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The development of mouse models that replicate the genetic and pathological features of human disease is important in preclinical research because these types of models enable the completion of meaningful pharmacokinetic, safety, and efficacy studies. Numerous relevant mouse models of human disease have been discovered in high-throughput screening programs, but there are important specific phenotypes revealed by histopathology that are not reliably detected by any other physiological or behavioral screening tests. As part of comprehensive phenotypic analyses of over 4000 knockout (KO) mice, histopathology identified 12 lines of KO mice with lesions indicative of an autosomal recessive myopathy. This report includes a brief summary of histological and other findings in these 12 lines. Notably, the inverted screen test detected muscle weakness in only 4 of these 12 lines (Scyl1, Plpp7, Chkb, and Asnsd1), all 4 of which have been previously recognized and published. In contrast, 6 of 8 KO lines showing negative or inconclusive findings on the inverted screen test (Plppr2, Pnpla7, Tenm1, Srpk3, Sidt2, Yif1b, Mrs2, and Pnpla2) had not been previously identified as having myopathies. These findings support the need to include histopathology in phenotype screening protocols in order to identify novel genetic myopathies that are not clinically evident or not detected by the inverted screen test.
Acute ischemic stroke has increasingly become a procedural disease following the demonstrated benefit of mechanical thrombectomy (MT) for emergent large vessel occlusion (ELVO) on clinical outcomes and tissue salvage in randomized trials. Given these data and anecdotal experience of decreased numbers of decompressive hemicraniectomies (DHCs) performed for malignant cerebral edema, we sought to correlate the numbers of strokes, thrombectomies, and DHCs performed over the timeline of the 2013 failed thrombolysis/thrombectomy trials, to the 2015 modern randomized MT trials, to post-DAWN and DEFUSE 3.
This is a multicenter retrospective compilation of patients who presented with ELVO in 11 US high-volume comprehensive stroke centers. Rates of tissue plasminogen activator (tPA), thrombectomy, and DHC were determined by current procedural terminology code, and specificity to acute ischemic stroke confirmed by each institution. Endpoints included the incidence of stroke, thrombectomy, and DHC and rates of change over time.
Between 2013 and 2018, there were 55,247 stroke admissions across 11 participating centers. Of these, 6145 received tPA, 4122 underwent thrombectomy, and 662 patients underwent hemicraniectomy. The trajectories of procedure rates over time were modeled and there was a significant change in MT rate (
= 0.002) without a concomitant change in the total number of stroke admissions, tPA administration rate, or rate of DHC.
This real-world study confirms an increase in thrombectomy performed for ELVO while demonstrating stable rates of stroke admission, tPA administration and DHC. Unlike prior studies, increasing thrombectomy rates were not associated with decreased utilization of hemicraniectomy.
This real-world study confirms an increase in thrombectomy performed for ELVO while demonstrating stable rates of stroke admission, tPA administration and DHC. Unlike prior studies, increasing thrombectomy rates were not associated with decreased utilization of hemicraniectomy.Aberrant expression of lymphoid enhancer-binding factor-1 (LEF1) has been identified in various hematological malignancies including multiple myeloma (MM). However, the exact role of LEF1 in MM remains largely unknown. Here, we showed that knockdown of LEF1 could apparently impair the proliferation, induce apoptosis and promote the ROS production in MM cell lines, suggesting that LEF1 might be involved in maintaining MM cell growth and survival. Moreover, we observed that the mRNA level of the deubiquitinase cylindromatosis (CYLD), a well-recognized tumor suppressor in MM, was significantly increased following LEF1 depletion in myeloma cells. SIS17 Further study showed that LEF1 could directly associate with the promoter of CYLD gene and thus repress its transcription in MM cells. Intriguingly, LEF1 depletion-mediated CYLD upregulation was sufficient to negatively modulate NF-κB signaling pathway in MM cells. Moreover, the decrease in NF-κB activity following LEF1 knockdown could be largely rescued when CYLD was silenced in MM cells. Taken together, our study provided the compelling evidence to show that LEF1 may augment the proliferation and survival of MM cells through direct repression of CYLD transcription and subsequent activation of NF-κB signaling pathway, corroborating that LEF1 may become a potential therapeutic target against MM.Three studies explore the possibility that attitudes toward "diversity" are multidimensional rather than unidimensional and that ideological differences in diversity attitudes vary as a function of diversity subtype. Study 1 (n = 1,001) revealed that the factor structure of attitudes toward 23 diverse community features was bidimensional. Factors involving demographic and viewpoint diversity emerged. Conservatives reported more positive attitudes toward viewpoint diversity, and liberals more positive attitudes toward demographic diversity. Study 2 (n = 1,012) replicated Study 1 findings, and extended Study 1 results by showing attitudes toward the general concept of diversity predicted attitudes toward demographic diversity but not viewpoint diversity. In Study 3, 386 participants rated how relevant a set of features was to their prototypical understanding of diversity. A confirmatory factor analysis (CFA) revealed people discriminate between viewpoint, demographic, and consumer diversity. Conservatives perceived viewpoint features as more relevant to "diversity," whereas liberals perceived demographic features as more relevant.Non-communicable diseases (NCDs) remain a challenge globally and in Indonesia. Workplace environments may place employees at risk for NCD behavioral factors. This study aimed to develop an integrated guidance post for NCD (in Indonesian, 'pos