Impact of Self-Monitoring Blood Glucose on Glycaemic Control Among Insulin-Treated Patients With Diabetes Mellitus in Northeastern Tanzania: A Randomised Controlled Trial.

Introduction: Tracking of blood glucose levels by patients and care providers remains an integral component in the management of diabetes mellitus (DM). Evidence, primarily from high-income countries, has illustrated the effectiveness of self-monitoring of blood glucose (SMBG) in controlling DM. However, there is limited data on the feasibility and impact of SMBG among patients in the rural regions of sub-Saharan Africa. This study is aimed at assessing SMBG, its adherence, and associated factors on the effect of glycaemic control among insulin-treated patients with DM in northeastern Tanzania. Materials and Methods: This was a single-blinded, randomised clinical trial conducted from December 2022 to May 2023. The study included patients with DM who had already been on insulin treatment for at least 3 months. A total of 85 participants were recruited into the study and categorised into the intervention and control groups by a simple randomization method using numbered envelopes. The intervention group received glucose metres, test strips, logbooks, and extensive SMBG training. The control group received the usual care at the outpatient clinic. Each participant was followed for a period of 12 weeks, with glycated haemoglobin (HbA1c) and fasting blood glucose (FBG) being checked both at the beginning and at the end of the study follow-up. The primary and secondary outcomes were adherence to the SMBG schedule, barriers associated with the use of SMBG, and the ability to self-manage DM, logbook data recording, and change in HbA1c. The analysis included descriptive statistics, paired t-tests, and logistic regression. Results: Eighty participants were analysed: 39 in the intervention group and 41 in the control group. In the intervention group, 24 (61.5%) of patients displayed favourable adherence to SMBG, as evidenced by tests documented in the logbooks and glucometer readings. Education on SMBG was significantly associated with adherence. Structured SMBG improved glycaemic control with a HbA1c reduction of -1.01 (95% confidence interval (CI) -1.39, -0.63) in the intervention group within 3 months from baseline compared to controls of 0.18 (95% CI -0.07, 0.44) (p < 0.001). Conclusion: Structured SMBG positively impacted glycaemic control among insulin-treated patients with DM in the outpatient clinic. The results suggest that implementing a structured testing programme can lead to significant reductions in HbA1c and FBG levels. Trial Registration: Pan African Clinical Trials Registry identifier: PACTR202402642155729.

Structure and dynamics of a pentameric KCTD5/CUL3/Gßγ E3 ubiquitin ligase complex.

Heterotrimeric G proteins can be regulated by posttranslational modifications, including ubiquitylation. KCTD5, a pentameric substrate receptor protein consisting of an N-terminal BTB domain and a C-terminal domain, engages CUL3 to form the central scaffold of a cullin-RING E3 ligase complex (CRL3KCTD5) that ubiquitylates Gßγ and reduces Gßγ protein levels in cells. The cryo-EM structure of a 5:5:5 KCTD5/CUL3NTD/Gß1γ2 assembly reveals a highly dynamic complex with rotations of over 60° between the KCTD5BTB/CUL3NTD and KCTD5CTD/Gßγ moieties of the structure. CRL3KCTD5 engages the E3 ligase ARIH1 to ubiquitylate Gßγ in an E3-E3 superassembly, and extension of the structure to include full-length CUL3 with RBX1 and an ARIH1~ubiquitin conjugate reveals that some conformational states position the ARIH1~ubiquitin thioester bond to within 10 Å of lysine-23 of Gß and likely represent priming complexes. Most previously described CRL/substrate structures have consisted of monovalent complexes and have involved flexible peptide substrates. The structure of the KCTD5/CUL3NTD/Gßγ complex shows that the oligomerization of a substrate receptor can generate a polyvalent E3 ligase complex and that the internal dynamics of the substrate receptor can position a structured target for ubiquitylation in a CRL3 complex.

Crystal structure of NRAS Q61K with a ligand-induced pocket near switch II.

