Multiplexed siRNA Immunoassay Unveils Spatial and Quantitative Dimensions of siRNA Function, Abundance, and Localization In Vitro and In Vivo.

Small interfering RNAs (siRNAs) have been successfully used as therapeutics to silence disease-causing genes when conjugated to ligands or formulated in lipid nanoparticles to target relevant cell types for efficacy while sparing other cells for safety. To support the development of new methods for delivery of siRNA therapeutics, we developed and characterized a panel of antibodies generated against chemically modified nucleotides used in therapeutic siRNA molecules, identifying a monoclonal antibody that detects a broad range of siRNA representing distinct sequences and modification patterns. By integrating this anti-siRNA antibody with additional reagents, we created a multiplex siRNA immunoassay that simultaneously quantifies siRNA uptake, trafficking, and silencing activity.

Trends and Challenges of the Modern Pathology Laboratory for Biopharmaceutical Research Excellence.

Pathology, a fundamental discipline that bridges basic scientific discovery to the clinic, is integral to successful drug development. Intrinsically multimodal and multidimensional, anatomic pathology continues to be empowered by advancements in molecular and digital technologies enabling the spatial tissue detection of biomolecules such as genes, transcripts, and proteins. Over the past two decades, breakthroughs in spatial molecular biology technologies and advancements in automation and digitization of laboratory processes have enabled the implementation of higher throughput assays and the generation of extensive molecular data sets from tissue sections in biopharmaceutical research and development research units.

Integration of rehabilitation services in primary, secondary, and tertiary levels of health care systems in low- and middle-income countries: a scoping review.

Purpose: Integration is a concept that seeks to strengthen the delivery of services to ensure people receive a continuum of care across the health system. We conducted a scoping review to explore how rehabilitation services have been integrated into health systems in low- and middle- income countries (LMICs).

Materials And Methods: We conducted a scoping review using Valentijn's Rainbow Model of Integrated Care (RMIC) as an organising framework.

The Journey to Early Identification and Intervention for Children with Disabilities in Fiji.

Early identification of developmental delay or disability and access to early intervention improves outcomes for children with disabilities and their families. However, in many low- and middle-income countries, services and systems to enable timely, co-ordinated care and support are lacking. The aim of this research was to explore the experiences of families of children with developmental disabilities in Fiji in accessing services for intervention and support across sectors.

Characterization of Selective M Acetylcholine Muscarinic Receptor Modulators on Dopamine Signaling in the Striatum.

The type-5 muscarinic acetylcholine receptor (mAChR, M) is almost exclusively expressed in dopamine (DA) neurons of the ventral tegmental area and substantia nigra pars compacta; therefore, they are ideally located to modulate DA signaling and underlying behaviors. However, the role of M in shaping DA release is still poorly characterized. In this study, we first quantitatively mapped the expression of M in different neurons of the mouse midbrain, then used voltammetry in mouse striatum to evaluate the effect of M-selective modulators on DA release.

Validation of a diet-induced Macaca fascicularis model of non-alcoholic steatohepatitis with dietary and pioglitazone interventions.

Aim: To develop an obese, insulin-resistant cynomolgus monkey model of non-alcoholic steatohepatitis (NASH) with fibrosis with a high fat/high cholesterol (HFHC) diet (with or without high fructose) and test its responsiveness to caloric restriction or pioglitazone.

Methods: First, two groups of monkeys (n = 24/group) with histologically proven NASH and fibrosis were fed the HFHC diet for 17 weeks. The treatment group was subjected to a 40% caloric restriction (CR) and had their diet switched from the HFHC diet to a chow diet (DSCR).

Access to ear and hearing care services in Cambodia: a qualitative enquiry into experiences of key informants.

Objective: In Cambodia, little is known about the state of ear and hearing care, or the roles providers or key stakeholders play in delivering services.

Method: This was an exploratory study using semi-structured qualitative interviews and a questionnaire addressed to key stakeholders to explore their perceptions and experiences in providing services to people suffering from ear disease or hearing loss in Cambodia.

Results: Several challenges were described including a lack of hearing services to meet the demand, especially outside Phnom Penh in primary care and aural rehabilitation.

Aluminosilicate Zeolite EMM-28 Containing Supercavities Determined by Continuous Rotation Electron Diffraction.