pembinaan terpadu penyakit tidak menular' [Posbindu PTM] early detection among employees in one of the Indonesian universities. Posbindu PTM is a community-based program oriented towards promotive and preventive efforts to control NCDs where the community acted as change agents. We conducted a process evaluation based on a quantitative approach through a survey (n = 313) and a qualitative method using in-depth interviews (n = 12) to support our findings that Posbindu PTM was acceptable and feasible to implement in a university context. High participation in Posbindu PTM showed that the program could encourage the university employees to join NCD prevention strategies from early detection to counseling and referral. All participants positively accepted Posbindu PTM for its benefits to health, the flexibility of the program, and the quality service provided by cadres. A need-based program planning, commitment from university leaders, adequate human resources and facilitation, and cooperation between departments, the clinic, and local primary health center and health department determined the success of Posbindu PTM implementation. In contrast, external activities negatively affected participants to join Posbindu PTM. There is a need for more routine scheduling and online-based application to enhance the program's performance. Posbindu PTM is essential for engaging employees with their health and may serve as a model for NCD prevention and control in similar settings. With Posbindu PTM implementation's success, a further stage is required to empower and sustain the Posbindu PTM program towards health-promoting universities.Chronic pain represents one of the most serious worldwide medical problems, in terms of both social and economic costs, often causing severe and intractable physical and psychological suffering. The lack of biological markers for pain, which could assist in forming clearer diagnoses and prognoses, makes chronic pain therapy particularly arduous and sometimes harmful. Opioids are used worldwide to treat chronic pain conditions, but there is still an ambiguous and inadequate understanding about their therapeutic use, mostly because of their dual effect in acutely reducing pain and inducing, at the same time, tolerance, dependence, and a risk for opioid use disorder. In addition, clinical studies suggest that opioid treatment can be associated with a high risk of immune suppression and the development of inflammatory events, worsening the chronic pain status itself. While opioid peptides and receptors are expressed in both central and peripheral nervous cells, immune cells, and tissues, the role of opioids and their receptors, when and why they are activated endogenously and what their exact role is in chronic pain pathways is still poorly understood. Thus, in this review we aim to highlight the interplay between pain and immune system, focusing on opioids and their receptors.Using baseline data from a community-collaborative cohort of women living with HIV in Canada, we assessed the prevalence and correlates of help-seeking among 1,057 women who reported experiencing violence in adulthood (≥16 years). After violence, 447 (42%) sought help, while 610 (58%) did not. Frequently accessed supports included health care providers (n = 313, 70%), family/friends (n = 244, 55%), and non-HIV community organizations (n = 235, 53%). All accessed supports were perceived as helpful. Independent correlates of help-seeking included reporting a previous mental health diagnosis, a history of injection drug use, experiencing childhood violence, and experiencing sexism. We discuss considerations for better supporting women who experience violence.The productivity and survival of honey bee (Apis mellifera) colonies depend on queen bee health. Colony-level neonicotinoid exposure has negative effects on reproductive fitness of honey bee queens. However, it is unclear if the observed effects are a direct outcome of neonicotinoid toxicity or result from suboptimal care of developing queens by exposed workers. The aim of this study was to evaluate larval survival, reproductive fitness, and histopathology of honey bee queens exposed to incremental doses (0, 5, 50 ng) of the neonicotinoid thiamethoxam (THI) applied directly to individual late larvae (7 days post-oviposition) of queens. The 5 ng dose represents a calculated high environmental level of exposure for honey bee queen larvae. Morphometric evaluation revealed that the total area of mandibular gland epithelium in queens exposed to 5 and 50 ng THI was reduced by 14% (P = .12) and 25% (P = .001), respectively. Decreased mandibular gland size may alter pheromone production, which could in part explain previously observed negative effects of THI on the reproductive fitness of queens. We also found that late larval exposure to THI reduced larval and pupal survival and decreased sperm viability in mated queens. These changes may interfere with queen development and reproductive longevity.Butyrylcholinesterase (BChE) is a nonspecific cholinesterase enzyme that hydrolyzes choline-based esters. BChE plays a critical role in maintaining normal cholinergic function like acetylcholinesterase (AChE) through hydrolyzing acetylcholine (ACh). Selective BChE inhibition has been regarded as a viable therapeutic approach in Alzheimer's disease. As of now, a limited number of selective BChE inhibitors are available. To identify BChE inhibitors rapidly and efficiently, we have screened 8998 compounds from several annotated libraries against an enzyme-based BChE inhibition assay in a quantitative high-throughput screening (qHTS) format. From the primary screening, we identified a group of 125 compounds that were further confirmed to inhibit BChE activity, including previously reported BChE inhibitors (e.g., bambuterol and rivastigmine) and potential novel BChE inhibitors (e.g., pancuronium bromide and NNC 756), representing diverse structural classes. These BChE inhibitors were also tested for their selectivity by comparing their IC50 values in BChE and AChE inhibition assays.
Homepage: https://www.selleckchem.com/products/sis17.html
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