The RAS isoforms (KRAS, HRAS and NRAS) have distinct cancer type-specific profiles. NRAS mutations are the second most prevalent RAS mutations in skin and hematological malignancies. Although RAS proteins were considered undruggable for decades, isoform and mutation-specific investigations have produced successful RAS inhibitors that are either specific to certain mutants, isoforms (pan-KRAS) or target all RAS proteins (pan-RAS). While extensive structural and biochemical investigations have focused mainly on K- and H-RAS mutations, NRAS mutations have received less attention, and the most prevalent NRAS mutations in human cancers, Q61K and Q61R, are rare in K- and H-RAS. This manuscript presents a crystal structure of the NRAS Q61K mutant in the GTP-bound form. Our structure reveals a previously unseen pocket near switch II induced by the binding of a ligand to the active form of the protein. This observation reveals a binding site that can potentially be exploited for development of inhibitors against mutant NRAS. Furthermore, the well-resolved catalytic site of this GTPase bound to native GTP provides insight into the stalled GTP hydrolysis observed for NRAS-Q61K.

Exploring the safety and quality of mobile X-ray imaging in a new infectious disease biocontainment unit: an in situ simulation and video-reflexive study.

OBJECTIVES: During a precommissioning inspection of a new biocontainment centre, radiographers noted structural features of quarantine rooms that could compromise staff and patient safety and the X-ray image quality, even after significant modifications had been made to an earlier radiography protocol. The aim of this study was to explore the safety and effectiveness of the modified protocol, in the new space, and identify improvements, if required. DESIGN: A qualitative study using in situ simulation and video-reflexive methods. SETTING: A newly built biocontainment centre, prior to its commissioning in 2021, in a large, tertiary hospital in Sydney, Australia. PARTICIPANTS: Five radiographers, and a nurse and a physician from the biocontainment centre, consented to participate. All completed the study. INTERVENTIONS: Two simulated mobile X-ray examinations were conducted in the unit prior to its commissioning; simulations were videoed. Participants and other stakeholders analysed video footage, collaboratively, and sessions were audio recorded, transcribed and analysed thematically. Problems and potential solutions identified were collated and communicated to the hospital executive, for endorsement and actioning, if possible. RESULTS: Four themes were identified from the data: infection exposure risks, occupational health and exposure risks, communication and X-ray image quality. Facilitated group reviews of video footage identified several important issues, across these four areas of risk, which had not been identified previously. CONCLUSIONS: In situ simulation is used, increasingly, to evaluate and improve healthcare practices. This study confirmed the added value of video-reflexive methods, which provided experienced participants with a richer view of a familiar protocol, in a new setting. Video footage can be examined immediately, or later if required, by a broader group of stakeholders, with diverse experience or expertise. Using video reflexivity, clinicians identified potential safety risks, which were collated and reported to the hospital executive, who agreed to implement modifications.

The Evidence-practice Gap in Minimal Intervention Dentistry: An International Comparison Between Dentists in Japan and Brazil.

OBJECTIVES: This study was designed to: 1) evaluate and compare the evidence-practice gap (EPG) in minimal intervention dentistry (MID) in Japan and Brazil by measuring concordance between dentists' clinical practice and published evidence; and 2) identify dentists' factors associated with the EPG in both countries. METHODS: We performed a cross-sectional study using a web-delivered questionnaire among 136 Japanese and 110 Brazilian dentists. The questionnaire consisted of three questions concerning "restoration diagnosis and treatment," "deep caries diagnosis and treatment," and "caries risk assessment" regarding MID. A chi-square test was used to analyze differences in concordance among clinical practice and evidence from the literature between Japanese and Brazilian dentists. Logistic regression analyses were performed to analyze dentists' factors associated with overall concordance for all three questions. RESULTS: Overall concordance was significantly higher in Brazil (55%) than in Japan (38%) (p<0.01). Concerning how evidence was obtained, textbooks, nonacademic journals, and seminars and workshops were used as information sources more frequently by Japanese than Brazilian dentists (p<0.001), whereas scientific journal articles in English were used more frequently by Brazilian dentists (p<0.001). On logistic regression analysis, overall concordance was higher for Japanese dentists who frequently obtained evidence from scientific journal articles in English (p<0.05), whereas Brazilian dentists who frequently obtained evidence from the Internet were associated with lower overall concordance (p<0.05). CONCLUSIONS: Because overall concordance was significantly higher in Brazil than in Japan, Japan may have a greater EPG in MID practice. Specific characteristics of Japanese and Brazilian dentists showed significant associations with overall concordance.

