Structure-based Discovery of Novel Small Molecule Wnt Signaling Inhibitors by Targeting the Cysteine-rich Domain of Frizzled.

Frizzled is the earliest discovered glycosylated Wnt protein receptor and is critical for the initiation of Wnt signaling. Antagonizing Frizzled is effective in inhibiting the growth of multiple tumor types. The extracellular N terminus of Frizzled contains a conserved cysteine-rich domain that directly interacts with Wnt ligands. Structure-based virtual screening and cell-based assays were used to identify five small molecules that can inhibit canonical Wnt signaling and have low IC50 values in the micromolar range. NMR experiments confirmed that these compounds specifically bind to the Wnt binding site on the Frizzled8 cysteine-rich domain with submicromolar dissociation constants. Our study confirms the feasibility of targeting the Frizzled cysteine-rich domain as an effective way of regulating canonical Wnt signaling. These small molecules can be further optimized into more potent therapeutic agents for regulating abnormal Wnt signaling by targeting Frizzled

Global and regional prevalence and outcomes of COVID-19 in people living with HIV: A cutting-edge systematic review and meta-analysis

BACKGROUND: The relationship between HIV infection and COVID-19 clinical outcome is uncertain, with conflicting data and hypotheses. We aimed to assess the prevalence and risk of severe COVID-19 and death in people living with HIV (PLWH) on the global and continental level. METHODS: Electronic databases were systematically searched in July 2021. Studies were screened and then extracted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Narratives were synthesised and data pooled for global and continental prevalence and relative risk of severity and mortality in HIV-infected COVID-19 patients using random-effect model. Risk of bias was assessed using the Newcastle-Ottawa score, Egger’s test and presented as funnel plots. RESULTS: A total of 46 studies were included involving 18,034,947 COVID-19 cases of which 31,269 were PLWH. The global prevalence of PLWH with SARS-CoV-2 infection was 1% (95% CI = 0.9% -1.1%) with the highest prevalence observed in sub-Saharan Africa. The relative risk (RR) of COVID-19 severity was significant only in Africa (RR, 95% CI = 1.14, 1.08 – 1.24) while risk of COVID-19 mortality was 1.53% (95% CI = 1.45 – 2.03) globally. The prevalence of PLWH in COVID-19 cases was significantly low, and the calculated global risk ratio show that HIV infection may be linked with increased COVID-19 death. The between-studies heterogeneity was significantly high while risk of publication bias was not significant. CONCLUSION: There is low prevalence of HIV-SARS-CoV-2 co-infection. HIV infection was linked with severe COVID-19 in Africa and increased risk of death globally

Workplace reform with changing management through the user participation workshop : the case study of Seiyo City Office / Ikumi Egawa

The research explains about workplace reform, aimed at improving productivity of General Affairs and Policy Planning department of Seiyo officeby changing management through the user participation workshop at 4th floor of Seiyo city office and on the changes of workplace reform. The purpose of this research is to find the changes that are worker's behaviour and worker’s awareness of workplace through workplace reform. The researchers surveyed changes, worker's behaviour and worker's awareness of workplace using workplace reform at 4th floor of Seiyo office as case study. In workplace reform, in order to create a place where new work style can be practiced, the researchers conducted the user participation workshops with workers a total of 6 times. Through the workshops, concept of work style and plan of renovation were proposed. In addition, the researchers did a survey using two methods which were a set of questionnaire and 3 observationsthat is before the workplace renovation, 3 months after the renovation, and 1 year and 3 months after the renovation. The findings obtained from the questionnaire in the first three months after the renovation showed that the opinions of the workers were divided between pros and cons against workplace reform. However, the survey of 1 year and three months after the renovation showed that almost all workers are satisfied with the new environment. In addition, the researchers found that a positive correlation exist between participation rate of workshops and the satisfaction level. The findings suggest the worth of workshops for workplace reform. In the Observation Survey, the workers needed to select a place freely where they can work comfortably after the workplace reform. For example, they chose to work in refresh space. In addition, the findings from the survey showed that the floor became livelier when the participation rate increses at that workplace. Additionally, the participants became more conscious of the work style such as features of work style, after workplace renovation; they are able to clearly differentiate between short intermittent works separated by conversation and phone and personal work on concentration

PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice

<p>Abstract</p> <p>Background</p> <p>Deficiency of the PERK eIF2α kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the <it>Perk </it>gene was specifically ablated in acinar cells of the exocrine pancreas in mice.</p> <p>Results</p> <p>We show that expression of PERK in the acinar cells is required to maintain their viability but is not required for normal protein synthesis and secretion. Exocrine pancreatic atrophy in PERK-deficient mice was previously attributed to uncontrolled ER-stress followed by apoptotic cell death based on studies in cultured fibroblasts. However, we have found no evidence for perturbations in the endoplasmic reticulum or ER-stress and show that acinar cells succumb to a non-apoptotic form of cell death, oncosis, which is associated with a pronounced inflammatory response and induction of the pancreatitis stress response genes. We also show that mice carrying a knockout mutation of PERK's downstream target, ATF4, exhibit pancreatic deficiency caused by developmental defects and that mice ablated for ATF4's transcriptional target CHOP have a normal exocrine pancreas.</p> <p>Conclusion</p> <p>We conclude that PERK modulates secretory capacity of the exocrine pancreas by regulating cell viability of acinar cells.</p

Automated detection and tracking of slalom paddlers from broadcast image sequences using cascade classifiers and discriminative correlation filters

This paper addresses the problem of automatic detection and tracking of slalom paddlers through a long sequence of sports broadcast images comprised of persistent view changes. In this context, the task of visual object tracking is particularly challenging due to frequent shot transitions (i.e. camera switches), which violate the fundamental spatial continuity assumption used by most of the state-of-the-art object tracking algorithms. The problem is further compounded by significant variations in object location, shape and appearance in typical sports scenarios where the athletes often move rapidly. To overcome these challenges, we propose a Periodically Prior Regularised Discriminative Correlation Filters (PPRDCF) framework, which exploits recent successful Discriminative Correlation Filters (DCF) with a periodic regularisation by a prior that constitutes a rich discriminative cascade classifier. The PPRDCF framework reduces the corruption of positive samples during online learning of the correlation filters by negative training samples. Our framework detects rapid shot transitions to reinitialise the tracker. It successfully recovers the tracker when the location, view or scale of the object changes or the tracker drifts from the object. The PPRDCF also provides the race context by detection of the ordered course obstacles and their spatial relations to the paddler. Our framework robustly outputs the evidence base pre-requisite to derived race kinematics for analysis of performance. Experiments are performed on task-specific dataset containing Canoe/Kayak Slalom race image sequences with successful results obtained

PERK eIF2α kinase regulates neonatal growth by controlling the expression of circulating insulin-like growth factor-I derived from the liver

Humans afflicted with the Wolcott-Rallison syndrome and mice deficient for PERK (pancreatic endoplasmic reticulum eIF2α kinase) show severe postnatal growth retardation. In mice, growth retardation in Perk−/− mutants is manifested within the first few days of neonatal development. Growth parameters of Perk−/− mice, including comparison of body weight to length and organ weights, are consistent with proportional dwarfism. Tibia growth plates exhibited a reduction in proliferative and hypertrophic chondrocytes underlying the longitudinal growth retardation. Neonatal Perk−/− deficient mice show a 75% reduction in liver IGF-I mRNA and serum IGF-I within the first week, whereas the expression of IGF-I mRNA in most other tissues is normal. Injections of IGF-I partially reversed the growth retardation of the Perk−/− mice, whereas GH had no effect. Transgenic rescue of PERK activity in the insulin- secreting β-cells of the Perk−/− mice reversed the juvenile but not the neonatal growth retardation. We provide evidence that circulating IGF-I is derived from neonatal liver but is independent of GH at this stage. We propose that PERK is required to regulate the expression of IGF-I in the liver during the neonatal period, when IGF-I expression is GH-independent, and that the lack of this regulation results in severe neonatal growth retardation

