Luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, reverses cerebrovascular dysfunction and cognitive impairments in 18-mo-old diabetic animals.

Diabetes mellitus (DM) is a leading risk factor for age-related dementia, but the mechanisms involved are not well understood. We previously discovered that hyperglycemia induced impaired myogenic response (MR) and cerebral blood flow (CBF) autoregulation in 18-mo-old DM rats associated with blood-brain barrier (BBB) leakage, impaired neurovascular coupling, and cognitive impairment. In the present study, we examined whether reducing plasma glucose with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin can ameliorate cerebral vascular and cognitive function in diabetic rats. Plasma glucose and HbA1c levels of 18-mo-old DM rats were reduced, and blood pressure was not altered after treatment with luseogliflozin. SGLT2i treatment restored the impaired MR of middle cerebral arteries (MCAs) and parenchymal arterioles and surface and deep cortical CBF autoregulation in DM rats. Luseogliflozin treatment also rescued neurovascular uncoupling, reduced BBB leakage and cognitive deficits in DM rats. However, SGLT2i did not have direct constrictive effects on vascular smooth muscle cells and MCAs isolated from normal rats, although it decreased reactive oxygen species production in cerebral vessels of DM rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.NEW & NOTEWORTHY This study demonstrates that luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, improved CBF autoregulation in association with reduced vascular oxidative stress and AGEs production in the cerebrovasculature of 18-mo-old DM rats. SGLT2i also prevented BBB leakage, impaired functional hyperemia, neurodegeneration, and cognitive impairment seen in DM rats. Luseogliflozin did not have direct constrictive effects on VSMCs and MCAs isolated from normal rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.

Why is the Private Forest Program Stunted in Nepal?

Private forest (PF) program has the potential to be one of the most efficient forest management programs in Nepal but it has not gained the momentum compared to the other forest management regimes. Considering this, this paper aims to portray policy provisions, existing institutional arrangements as well as landholder experiences and perceptions over the existing mechanisms of PF registration, management, and forest product harvesting. Using the Sudoorpashchim province of Nepal as a case study, we conducted policy and literature reviews, key informant interviews, household surveys, and field observations. We found only 300 PFs registered in the Sudoorpashchim province, with lowland districts having the highest proportion (87%). Institutional arrangements and procedures for timber harvesting and selling were found to be lengthy and complex, with this being a major issue for PF owners with small forest areas. Government initiatives are inadequate to facilitate PF development due to poor implementation of policy provisions, as well as the lack of appropriate incentives and program packages. Despite a very small government investment in PF development, we found the return from PFs in terms of timber supply to be substantially higher than other forest management regimes. Among others, PF owners perceive the cumbersome regulatory procedures and lack of technical support to be the most pertinent factors responsible for the limited growth of PFs. Based on our results, we have discussed and recommended a number of policy and institutional measures to mainstream PF development programs, in order to support economic prosperity of the nation.

Prevalence of Maxillary and Mandibular Frenal Attachment and Its Association with Age, Gender, and Oral Hygiene Status in Nepalese Population Seeking Dental Treatment.

Objective: Frenum attachments are folds of mucous membrane that connect the lips to the alveolar mucosa and underlying periosteum. Aberrant positioning of the maxillary and mandibular labial frenum can lead to various clinical issues, including mucogingival problems and midline diastema. The objective of this study was to assess the prevalence of maxillary and mandibular frenal attachments and their association with age, gender, and oral hygiene status in the Nepalese population seeking dental treatment. Materials and Methods: This descriptive cross-sectional study was conducted over a period of 6 months, from February 2023 to August 2023, among patients visiting the Department of Periodontology and Oral Implantology, aged 6 years and above, after obtaining official permission from the Institutional Review Committee (IRC-KUSMS Approval No. 8/23). The study collected data on morphological variations of frenal attachment and various periodontal parameters such as Oral Hygiene Index-Simplified (OHI-S), pocket depth, recession, and midline diastema in both arches. Descriptive statistics, including frequency and percentage, were used to analyze the data. The χ2-test was employed to determine the correlation between gender and types of frenulum attachment, while analysis of variance was used to assess the association of frenal attachments with oral hygiene status. Results: Among 380 patients, the prevalence of frenal attachment was as follows: gingival 248 (65.30%), mucosal 71 (18.70%), papillary 42 (11.10%), and papillary penetrating 19 (5.00%) in the maxilla, and mucosal 225 (59.20%) and gingival 155 (40.78%) in mandible. Among the different morphological variations of frenal attachments, normal frenum was the most common, accounting for 231 cases (60.80%), followed by frenum with a nodule, with 101 cases (26.60%). Conclusions: The study found significant associations between frenal attachment and gender, as well as oral hygiene status. The prevalence of frenal attachments in this study was comparable to findings from previous research.