The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG.

The ERG (ETS-related gene) transcription factor is linked to various types of cancer, including leukemia. However, the specific ERG domains and co-factors contributing to leukemogenesis are poorly understood. Drug targeting a transcription factor such as ERG is challenging. Our study reveals the critical role of a conserved amino acid, proline, at position 199, located at the 3' end of the PNT (pointed) domain, in ERG's ability to induce leukemia. P199 is necessary for ERG to promote self-renewal, prevent myeloid differentiation in hematopoietic progenitor cells, and initiate leukemia in mouse models. Here we show that P199 facilitates ERG's interaction with the NCoR-HDAC3 co-repressor complex. Inhibiting HDAC3 reduces the growth of ERG-dependent leukemic and prostate cancer cells, indicating that the interaction between ERG and the NCoR-HDAC3 co-repressor complex is crucial for its oncogenic activity. Thus, targeting this interaction may offer a potential therapeutic intervention.

Molecular identification and in vitro assessment of zoonotic-potential of a novel Orthobunyavirus isolated from broiler chicken in Malaysia.

We have previously isolated a novel avian Orthobunyavirus, Kedah Fatal Kidney Syndrome (KFKS) virus from a broiler farm in Kedah, Malaysia in 2020 with a severe kidney lesion in chickens. The virus was designated as KFKS2_CS virus. Sequence analysis of partial nucleocapsid (N) and nonstructural (NSs) sequence of this virus showed the highest sequence identity with previous KFKS1 from Malaysia (100%) and 97% with a zoonotic Umbre (UMB) virus, which was reported to cause encephalitis in immunocompromised humans in India. Phylogenetic analysis revealed that this virus was clustered together with previous KFKS1 virus from Malaysia, UMB and Cristoli viruses. This study aimed to assess the zoonotic potential of this KFKS2_CS virus in vitro by determining its ability to inhibit the production of interferon (IFN) in human glioblastoma multiforme (GBM) brain cells using reverse-transcriptase polymerase reaction (RT-PCR). This virus blocked the production of interferon-a in this human brain cells. In conclusion, this KFKS2_CS virus may have a zoonotic potential and become a public health concern in the future.

Effectiveness of adjunctive rifampicin for treatment of Staphylococcus aureus bacteraemia: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To assess whether the addition of rifampicin to conventional treatment of Staphylococcus aureus bacteraemia (SAB) reduces bacteriological or clinical failure or death. DATA SOURCES: PubMed, Embase and Cochrane CENTRAL databases were searched from inception to 31 December 2022. Reference lists and PubMed citations of eligible studies were checked. REVIEW METHODS: Two study authors independently identified randomized controlled trials (RCTs) involving adult participants with SAB, in which an intervention group received adjunctive rifampicin and the control group received usual care with or without a placebo. Dichotomous data (bacteriological and clinical failure and deaths) were analysed and pooled across studies using risk ratio (RR) with 95% confidence intervals (CI) using a Mantel-Haenszel random-effect model. The key variable of interest being whether rifampicin was used. RESULTS: Six RCTs including 894 participants-of which 758 (85%) were from one trial-met the inclusion criteria. The addition of rifampicin to conventional treatment of SAB significantly reduced bacteriological failure by 59% (RR 0.41, 95% CI 0.21-0.81, I2 = 0%, number need to treat 27). However, it did not reduce clinical failure (RR 0.70, 95% CI 0.47-1.03, I2 = 0%) or deaths (RR 0.96, 95% CI 0.70-1.32, I2 = 0%). Further, it did not reduce the duration of bacteraemia, or the length of hospital stay. Adjunctive rifampicin reduced SAB recurrences (1% versus 4%, P = 0.01). Emergence of rifampicin resistance during treatment was uncommon (<1%). CONCLUSION: Although adjunctive rifampicin reduced the risk of bacteriological failure and recurrences, we found no mortality benefit to support its use in SAB.

