Pten Signaling in Regulatory T Cells and Inflammatory Disease

Regulatory T (Treg) cells suppress CD4+ T cell responses during homeostasis and inflammation to prevent autoimmunity and other immune disorders. Although the transcriptional and epigenetic programs impacting Treg cell function have been extensively studied, the signaling and metabolic pathways underlying Treg stability and function are not fully understood. In this study, we determined the role of the phosphatase PTEN in Treg cells. We found that specific depletion of PTEN in Treg cells results in excessive TH1 and T follicular helper cells (TFH) responses, associated with elevated germinal center (GC) B cells and spontaneous development of autoimmune and lymphoproliferative disease in vivo. Interestingly, the exaggerated TFH and GC responses and autoimmune symptoms are suppressed when IFN-γ expression is abrogated in mice containing Pten-deficient Treg cells. Thus, the uncontrolled TH1-mediated inflammation in these mice drives aberrant TFH responses and autoimmune and lymphoproliferative disease. Mechanistically, we linked PTEN to mTORC2-mediated control of transcriptional and metabolic programs that enforce Treg cell stability and function. Consistent with this notion, deletion of Rictor, the obligate component for mTORC2, restores Treg cell function and stability in the absence of Pten. Similarly, partially restoring the activity of Foxo1, a downstream transcription factor negatively regulated by mTORC2 signaling, also largely rectified the defects of PTEN-deficient Treg cells. Together, these results establish that Treg cells rely on the PTEN-mTORC2-Foxo1 axis to maintain their stability and suppressive activity in controlling TH1 and TFH cell responses

A PROSPECTIVE COHORT STUDY ON INCIDENCE AND RISK FACTORS FOR LOW BIRTH WEIGHT AMONG INSTITUTIONAL DELIVERIES IN KATHMANDU, NEPAL

Background: Low birth weight (LBW) in developing countries are mainly due to preterm delivery and intrauterine growth retardation. Among other causes of low birth weight, maternal factors are predominant. Aim: This study aimed to identify how strongly maternal risk factors associated to low birth weight. Method and Materials: The study used cohort prospective design among 700 pregnant women attended in antenatal care outdoor patient in Paropakar Maternity Women's hospital with 6 months follow up. Results: Among 700 respondents, 23 (3%) were lost in follow up. Out of 677 mothers, 151 (22%) gave birth of LBW. The mean birth weight was 2724gm. The mean maternal weight was 48kg, height was150cm and BMI was 21.2kg/m2. The cumulative incidence of LBW in the cohort was 22%. Mothers with weight <45kg had 11 times higher risk of giving of LBW babies (RR=10.92, CI:7.90-15.08); BMI <18.5kg/m2 had 3 times higher risk of giving LBW babies (RR=3.08, CI: 2.30 - 4.12). Mothers without having past history of LBW, and preterm delivery were 0.3 times, and 0.44 times chances of giving LBW babies respectively. There are positive association of LBW with primigravida (RR=1.09), and primiparity (RR=1.41), however, it could not reach statistically significant. Conclusion: The study concluded that maternal weight <45kg is the strongest risk factor for LBW. Other maternal risk factors were weight <45kg, BMI<18.5kg/m2, mothers without past history of LBW, and preterm are also statistically significant to LBW. KEYWORDS: Low birth weight; Cohort; Hospital-based; Maternal anthropometry

KEY FACTORS ASSOCIATED WITH LOW BIRTH WEIGHT AT TERM IN NEPAL: A CASE CONTROL STUDY

Background:Low Birth Weight (LBW) is a major public health problem in developing countries including Nepal. Nepal has a prevalence of LBW of 21%. There are various factors associated to high prevalence of LBW. This study aimed to identify specific factors associated to LBW at term in hospital settings in Nepal. Methodology: This study used a hospital based case control design. Hospital nurses interviewed mothers aged 15-45 years who had delivered a full term, single and live baby. Results: A total of 1533 respondents (511 cases and 1022 controls) were taken which is slightly more than the estimated sample size. The mean weight of newborns among case group was 2215 gm (SD:203); and among control group was 3012gm (SD:367). This study revealed that factors such as mothers under 20 years old (OR=1.436, 95% CI:1.074-1.920); height below 145cm (OR=1.504, 95% CI:1.087 -2.083); primigravida (OR=1.423, 95% CI:1.132-1.788); illiterate (OR=1.407 95% CI:1.011-1.957); <4 ANC visits (OR=1.534, 95% CI:1.202-1.957); and iron supplement <180 tabs (OR=1.434, 95% CI:1.152-1.786) were associated with LBW. However, variables like <20 years at the first pregnancy (OR=1.139, 95% CI: 0.904-1.433), disadvantaged ethnicity (OR=1.077, 95% CI: 0.861-1.347) were not associated with LBW in this study.Conclusion: Maternal height, education, number of ANC visits, and iron consumption were strong predictors for LBW in Nepal. It would benefit the country to develop effective strategies on maternal nutrition, female education, and quality ANC to overcome LBW.KEYWORDS: Low Birth Weight; Socio-demographic and antenatal care, Case control design