A new aluminosilicate zeolite, denoted EMM-28, has been successfully synthesized on a large scale using 1,1-(3,3-(1,3-phenylene)bis(propane-3,1-diyl))bis(1-methylpyrrolidinium) hydroxide as an organic structure directing agent (OSDA), which was scaled up to an ∼20 g scale with a yield of 77%. It crystallizes as thin plates (40-100 nm in thickness), and the corresponding powder X-ray diffraction (PXRD) pattern shows significant peak broadening which makes it insufficient for structure determination. Continuous rotation electron diffraction (cRED) data collected from 13 crystals were successfully used to solve and refine the structure of EMM-28.

Barriers to access to ear and hearing care services in low- and middle- income countries: A scoping review.

People living in low- and middle- income countries (LMICs) meet significant challenges in accessing ear and hearing care (EHC) services. We conducted a scoping review to identify and summarise such barriers, to recognise gaps in the literature, and to identify potential solutions. Reviewers independently screened titles, abstracts and full-text articles and charted data.

Comprehensive BCMA Expression Profiling in Adult Normal Human Brain Suggests a Low Risk of On-target Neurotoxicity in BCMA-targeting Multiple Myeloma Therapy.

B-cell maturation antigen (BCMA) is a target for the treatment of multiple myeloma with cytolytic therapies, such as chimeric antigen receptor T-cells or T-cell redirecting antibodies. To better understand the potential for "on-target/off-tumor" toxicity caused by BCMA-targeting cytolytic therapies in the brain, we investigated normal brain BCMA expression. An immunohistochemistry (IHC) assay using the E6D7B commercial monoclonal antibody was applied to 107 formalin-fixed, paraffin-embedded brain samples (cerebrum, basal ganglia, cerebellum, brainstem; 63 unique donors).

The Future of Disability Research in Australia: Protocol for a Multiphase Research Agenda-Setting Study.

Background: For people with disabilities to live a good life, it is essential that funded research in health and social care addresses their interests, meets their needs, and fills gaps in our understanding of the impact that services, systems, and policies may have on them. Decisions about research funding should be based on an understanding of the research priorities of people with disabilities, their supporters and allies, disability researchers, service providers, and policy makers working in the field.

Objective: The aim of this protocol is to describe the research design and methods of a large-scale, disability research agenda-setting exercise conducted in 2021 in Australia.

Development of a Digital Case Management Tool for Community Based Inclusive Development Program.

Disability inclusive development practices require reliable data to identify people with disabilities, their barriers to participation and support needs. Although several tools are available for measuring different components of disability, it is often difficult for program teams in low resource settings, including lay community workers of community based inclusive development (CBID) programs, to collect and analyze data for program monitoring and evaluation. This paper presents the development of a digital CBID Modular Tool with automated data analysis to support routine case management processes and monitoring of a CBID program in Laos PDR.

Combining Child Functioning Data with Learning and Support Needs Data to Create Disability-Identification Algorithms in Fiji's Education Management Information System.

Disability disaggregation of Fiji's Education Management Information System (FEMIS) is required to determine eligibility for inclusive education grants. Data from the UNICEF/Washington Group Child Functioning Module (CFM) alone is not accurate enough to identify disabilities for this purpose. This study explores whether combining activity and participation data from the CFM with data on environmental factors specific to learning and support needs (LSN) more accurately identifies children with disabilities.

Human ileal organoid model recapitulates clinical incidence of diarrhea associated with small molecule drugs.

Drug-induced gastrointestinal toxicity (GIT) is a common treatment-emergent adverse event that can negatively impact dosing, thereby limiting efficacy and treatment options for patients. An in vitro assay of GIT is needed to address patient variability, mimic the microphysiology of the gut, and accurately predict drug-induced GIT. Primary human ileal organoids (termed 'enteroids') have proven useful for stimulating intestinal stem cell proliferation and differentiation to multiple cell types present in the gut epithelium.

Multiplex immunofluorescence staining and image analysis assay for diffuse large B cell lymphoma.