Be Stars in the Open Cluster NGC 6830

We report the discovery of 2 new Be stars, and re-identify one known Be star in the open cluster NGC 6830. Eleven H-alpha emitters were discovered using the H-alpha imaging photometry of the Palomar Transient Factory Survey. Stellar membership of the candidates was verified with photometric and kinematic information using 2MASS data and proper motions. The spectroscopic confirmation was carried out by using the Shane 3-m telescope at Lick observatory. Based on their spectral types, three H-alpha emitters were confirmed as Be stars with H-alpha equivalent widths > -10 Angstrom. Two objects were also observed by the new spectrograph SED-Machine on the Palomar 60 inch Telescope. The SED-Machine results show strong H-alpha emission lines, which are consistent with the results of the Lick observations. The high efficiency of the SED-Machine can provide rapid observations for Be stars in a comprehensive survey in the future.Comment: 11 pages, 8 figures, AJ in pres

METTL13 methylation of eEF1A increases translational output to promote tumorigenesis

Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.We thank Pal Falnes, Jerry Pelletier, and Julien Sage for helpful discussion, Lauren Brown and William Devine for SDS-1-021, and members of the Gozani and Mazur laboratories for critical reading of the manuscript. This work was supported in part by grants from the NIH to S.M.C. (K99CA190803), M.P.K. (5K08CA218690-02), J.A.P. (R35GM118173), M.C.B. (1DP2HD084069-01), J.S. (1R35GM119721), I.T. (R01CA202021), P.K.M. (R00CA197816, P50CA070907, and P30CA016672), and O.G. (R01GM079641). J.E.E. received support from Stanford ChEM-H, and A.M. was supported by the MD Anderson Moonshot Program. I.T. is a Junior 2 Research Scholar of the Fonds de Recherche du Quebec - Sante (FRQ-S). P.K.M. is supported by the Neuroendocrine Tumor Research Foundation and American Association for Cancer Research and is the Andrew Sabin Family Foundation Scientist and CPRIT scholar (RR160078). S.H. is supported by a Deutsche Forschungsgemeinschaft Postdoctoral Fellowship. J.W.F. is supported by 5T32GM007276. (K99CA190803 - NIH; 5K08CA218690-02 - NIH; R35GM118173 - NIH; 1DP2HD084069-01 - NIH; 1R35GM119721 - NIH; R01CA202021 - NIH; R00CA197816 - NIH; P50CA070907 - NIH; P30CA016672 - NIH; R01GM079641 - NIH; Stanford ChEM-H; MD Anderson Moonshot Program; Neuroendocrine Tumor Research Foundation; American Association for Cancer Research; Deutsche Forschungsgemeinschaft Postdoctoral Fellowship; 5T32GM007276)Supporting documentationAccepted manuscrip

Real-Time Detection and Rapid Multiwavelength Follow-up Observations of a Highly Subluminous Type II-P Supernova from the Palomar Transient Factory Survey

The Palomar Transient Factory (PTF) is an optical wide-field variability survey carried out using a camera with a 7.8 square degree field of view mounted on the 48-in Oschin Schmidt telescope at Palomar Observatory. One of the key goals of this survey is to conduct high-cadence monitoring of the sky in order to detect optical transient sources shortly after they occur. Here, we describe the real-time capabilities of the PTF and our related rapid multiwavelength follow-up programs, extending from the radio to the gamma-ray bands. We present as a case study observations of the optical transient PTF10vdl (SN 2010id), revealed to be a very young core-collapse (Type II-P) supernova having a remarkably low luminosity. Our results demonstrate that the PTF now provides for optical transients the real-time discovery and rapid-response follow-up capabilities previously reserved only for high-energy transients like gamma-ray bursts.Comment: ApJ, in press; all spectroscopic data available from the Weizmann Institute of Science Experimental Astrophysics Spectroscopy System (WISEASS; http://www.weizmann.ac.il/astrophysics/wiseass/