Understanding routine (non-outbreak) respiratory protective equipment behaviour of hospital workers in different clinical settings - lessons for the future post-COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has drawn attention to the importance of facial (respiratory and eye) protective equipment (FPE). Optimal use of FPE in non-outbreak situations will enable front-line staff, such as emergency department (ED) clinicians, to adapt more rapidly and safely to the increased demands and skills required during an infectious disease outbreak. METHODS: A survey, designed to determine the attitudes, beliefs and knowledge of healthcare workers around the use of FPE for protection against respiratory infections, was distributed to staff in a respiratory ward, an adult ED and a paediatric ED in Sydney, Australia prior to COVID-19. RESULTS: The survey revealed differences between the respiratory ward and the EDs, and between professional groups. ED staff, particularly paediatric clinicians, were less likely than ward staff to use FPE appropriately during routine care. Medical staff were more likely to work outside of infection prevention and control policies. DISCUSSION: The busy, relatively chaotic ED environment presents unique challenges for optimal compliance with safe use of FPE when caring for patients with respiratory symptoms. CONCLUSIONS: Building upon the lessons of the pandemic, it is timely to address the specific infection prevention and control needs of the ED environment to improve compliance with the use of FPE during non-outbreak situations.

New developments in the management of vulvovaginal atrophy: a comprehensive overview.

INTRODUCTION: Proper recognition and individualized therapy of vulvovaginal atrophy (VVA) is paramount. AREAS COVERED: Assessment of VVA should be performed using several questionnaires in combination with wet mount microscopy to determine Vaginal Cell Maturation Index (VCMI) and infections. PubMed searches were carried out between 1 march 2022 and 15 October 2022.Low dose vaginal estriol seems safe, efficient, and could be used in patients with contraindications for steroid hormones such as women with a history of breast cancer, and should therefore be considered as first choice hormonal treatment, when non-hormonal treatments fail. New estrogens, androgens, and several Selective Estrogen Receptor Modulators (SERMs) are being developed and tested. Intravaginal Hyaluronic Acid (HA) or Vit D can help women who can't or don't want to use hormones. EXPERT OPINION: Proper treatment is not possible without a correct and full diagnosis, including microscopy of the vaginal fluid. Low dose vaginal estrogen treatment, especially with estriol, is very efficient and is preferred in most women with VVA. Oral ospemifene and vaginal dihydroepiandrosterone (DHEA) are now considered efficient and safe alternative therapies for VVA. More safety data are waited for several SERMs and for a newly introduced estrogen: estetrol (E4), although so far no major side effects were seen from these drugs. Indications for laser treatments are questionable.

Causes of the Evidence-practice Gap and Its Association with the Effects of Minimal Intervention Dentistry Education to Clinicians.