With the explosion of immuno-oncology and the approval of many immune checkpoint therapies by regulatory agencies in the last few years, understanding the tumor microenvironment (TME) in the context of patients' immune status has become essential. Among available immune profiling techniques, multiplex immunofluorescence (mIF) assays offer the unique advantage of preserving the architectural features of the tumor and revealing the spatial relationships between tumor cells and immune cells. A number of mIF and image analysis assays have been described for solid tumors but most are not sufficiently suitable in lymphoma, where the lack of clear tumor-stromal boundaries and high tumor density present significant challenges.

Vision impairment and refractive errors in refugees presenting to community optometry clinics in Victoria, Australia.

Background: There is a paucity of data relating to refugee eye health in Australia. This study aimed at investigating the spectrum of vision impairment and other ocular conditions in refugees utilising the Victorian Eyecare Service operated by the Australian College of Optometry.

Methods: A cross-sectional study of electronic clinical records of 518 individuals (adults and children) recognised as refugees by the Australian College of Optometry and treated between January 2013 and May 2014 were identified.

Parallelism between risk and perception of risk among caregivers during anesthesia delivery.

The paper examines the different perceptions of risk associated with anesthesia systems from the viewpoint of the product manufacturer and the caregiver. Only a little research has been done with regard to the impact of perception of risk on patient safety in anesthesia. The role of the manufacturer in mitigating the perception of risk will be central for the work.

The UNICEF/Washington Group Child Functioning Module-Accuracy, Inter-Rater Reliability and Cut-Off Level for Disability Disaggregation of Fiji's Education Management Information System.

This paper explores the validity (sensitivity and specificity) of different cut-off levels of the UNICEF/Washington Group Child Functioning Module (CFM) and the inter-rater reliability between teachers and parents as proxy respondents, for disaggregating Fiji's education management information system (EMIS) by disability. The method used was a cross-sectional diagnostic accuracy study comparing CFM items to standard clinical assessments for 472 primary school aged students in Fiji. Whilst previous domain-specific results showed "good" to "excellent" accuracy of the CFM domains seeing, hearing, walking and speaking, newer analysis shows only "fair" to "poor" accuracy of the cognitive domains (learning, remembering and focusing attention) and "fair" of the overall CFM (area under the Receiver Operating Characteristic curve: 0.

Factors Influencing Disability Inclusion in General Eye Health Services in Bandung, Indonesia: A Qualitative Study.

The Inclusive System for Effective Eye-care (I-SEE) is a pilot project for disability inclusion in eye health in Bandung district of Indonesia. The aim of this research was to investigate factors influencing the introduction, i.e.

Unmet Needs and Use of Assistive Products in Two Districts of Bangladesh: Findings from a Household Survey.

Access to assistive products (AP) is an under-researched public health issue. Using an adaptation of a draft World Health Organization tool-the 'Assistive Technology Assessment-Needs (ATA-N)' for measuring unmet needs and use of AP, we aimed to understand characteristics of AP users, self-reported needs and unmet needs for AP, and current access patterns in Bangladesh. The ATA-N was incorporated in a Rapid Assessment of Disability (RAD), a population-based survey to estimate prevalence and correlates of disability.

UBE2G1 governs the destruction of cereblon neomorphic substrates.

The cereblon modulating agents (CMs) including lenalidomide, pomalidomide and CC-220 repurpose the Cul4-RBX1-DDB1-CRBN (CRL4) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the K48-linked polyubiquitination of CRL4 neomorphic substrates via a sequential ubiquitination mechanism. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs.

KIAA1199 expression and hyaluronan degradation colocalize in multiple sclerosis lesions.

Modification of hyaluronan (HA) accumulation has been shown to play a key role in regulating inflammatory processes linked to the progression of multiple sclerosis (MS). The aim of this study was to characterize the enzymatic activity involved in HA degradation observed within focal demyelinating lesions in the experimental autoimmune encephalomyelitis (EAE) animal model. EAE was induced in 3-month-old female C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein 33-35 (MOG33-35) peptide.

Postactivation potentiation improves athletic performance without affecting plasma oxidative level.

Background: Several authors reported evidences for postactivation potentiation (PAP) but so far, few studies suggested suitable methods for use it to improve performance. On the other hand, it is well known that a fatiguing exercise can leads to a temporary imbalance between the production of reactive oxygen species (ROS) and their disposal. The purpose of our research was to evaluate the effects on performance and plasma oxidative stress of a specific program of conditioning in replacement of traditional sequences of warm-up.