Notes

System Pharmacology-Based Evaluation along with Trial and error Quest for Antidiabetic Systems involving Gegen Qinlian Decoction.
Among many immune changes, an elevated B/T8-cell ratio and a reduced rate of activated monocytes were mainly observed in patients with severe COVID-19. Both parameters were associated with death in cohort 1.The dimeric cytokine IL-12 is important in the control of various infections but also contributes to the pathology of certain diseases making it a potential target for therapy. However, its specific inhibition with antibodies is complicated by the fact that its two subunits are present in other cytokines p40 in IL-23 and p35 in IL-35. This has led to erroneous conclusions like the alleged implication of IL-12 in experimental autoimmune encephalomyelitis (EAE). Here, we report the development of a mouse anti-mouse IL-12 vaccine and the production of monoclonal antibodies (mAbs) that do not react with p40 or p35 (in IL-35) but specifically recognize and functionally inhibit the IL-12 heterodimer. Using one of these mAbs, MM12A1.6, that strongly inhibited IFN-γ production and LPS-induced septic shock after viral infection, we demonstrate the critical role played by IL-12 in the rejection of male skin graft by female C57BL/6 syngeneic recipients and in the clearance of an immunogenic mastocytoma tumor variant by DBA/2 mice, but not in a parent to F1 immune aggression model nor in MOG-induced EAE, which was clearly prevented by anti-p40 mAb C17.8. Given this selective inhibition of IL-12, these mAbs provide new options for reassessing IL-12 function in vivo.
Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np-LMS), including local recurrences and distant metastases.

TP53, RB1, p16, and PTEN expression aberrations were determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 227 np-LMS and a comparison group of 262 primary leiomyosarcomas (p-LMS). Thirty-five of the np-LMS had a matched p-LMS specimen in the TMAs. Correlative studies included differentiation scoring, ER and PR IHC, and CDKN2A/p16 fluorescence in situ hybridization.

Dysregulation of TP53, p16/RB1, and PTEN was demonstrated in 90%, 95%, and 41% of np-LMS, respectively. PTEN inactivation was more common in soft tissue np-LMS than uterine np-LMS (55% vs 31%; P = .0005). Moderate-strong ER expression was more common in uterine np-LMS than soft tissue np-LMS (50% vs 7%; P < .0001). Co-inactivation of TP53 and RB1 was found in 81% of np-LMS and was common in both soft tissue and uterine np-LMS (90% and 74%, respectively). RB1, p16, and PTEN aberrations were nearly always conserved in p-LMS and np-LMS from the same patients.

These studies show that nearly all np-LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS.
These studies show that nearly all np-LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS.
To investigate the aetiology of acute-onset binocular diplopia (AOBD) in neurological units and identify the key diagnostic procedures in this setting.

Clinico-demographic data from patients hospitalized for AOBD from 2008 to 2019 were retrospectively reviewed. AOBD due to an underlying neurological disorder known to cause diplopia was addressed as secondary diplopia. Ophthalmoparesis plus was defined when subtle neurological signs/symptoms other than ophthalmoparesis were detected during neurological examination.

A total of 171 patients (mean age 57.6years) were included in the study. A total of 89 subjects (52%) had an oculomotor disturbance consistent with sixth nerve palsy, and 42 (24.6%) showed multiple oculomotor nerve involvement. The most common cause of AOBD was presumed to be microvascular in 56 patients (32.7%), while a secondary aetiology was identified in 102 (59.6%). Ophthalmoparesis plus and multiple oculomotor nerve involvement significantly predicted a secondary aetiology in multivariabderlying disease cannot be excluded. Brain MRI was found to perform well in all clinical scenarios, and it should be always considered when managing AOBD.Compositional data are common in many fields, both as outcomes and predictor variables. The inventory of models for the case when both the outcome and predictor variables are compositional is limited, and the existing models are often difficult to interpret in the compositional space, due to their use of complex log-ratio transformations. We develop a transformation-free linear regression model where the expected value of the compositional outcome is expressed as a single Markov transition from the compositional predictor. Our approach is based on estimating equations thereby not requiring complete specification of data likelihood and is robust to different data-generating mechanisms. GRL0617 Our model is simple to interpret, allows for 0s and 1s in both the compositional outcome and covariates, and subsumes several interesting subcases of interest. We also develop permutation tests for linear independence and equality of effect sizes of two components of the predictor. Finally, we show that despite its simplicity, our model accurately captures the relationship between compositional data using two datasets from education and medical research.Phylogenetic comparative methods are often used to test functional relationships between traits. However, million-year macroevolutionary observational datasets cannot definitively prove causal links between traits-correlation does not equal causation and experimental manipulation over such timescales is impossible. Although this caveat is widely understood, it is less appreciated that different phylogenetic approaches imply different causal assumptions about the functional relationships of traits. To make meaningful inferences, it is critical that our statistical methods make biologically reasonable assumptions. Here we illustrate the importance of causal reasoning in comparative biology by examining a recent study by Avaria-Llautureo et al (2019). that tested for the evolutionary coupling of metabolic rate and body temperature across endotherms and found that these traits were unlinked through evolutionary time and that body temperatures were, on average, higher in the early Cenozoic than they are today. We argue that the causal assumptions embedded into their models made it impossible for them to test the relevant functional and evolutionary hypotheses.
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