KEY FACTORS ASSOCIATED WITH LOW BIRTH WEIGHT AT TERM IN NEPAL: A CASE CONTROL STUDY

Background:Low Birth Weight (LBW) is a major public health problem in developing countries including Nepal. Nepal has a prevalence of LBW of 21%. There are various factors associated to high prevalence of LBW. This study aimed to identify specific factors associated to LBW at term in hospital settings in Nepal. Methodology: This study used a hospital based case control design. Hospital nurses interviewed mothers aged 15-45 years who had delivered a full term, single and live baby. Results: A total of 1533 respondents (511 cases and 1022 controls) were taken which is slightly more than the estimated sample size. The mean weight of newborns among case group was 2215 gm (SD:203); and among control group was 3012gm (SD:367). This study revealed that factors such as mothers under 20 years old (OR=1.436, 95% CI:1.074-1.920); height below 145cm (OR=1.504, 95% CI:1.087 -2.083); primigravida (OR=1.423, 95% CI:1.132-1.788); illiterate (OR=1.407 95% CI:1.011-1.957); <4 ANC visits (OR=1.534, 95% CI:1.202-1.957); and iron supplement <180 tabs (OR=1.434, 95% CI:1.152-1.786) were associated with LBW. However, variables like <20 years at the first pregnancy (OR=1.139, 95% CI: 0.904-1.433), disadvantaged ethnicity (OR=1.077, 95% CI: 0.861-1.347) were not associated with LBW in this study.Conclusion: Maternal height, education, number of ANC visits, and iron consumption were strong predictors for LBW in Nepal. It would benefit the country to develop effective strategies on maternal nutrition, female education, and quality ANC to overcome LBW.KEYWORDS: Low Birth Weight; Socio-demographic and antenatal care, Case control design

Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis

Regulatory T (Treg) cells respond to immune and inflammatory signals to mediate immunosuppression, but how functional integrity of Treg cells is maintained under activating environments remains elusive. Here we found that autophagy was active in Treg cells and supported their lineage stability and survival fitness. Treg cell-specific deletion of the essential autophagy gene Atg7 or Atg5 led to loss of Treg cells, increased tumor resistance, and development of inflammatory disorders. Atg7-deficient Treg cells had increased apoptosis and readily lost Foxp3 expression, especially after activation. Mechanistically, autophagy deficiency upregulated mTORC1 and c-Myc function and glycolytic metabolism that contributed to defective Treg function. Therefore, autophagy couples environmental signals and metabolic homeostasis to protect lineage and survival integrity of Treg cells in activating contexts

The COVID‐19 Pandemic Not Only Poses Challenges, but Also Opens Opportunities for Sustainable Transformation

The COVID-19 pandemic has impacted social, economic, and environmental systems worldwide, slowing down and reversing the progress made in achieving the Sustainable Development Goals (SDGs). SDGs belong to the 2030 Agenda to transform our world by tackling humankind's challenges to ensure well-being, economic prosperity, and environmental protection. We explore the potential impacts of the pandemic on SDGs for Nepal. We followed a knowledge co-creation process with experts from various professional backgrounds, involving five steps: online survey, online workshop, assessment of expert's opinions, review and validation, and revision and synthesis. The pandemic has negatively impacted most SDGs in the short term. Particularly, the targets of SDG 1, 4, 5, 8, 9, 10, 11, and 13 have and will continue to have weakly to moderately restricting impacts. However, a few targets of SDG 2, 3, 6, and 11 could also have weakly promoting impacts. The negative impacts have resulted from impeding factors linked to the pandemic. Many of the negative impacts may subside in the medium and long terms. The key five impeding factors are lockdowns, underemployment and unemployment, closure of institutions and facilities, diluted focus and funds for non-COVID-19-related issues, and anticipated reduction in support from development partners. The pandemic has also opened a window of opportunity for sustainable transformation, which is short-lived and narrow. These opportunities are lessons learned for planning and action, socio-economic recovery plan, use of information and communication technologies and the digital economy, reverse migration and “brain gain,” and local governments' exercising authorities

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis

Background: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. Methods: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. Results and Conclusion: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Genetic Algorithm-Based Methodology for Unstructured Design of Truss Structures

166 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1999.In this study, a new string representation scheme is developed that efficiently represents skeletal structures in strings and allows evolution of optimum structural designs under the action of the genetic operators; a new structural synthesis scheme is developed to synthesize structures from the information decoded from strings; a new generalized penalty function is developed that is able to handle many different kinds of design constraints; and a new fitness functions is developed that is able to handle various kinds of design objectives. The methodology is implemented as a software application. The methodology is demonstrated on some design examples and the results presented. The methodology is validated by comparing the evolved designs with the general engineering practice that has evolved through experience.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD