached 97%, and a significant volume reduction (≥50%) has been seen in 24% of lesions. In cases of hormone-secreting neoplasms, normalization (in 18 patients; 39%) or improvement (in 22 patients; 48%) of endocrinological function has been noted. Importantly, such effects have been sufficiently durable. Complications have been extremely rare and limited to transient cranial nerve palsy (in 2% of cases). Notably, no patient in our series has had a new pituitary hormone deficit after irradiation. Thus, subtotal resection followed by GKS may be considered a valuable alternative to aggressive surgery for a PA invading the CS.

Gamma Knife Radiosurgery for Symptomatic Cavernous Malformations: Tokyo Women's Medical University Experience.

OBJECTIVE: This retrospective study evaluated the results of Gamma Knife surgery (GKS) for symptomatic cavernous malformations (CM) of the brain. METHODS: From 1993 till 2014, 11 patients (mean age 44 years) with a symptomatic CM underwent GKS at Tokyo Women's Medical University. In six cases, the disease manifested with hemorrhaging. Seizures and a neurological deficit were noted in four patients each. The CM were located in the brainstem (in 5 cases), basal ganglia (in 2 cases), thalamus (in 2 cases), and cerebral lobe (in 2 cases). The mean lesion volume was 1.46 cc. The mean marginal dose was 15.3 Gy. The mean length of follow-up after GKS was 78.5 months. RESULTS: At the last follow-up, the general status was considered excellent, fair, and poor in 8 patients (73%), 1 patient (9%), and 2 patients (18%), respectively. The annual hemorrhage rates per case-year were 2.94% from birth till GKS, 20.20% from the first hemorrhage till GKS, 4.54% within the first 2 years after GKS, and 1.39% within the entire follow-up period after GKS. Two patients attained seizure-free status after treatment. CONCLUSION: GKS may be considered as a possible management option for symptomatic CM, since it reduces the subsequent hemorrhage risk after the initial bleeding episode. Moreover, in some patients, cessation of symptomatic epilepsy after treatment may be expected.

Computer Simulation of Platelet Adhesion around Stent Struts in the Presence and Absence of Tissue Defects around Them.

AIM: To predict platelet accumulation around stent struts in the presence or absence of tissue defects around them. METHODS: Computer simulations were performed using virtual platelets implementing the function of the three membrane proteins: glycoprotein (GP) Ibα, GPIIb/IIIa, and GPVI. These platelets were perfused around the stent struts implanted into the vessel wall in the presence or absence of tissue defects around them using within the simulation platform. The number of platelets that adhered around stent struts was calculated by solving the blood flow using Navier-Stokes equation along with the adhesion of membrane protein modeled within the platform. RESULTS: Platelet accumulation around stent struts occurred mostly at the downstream region of the stent strut array. The majority of platelets adhered at the downstream of the first bend regardless of the tissue defect status. Platelet adhesion around stent struts occurred more rapidly in the presence of tissue defects. CONCLUSION: Computer simulation using virtual platelets suggested a higher rate of platelet adhesion in the presence of tissue defects around stent struts.

Results of surgical treatment after Gamma Knife radiosurgery for cerebral arteriovenous malformations: patient series.

BACKGROUND: Gamma Knife radiosurgery (GKRS) is a safe and effective treatment, but it has a risk of bleeding. Herein, the authors describe their experience with some patients who required surgical removal of cerebral arteriovenous malformations (AVMs) located mainly in eloquent areas of the brain after GKRS, and they consider the advantages of surgical removal after GKRS. OBSERVATIONS: Twelve patients who had undergone surgical removal of AVMs after GKRS at Tokyo Women's Medical University between April 2013 and July 2019 were selected for analysis. All participants underwent GKRS as first-line therapy for AVMs located in an eloquent region or if requested by the patient. Complete obliteration was achieved in 7 patients, and the size of the nidus decreased in 3 patients during the follow-up period. The Spetzler-Martin grade decreased in 11 patients. Three patients experienced symptomatic intracerebral hemorrhage before and after confirmation of complete obliteration of the nidus via GKRS, and 7 patients experienced some neurological deficits because of an encapsulated expanding hematoma. All patients underwent resection of the nidus without complications. The preoperative neurological deficits improved in 6 patients and remained unchanged in 6 patients. LESSONS: This report indicates that performing GKRS before surgery may be useful for future multimodal therapy.

Nrp1 is Activated by Konjac Ceramide Binding-Induced Structural Rigidification of the a1a2 Domain.

Konjac ceramide (kCer) is a plant-type ceramide composed of various long-chain bases and a-hydroxyl fatty acids. The presence of d4t,8t-sphingadienine is essential for semaphorin 3A (Sema3A)-like activity. Herein, we examined the three neuropilin 1 (Nrp1) domains (a1a2, b1b2, or c), and found that a1a2 binds to d4t,8t-kCer and possesses Sema3A-like activity. kCer binds to Nrp1 with a weak affinity of mM dissociation constant (Kd). We wondered whether bovine serum albumin could influence the ligand-receptor interaction that a1a2 has with a single high affinity binding site for kCer (Kd in nM range). In the present study we demonstrated the influence of bovine serum albumin. Thermal denaturation indicates that the a1a2 domain may include intrinsically disordered region (IDR)-like flexibility. A potential interaction site on the a1 module was explored by molecular docking, which revealed a possible Nrp1 activation mechanism, in which kCer binds to Site A close to the Sema3A-binding region of the a1a2 domain. The a1 module then accesses a2 as the IDR-like flexibility becomes ordered via kCer-induced protein rigidity of a1a2. This induces intramolecular interaction between a1 and a2 through a slight change in protein secondary structure.

Mindfulness-Based Cognitive Therapy for Psychological Distress, Fear of Cancer Recurrence, Fatigue, Spiritual Well-Being, and Quality of Life in Patients With Breast Cancer-A Randomized Controlled Trial.

CONTEXT: Mindfulness-based interventions have been receiving growing attention in cancer care. OBJECTIVES: The purpose of this randomized controlled trial is to examine the effectiveness of mindfulness-based cognitive therapy (MBCT) for psychological distress (anxiety and depression), fear of cancer recurrence (FCR), fatigue, spiritual well-being, and quality of life (QOL) in Japanese ambulatory patients with Stage I-III breast cancer. METHODS: A total of 74 patients were randomly assigned to either an eight-week MBCT intervention group (n = 38) or a wait-list control group (n = 36). The primary outcome was psychological distress, measured on Hospital Anxiety and Depression Scale. The secondary outcomes were FCR (Concerns About Recurrence Scale-overall anxiety subscale), fatigue (Brief Fatigue Inventory), spiritual well-being (Functional Assessment of Chronic Illness Therapy-Spiritual), QOL (Functional Assessment of Cancer Therapy-General), and mindfulness skills (Five Facet Mindfulness Questionnaire). The participants were assessed at baseline (T0), Week 8 (T1), and Week 12 (T2). The results were analyzed using a intention-to-treat linear mixed model. RESULTS: The participants in the MBCT group experienced significantly better outcomes in their psychological distress (Cohen's d = 1.17; P < 0.001), FCR (d = 0.43; P < 0.05), fatigue (d = 0.66; P < 0.01), spiritual well-being (d = 0.98; P < 0.001), and QOL (d = 0.79; P < 0.001) compared with the control group. The difference remained significant at T2 (four weeks after completion of the intervention). CONCLUSION: MBCT was demonstrated to improve well-being that encompasses psychological, physical, and spiritual domains in Japanese patients with nonmetastatic breast cancer. The favorable effect was maintained up to four weeks after the completion of the intervention.