HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells.

Maturity-onset diabetes of the young 1 (MODY1) is a monogenic diabetes condition caused by heterozygous HNF4A mutations. We investigate how HNF4A haploinsufficiency from a MODY1/HNF4A mutation influences the development of foregut-derived liver and pancreatic cells through differentiation of human induced pluripotent stem cells from a MODY1 family down the foregut lineage. In MODY1-derived hepatopancreatic progenitors, which expressed reduced HNF4A levels and mislocalized HNF4A, foregut genes were downregulated, whereas hindgut-specifying HOX genes were upregulated. MODY1-derived hepatocyte-like cells were found to exhibit altered morphology. Hepatic and β cell gene signatures were also perturbed in MODY1-derived hepatocyte-like and β-like cells, respectively. As mutant HNF4A (p.Ile271fs) did not undergo complete nonsense-mediated decay or exert dominant negativity, HNF4A-mediated loss of function is likely due to impaired transcriptional activation of target genes. Our results suggest that in MODY1, liver and pancreas development is perturbed early on, contributing to altered hepatic proteins and β cell defects in patients

HNF4A haploinsufficiency in MODY1 abrogates liver and pancreas differentiation from patient-derived induced pluripotent stem cells

Maturity-onset diabetes of the young 1 (MODY1) is a monogenic diabetes condition caused by heterozygous HNF4A mutations. We investigate how HNF4A haploinsufficiency from a MODY1/HNF4A mutation influences the development of foregut-derived liver and pancreatic cells through differentiation of human induced pluripotent stem cells from a MODY1 family down the foregut lineage. In MODY1-derived hepatopancreatic progenitors, which expressed reduced HNF4A levels and mislocalized HNF4A, foregut genes were downregulated, whereas hindgut-specifying HOX genes were upregulated. MODY1-derived hepatocyte-like cells were found to exhibit altered morphology. Hepatic and β cell gene signatures were also perturbed in MODY1-derived hepatocyte-like and β-like cells, respectively. As mutant HNF4A (p.Ile271fs) did not undergo complete nonsense-mediated decay or exert dominant negativity, HNF4A-mediated loss of function is likely due to impaired transcriptional activation of target genes. Our results suggest that in MODY1, liver and pancreas development is perturbed early on, contributing to altered hepatic proteins and β cell defects in patients.publishedVersio

A review and reflection on online learning and assessments in higher education after the pandemic

The 2020 COVID-19 pandemic has pushed many higher education institutions to deliver courses using online mode due to the movement restrictions. However, many academicians were under-prepared. Now that the pandemic is over, it is time to reflect on these online teaching practices and consider their suitability and sustainability in this post-pandemic era. This study used a case study approach and examined blended and hybrid learning and online assessments and their use in higher education institutions. It adopted a crowdsourcing approach to gather the relevant literature and was backed by the reflection and experience of the academicians in a branch campus of an Australian university in Malaysia. This study suggests that academicians could still use blended and hybrid learning as an alternative but must upskill themselves. Furthermore, selective online assessments could still be used. This study would be helpful to academicians and policymakers in higher education when deciding the teaching mode and assessments in the post-pandemic era

Development of “LvL UP 1.0”: a smartphone-based, conversational agent-delivered holistic lifestyle intervention for the prevention of non-communicable diseases and common mental disorders

BackgroundNon-communicable diseases (NCDs) and common mental disorders (CMDs) are the leading causes of death and disability worldwide. Lifestyle interventions via mobile apps and conversational agents present themselves as low-cost, scalable solutions to prevent these conditions. This paper describes the rationale for, and development of, “LvL UP 1.0″, a smartphone-based lifestyle intervention aimed at preventing NCDs and CMDs.Materials and MethodsA multidisciplinary team led the intervention design process of LvL UP 1.0, involving four phases: (i) preliminary research (stakeholder consultations, systematic market reviews), (ii) selecting intervention components and developing the conceptual model, (iii) whiteboarding and prototype design, and (iv) testing and refinement. The Multiphase Optimization Strategy and the UK Medical Research Council framework for developing and evaluating complex interventions were used to guide the intervention development.ResultsPreliminary research highlighted the importance of targeting holistic wellbeing (i.e., both physical and mental health). Accordingly, the first version of LvL UP features a scalable, smartphone-based, and conversational agent-delivered holistic lifestyle intervention built around three pillars: Move More (physical activity), Eat Well (nutrition and healthy eating), and Stress Less (emotional regulation and wellbeing). Intervention components include health literacy and psychoeducational coaching sessions, daily “Life Hacks” (healthy activity suggestions), breathing exercises, and journaling. In addition to the intervention components, formative research also stressed the need to introduce engagement-specific components to maximise uptake and long-term use. LvL UP includes a motivational interviewing and storytelling approach to deliver the coaching sessions, as well as progress feedback and gamification. Offline materials are also offered to allow users access to essential intervention content without needing a mobile device.ConclusionsThe development process of LvL UP 1.0 led to an evidence-based and user-informed smartphone-based intervention aimed at preventing NCDs and CMDs. LvL UP is designed to be a scalable, engaging, prevention-oriented, holistic intervention for adults at risk of NCDs and CMDs. A feasibility study, and subsequent optimisation and randomised-controlled trials are planned to further refine the intervention and establish effectiveness. The development process described here may prove helpful to other intervention developers

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Women's Usage Behavior and Perceived Usefulness with Using a Mobile Health Application for Gestational Diabetes Mellitus: Mixed-Methods Study

10.3390/ijerph18126670INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH181

Low field domain wall dynamics in artificial spin-ice basis structure

Artificial magnetic spin-ice nanostructures provide an ideal platform for the observation of magnetic monopoles. The formation of a magnetic monopole is governed by the motion of a magnetic charge carrier via the propagation of domain walls (DWs) in a lattice. To date, most experiments have been on the static visualization of DW propagation in the lattice. In this paper, we report on the low field dynamics of DW in a unit spin-ice structure measured by magnetoresistance changes. Our results show that reversible DW propagation can be initiated within the spin-ice basis. The initial magnetization configuration of the unit structure strongly influences the direction of DW motion in the branches. Single or multiple domain wall nucleation can be induced in the respective branches of the unit spin ice by the direction of the applied field.Published versio

Single-cell analyses of human islet cells reveal de-differentiation signatures

Abstract Human pancreatic islets containing insulin-secreting β-cells are notoriously heterogeneous in cell composition. Since β-cell failure is the root cause of diabetes, understanding this heterogeneity is of paramount importance. Recent reports have cataloged human islet transcriptome but not compared single β-cells in detail. Here, we scrutinized ex vivo human islet cells from healthy donors and show that they exhibit de-differentiation signatures. Using single-cell gene expression and immunostaining analyses, we found healthy islet cells to contain polyhormonal transcripts, and INS+ cells to express decreased levels of β-cell genes but high levels of progenitor markers. Rare cells that are doubly positive for progenitor markers/exocrine signatures, and endocrine/exocrine hormones were also present. We conclude that ex vivo human islet cells are plastic and can possibly de-/trans-differentiate across pancreatic cell fates, partly accounting for β-cell functional decline once isolated. Therefore, stabilizing β-cell identity upon isolation may improve its functionality

Investigating fluorescent dyes in fluorescence-assisted screenings

Screening of bead-based peptide libraries against fluorescent dye-labeled target proteins was found to be significantly influenced by the dye characteristics. Commercially available red fluorescent dyes with net negative charges adversely showed strong interactions with library beads. The introduction of zwitterionic dyes significantly reduced the unwanted interactions, which sheds light upon using the right fluorescent probe for acquisition of reliable results in various fluorescence-assisted applications.114sciescopu

Online Learning and Assessments in the Higher Education after the Pandemic : Stay or Scrap?

All higher education institutions have moved to online mode due to the movement restrictions in the 2020 COVID-19 pandemic, but many academicians were under-prepared. Now that the movement restrictions have been lifted, it is time to reflect on these teaching practices and consider their suitability and continuance use in this post-pandemic era. This study used a case study approach and examined blended and hybrid learning and online assessments and their suitability in the post-pandemic era. It adopted a crowdsourcing approach to gather the relevant literature and was backed by the reflection and experience of the academicians in a branch campus of an Australian university in Malaysia. This study suggests that academicians could still use blended and hybrid learning where needed, but they must upskill themselves. Furthermore, selective online assessments could still be used. This study would be helpful to academicians and policymakers in higher education when deciding the teaching mode and assessments in the post-pandemic era