OBJECTIVES: To identify causes of the evidence-practice gap (EPG) in dentistry in Japan and analyze whether these causes are associated with: (a) improvement of EPG in minimal intervention dentistry (MID) following an educational intervention and (b) specific dentist characteristics. METHODS: We conducted a mixed-methods questionnaire survey among 197 Japanese dentists that integrated both quantitative and qualitative data. Causative factors for the EPG identified in the quantitative survey were clarified by qualitative analysis. We measured the EPG in a baseline survey using an EPG measurement tool based on MID. To examine how feedback using the latest scientific evidence affected change in the EPG, we measured the EPG again immediately after feedback was provided to participating dentists. RESULTS: Qualitative analysis classified all dentists into one of four "EPG cause" groups, namely "evidence-", "dentist-", "patient-", and "health insurance system-related" causes. Quantitative analysis confirmed that improvement in the EPG following the feedback intervention was indeed associated with group classification. The highest concordance was found for the "evidence-related" group while the lowest concordance was in the "dentist-related" group (p=0.004). Concordance improved after evidence feedback in all groups but was lowest in the "dentist-related" group. More dentists reported practice busyness in the "dentist-related" group. CONCLUSIONS: In this study, we identified four groups of causes of EPG among Japanese dentists. The degree of concordance between evidence and clinical practice was the lowest in the "dentist-related" group, and the results of this study are expected to provide useful information for the development of intervention methods for closing the EPG in the future.

Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.

B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.

Molecular identification and in vitro assessment of zoonotic-potential of a novel Orthobunyavirus isolated from broiler chicken in Malaysia

@#We have previously isolated a novel avian Orthobunyavirus, Kedah Fatal Kidney Syndrome (KFKS) virus from a broiler farm in Kedah, Malaysia in 2020 with a severe kidney lesion in chickens. The virus was designated as KFKS2_CS virus. Sequence analysis of partial nucleocapsid (N) and nonstructural (NSs) sequence of this virus showed the highest sequence identity with previous KFKS1 from Malaysia (100%) and 97% with a zoonotic Umbre (UMB) virus, which was reported to cause encephalitis in immunocompromised humans in India. Phylogenetic analysis revealed that this virus was clustered together with previous KFKS1 virus from Malaysia, UMB and Cristoli viruses. This study aimed to assess the zoonotic potential of this KFKS2_CS virus in vitro by determining its ability to inhibit the production of interferon (IFN) in human glioblastoma multiforme (GBM) brain cells using reverse-transcriptase polymerase reaction (RT-PCR). This virus blocked the production of interferon-a in this human brain cells. In conclusion, this KFKS2_CS virus may have a zoonotic potential and become a public health concern in the future.

Does a Caesarean Section Scar Affect Placental Volume, Vascularity and Localization?

Caesarean section is associated with an increased risk of abnormal placental implantation and adverse pregnancy outcomes in subsequent pregnancies. Besides the placenta accrete spectrum, only a few of the previous studies focused on other placental development alterations in the scarred uterus. We assessed placental development deviations in the uterus with a Caesarean section scar by evaluating placental volume (PV) and vascular flow indexes. From 1 January 2021 until 31 March 2022, placental volumes and vascularization indexes (VI, FI, VFI) were prospectively measured by 3D power Doppler and VOCAL techniques in 221 patients attending the first trimester screening program. We also calculated the placental quotient to standardize PV to the gestational age. No statistically significant differences in the values of placental volume, placental quotient and placental vascularization indexes were detected between women with previous Caesarean section delivery or women with vaginal delivery. FI was significantly lower in nulliparous in the first trimester. The results of our study suggest that 3D placental evaluation was not able to detect placental development alteration in the uterus with a Caesarean section scar. Future research needs to verify whether 3D power Doppler and Vocal techniques can provide more information if used in an earlier gestational age.

High-Throughput Evaluation of Emission and Structure in Reduced-Dimensional Perovskites.

High-throughput experimentation (HTE) seeks to accelerate the exploration of materials space by uniting robotics, combinatorial methods, and parallel processing. HTE is particularly relevant to metal halide perovskites (MHPs), a diverse class of optoelectronic materials with a large chemical space. Here we develop an HTE workflow to synthesize and characterize light-emitting MHP single crystals, allowing us to generate the first reported data set of experimentally derived photoluminescence spectra for low-dimensional MHPs. We leverage the accelerated workflow to optimize the synthesis and emission of a new MHP, methoxy-phenethylammonium lead iodide ((4-MeO-PEAI)2-PbI2). We then synthesize 16 000 MHP single crystals and measure their photoluminescence to study the effects of synthesis parameters and compositional engineering on the emission intensity of 54 distinct MHPs: we achieve an acceleration factor of more than 100 times over previously reported HTE MHP synthesis and characterization methods. Using insights derived from this analysis, we screen an existing database for new, potentially emissive MHPs. On the basis of the Tanimoto similarity of the bright available emitters, we present our top candidates for future exploration. As a proof of concept, we use one of these (3,4-difluorophenylmethanamine) to synthesize an MHP which we find has a photoluminescence quantum yield of 10%.

Root Canal Treatment Survival Analysis in National Dental PBRN Practices.

Few studies have examined the longevity of endodontically treated teeth in nonacademic clinical settings where most of the population receives its care. This study aimed to quantify the longevity of teeth treated endodontically in general dentistry practices and test the hypothesis that longevity significantly differed by the patient's age, gender, dental insurance, geographic region, and placement of a crown and/or other restoration soon after root canal treatment (RCT). This retrospective study used deidentified data of patients who underwent RCT of permanent teeth through October 2015 in 99 general dentistry practices in the National Dental Practice-Based Research Network (Network). The data set included 46,702 patients and 71,283 RCT permanent teeth. The Kaplan-Meier (product limit) estimator was performed to estimate survival rate after the first RCT performed on a specific tooth. The Cox proportional hazards model was done to account for patient- and tooth-specific covariates. The overall median survival time was 11.1 y; 26% of RCT teeth survived beyond 20 y. Tooth type, presence of dental insurance any time during dental care, placement of crown and/or receiving a filling soon after RCT, and Network region were significant predictors of survival time (P < 0.0001). Gender and age were not statistically significant predictors in univariable analysis, but in multivariable analyses, gender was significant after accounting for other variables. This study of Network practices geographically distributed across the United States observed shorter longevity of endodontically treated permanent teeth than in previous community-based studies. Also, having a crown placed following an RCT was associated with 5.3 y longer median survival time. Teeth that received a filling soon after the RCT before the crown was placed had a median survival time of 20.1 y compared to RCT teeth with only a crown (11.4 y), only a filling (11.2 y), or no filling and no crown (6.5 y).

Literature Review of Cervical Regeneration after Loop Electrosurgical Excision Procedure, and Study Project (CeVaLEP) Proposal.

OBJECTIVE: To compile existing knowledge on the level of cervical regeneration (detected by ultrasound) after loop electrosurgical excision procedure (LEEP) and to suggest research protocol for further studies. METHODS: We conducted a literature search of Medline, Web of Science, Scopus, and Cochrane databases using the keywords "cervix" and "regeneration" without year restrictions. Our eligibility criteria included studies that analysed cervical volume and length regeneration using ultrasound. A literature review was conducted following PRISMA guidelines and registered in PROSPERO (reg. no. CRD42021264062). Information about the studies was extracted from each analysed study on an Excel datasheet and the average regeneration with standard deviation was calculated. All included studies' possible biases were assessed by the National Institutes of Health's (NIH) quality assessment tool. RESULTS: The literature search identified 802 papers and four trials (n = 309) that met our criteria. They investigated cervical length and volume regeneration after LEEP using ultrasound, concluding that there is a profound regeneration deficit. Average cervical length regeneration after 6 months was 83.4% (±10.8%) and volume regeneration was 87.4% (±6.1%). All analysed studies had their biases; therefore, based on the conducted studies' protocols, we present a CeVaLEP research protocol to guide high-quality studies. CONCLUSION: After LEEP, there is a cervical regeneration deficit. There is a lack of high-quality studies that assess cervical volume regeneration and its relation to obstetrical outcomes. There is a gap in the field and more research is needed to define the prenatal risks related to cervical regeneration.

Structures of RGL1 RAS-Association Domain in Complex with KRAS and the Oncogenic G12V Mutant.