Role of histone variants H2BC1 and H2AZ.2 in H2AK119ub nucleosome organization and Polycomb gene silencing.

Ubiquitination of histone H2A at lysine 119 residue (H2AK119ub) plays critical roles in a wide range of physiological processes, including Polycomb gene silencing 1,2 , replication 3-5 , DNA damage repair 6-10 , X inactivation 11,12 , and heterochromatin organization 13,14 . However, the underlying mechanism and structural basis of H2AK119ub remains largely elusive. In this study, we report that H2AK119ub nucleosomes have a unique composition, containing histone variants H2BC1 and H2AZ.2, and importantly, this composition is required for H2AK119ub and Polycomb gene silencing. Using the UAB domain of RSF1, we purified H2AK119ub nucleosomes to a sufficient amount and purity. Mass spectrometry analyses revealed that H2AK119ub nucleosomes contain the histone variants H2BC1 and H2AZ.2. A cryo-EM study resolved the structure of native H2AK119ub nucleosomes to a 2.6A resolution, confirming H2BC1 in one subgroup of H2AK119ub nucleosomes. Tandem GST-UAB pulldown, Flag-H2AZ.2, and HA-H2BC1 immunoprecipitation revealed that H2AK119ub nucleosomes could be separated into distinct subgroups, suggesting their composition heterogeneity and potential dynamic organization. Knockout or knockdown of H2BC1 or H2AZ.2 reduced cellular H2AK119ub levels, establishing H2BC1 and H2AZ.2 as critical determinants of H2AK119ub. Furthermore, genomic binding profiles of H2BC1 and H2AZ.2 overlapped significantly with H2AK119ub binding, with the most significant overlapping in the gene body and intergenic regions. Finally, assays in developing embryos reveal an interaction of H2AZ.2, H2BC1, and RING1A in vivo . Thus, this study revealed, for the first time, that the H2AK119ub nucleosome has a unique composition, and this composition is required for H2AK119ub and Polycomb gene silencing.

Cooperation between PRMT1 and PRMT6 drives lung cancer health disparities among Black/African American men.

Lung cancer is the third most common cancer with Black/AA men showing higher risk and poorer outcomes than NHW men. Lung cancer disparities are multifactorial, driven by tobacco exposure, inequities in care access, upstream health determinants, and molecular determinants including biological and genetic factors. Elevated expressions of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis have been observed in many cancers. Most importantly, our study shows that PRMT6 displays higher expression in lung cancer tissues of Black/AA men compared to NHW men. In this study, we investigated the underlying mechanism of PRMT6 and its cooperation with PRMT1 to form a heteromer as a driver of lung cancer. Disrupting PRMT1/PRMT6 heteromer by a competitive peptide reduced proliferation in non-small cell lung cancer cell lines and patient-derived organoids, therefore, giving rise to a more strategic approach in the treatment of Black/AA men with lung cancer and to eliminate cancer health disparities.

Early Implant Placement with Immediate Loading in the Mandibular Anterior Region: A Rapid Solution to Edentulism.

The aim of this article is to present the case of an early implant placement with immediate loading in the mandibular anterior region as a rapid solution to edentulism. A 40-year-old healthy male patient reported with a chief complaint of loosening of tooth in the lower front region of the jaw. On intraoral examination, there was a mobile tooth with respect to 41. The mobile tooth was extracted, and early implant placement was done along with Bio-Oss bone grafts to fill the jumping distance with no barrier membrane. Immediate provisionalisation was done on early-placed dental implants. After 5 months of the healing period, the final implant-level impressions were made, and the provisional crown was replaced with the final zirconia crown. This case report demonstrates satisfactory esthetic and functional outcomes along with various other advantages.