Ral Guanine Nucleotide Dissociation Stimulator Like 1 (RGL1) is a RAS effector protein that activates Ral GTPase by stimulating nucleotide exchange. Most structures of RAS-effector complexes are for the HRAS isoform; relatively few KRAS-effector structures have been solved, even though KRAS mutations are more frequent in human cancers. We determined crystal structures of KRAS/RGL1-RAS-association (RA) domain complexes and characterized the interaction in solution using nuclear magnetic resonance spectroscopy, size-exclusion chromatography combined with multi-angle light scattering and biolayer interferometry. We report structures of wild-type KRAS and the oncogenic G12V mutant in complex with the RA domain of RGL1 at < 2 Å resolution. KRASWT/RGL1-RA crystallized as a 1:1 heterodimer, whilst KRASG12V/RGL1-RA crystallized as a heterotetrameric structure in which RGL1-RA dimerized via domain-swapping the C-terminal beta-strand. Solution data indicated that KRASWT and KRASG12V in complex with RGL1-RA both exist predominantly as 1:1 dimers, while tetramerization occurs through very slow association. Through detailed structural analyses, the distance and angle between RAS α1 helix and RBD/RA α1 helix were found to differ significantly among RAS and RBD/RA complexes. The KRAS/RGL1-RA structures possess some of the largest α1RAS/α1Effector distances (21.7-22.2 Å), whereas the corresponding distances in previously reported RAS/RAF complexes are significantly shorter (15.2-17.7 Å). Contact map analysis identified unique structural signatures involving contacts between the ß1-ß2 loop of RA and the α1 helix of RAS, clearly distinguishing the KRAS/RGL1-RA (and other RAS/RA complexes) from RAS/RBD complexes. These results demonstrate that RAS effectors employ an assortment of finely-tuned docking surfaces to achieve optimal interactions with RAS.

[Involvement of the Piezo1 and TRPV4 stretch-activated channels in pulmonary hypertension]. / Implication des canaux mécanosensibles Piezo1 et TRPV4 dans l'hypertension pulmonaire.

Pulmonary hypertension is a pulmonary circulation pathology characterized by remodelling and hyperreactivity of the pulmonary arteries. Vasodilatation/vasoconstriction balance is modified in favour of constriction via, among other things, the proliferation of smooth muscle cells and the development of endothelial dysfunction. In addition, the pulmonary arteries undergo modification of mechanical forces, inducing modified activation of stretch-activated channels (SAC) such as Piezo1 and TRPV4. These ionic channels are sensitive to stretch and their activation can induce various cellular physiological responses, which strongly contribute to development and continuation of the pathology.

Lab-Based Retrospective 10-Year Analysis Shows Seasonal Variation of Vaginal Candida Infection Rates in Belgium.

Candida vulvovaginitis is a frequent condition, and although several risk factors are known, its behavior is still enigmatic. The seasonal influence of climate conditions and living habits on its prevalence was studied. In a retrospective lab-based cohort over 10 years, we studied the prevalence of Candida in 12,941 vaginal cultures taken from women attending a vulvovaginitis clinic. The prevalence of non-albicans and albicans species were compared per month to detect differences in positivity rates in summer versus winter months. Chi-square and chi-square for trend were used. Of the 2109 (16.3%) Candida spp. positive swabs, 201 (1.0%) revealed non-albicans species, varying between 1.0% and 2.0% per month, but without significant monthly differences. Over the 10 years, compared to other months, vaginal Candida was more frequent in June (19.0%, p = 0.008) and less frequent in December (14.5%, p = 0.04). The Candida prevalence was 15.5% in summer (June/July/August) versus 14.0% in the winter (Dec/Jan/Feb, p = 0.04). Change in temperature, dietary habits, and bodily adaptations due to increased amount of sunlight were discussed as potential pathophysiological mechanisms to explain the excess of Candida in summertime. Further confirmatory research would be beneficial. Women at risk for Candida vulvovaginitis should pay more attention to living habits in summertime to avoid recurrences.