Family Research Articles

Tracing trans-imperial transfers of enslaved people between the Dutch and Danish West Indies, 1834–1848

ABSTRACT Previous studies indicate that Caribbean trans-imperialism is an early modern phenomenon that faded away in the late eighteenth and early nineteenth century. Using among others 74 Curaçao export requests for enslaved people and the St. Thomas population censuses of 1841 and 1846, however, we demonstrate that strong trans-imperial connections still existed between Dutch Curaçao and Danish St. Thomas in the period 1834–1848. Our innovative research approach combines source material from two Caribbean islands belonging to two different colonial governments to trace free and enslaved individuals across colonial borders. In addition, we elaborate on the trans-imperial networks of Susanna Paul and her family, who transported more than twenty enslaved individuals during the study period. We find that familial and social relations were central in the export requests, and enslaved individuals often had to accompany their moving owners or were sold to their owner´s family members. Particularly Jewish and Catholic networks were involved in the trans-imperial slave movements, whereas Protestants were largely absent. Most free people involved belonged to the upper classes, but also individuals with less prestigious occupations had the means to participate in transfers of enslaved people. Enslaved individuals exported to St. Thomas were mostly young females and worked for their (new) owners as domestic servants. This contrasts strongly with the simultaneously occurring male-dominated transfers from Curaçao to Puerto Rico´s upcoming plantation economy.

Genotype and phenotype characteristics of DFNB67 hearing loss patients with LHFPL5 variants

The current study aimed to analyze the genotype and phenotype characteristics of families with hearing loss caused by LHFPL5 gene variants. The clinical and molecular genetic data of two Han Chinese families with heredity hearing loss who visited Tianjin Medical University General Hospital and Chinese PLA General Hospital from May to November 2023 were retrospectively analyzed. The probands from two families are a 35-year-old female deaf-mute patient and a 5-year-old boy with hearing loss. Whole exome sequencing was used to identified candidate pathogenic genes in probands, and variant loci were verified by Sanger sequencing among family members. Additionally, the phenotypic characteristics were analyzed by hearing and vestibular assessment. The clinical phenotypes of patients from two families were bilateral congenital total deafness and rare progressive severe to profound sensorineural hearing loss. Homozygous variant LHFPL5 (p.Tyr67Cys) and compound heterozygous variants LHFPL5 (p.Tyr67Cys, p.Ser88del) were identified. This study extends the LHFPL5 variant spectrum and enriches the knowledge of auditory phenotypes, providing an important basis for accurate diagnosis and intervention of hearing loss caused by LHFPL5 variants.

Acceptability and feasibility of Problem Management Plus to address mental health problems among remand prisoners in the Netherlands: a pilot randomised controlled trial protocol.

Worldwide, the prevalence of mental health problems in prison populations is higher than in the general population. While prisons may provide opportunities to address mental health problems, the prison setting can also include obstacles to the actual delivery of interventions, such as mental health care staff deficiencies. A brief scalable psychological intervention such as the World Health Organization's (WHO) Problem Management Plus (PM +) intervention, which is delivered by trained non-specialists, could be valuable in addressing common mental health problems in the prison setting. The primary aim of the study is to evaluate the feasibility and acceptability of PM + , adapted for use in Dutch remand prisons. The secondary aim is to examine barriers and facilitators for scaling up the adapted version of PM + in the Dutch prison setting. This single-blind pilot randomised controlled trial (RCT) will compare individual PM + with care-as-usual (PM + /CAU) to CAU only. Dutch-speaking remand prisoners (18years or older; N = 60) who report an elevated level of psychological distress (K10 ≥ 16) will be included. The feasibility of the intervention will be reviewed using different measures such as recruitment success, intervention retention, protocol adherence, number of serious adverse events, and stakeholders' views. Participants will be assessed for self-reported anxiety, depression, self-identified problems, vulnerability for suicide and self-harm behaviour and post-traumatic stress disorder (PTSD) symptoms at baseline, one-week post-intervention and three-month follow-up. The pilot RCT will be followed by a process evaluation. For the process evaluation, stakeholders will be interviewed (N = 25), including 1) RCT participants, 2) PM + helpers, supervisors and trainers, 3) prison professionals, and 4) family members & friends of RCT participants. Data of the process evaluation will be analysed using reflexive thematic analysis. This pilot RCT will be the first to study the potential of WHO-developed scalable interventions aimed at reducing mental health problems within (Dutch) prisons. Results from this study could subsequently inform a potential full-powered RCT. This trial is registered on ClinicalTrials.gov (number NCT05927987) on 13/06/2023.

USP39 promote post-translational modifiers to stimulate the progress of cancer.

Deubiquitinating enzymes (DUBs) are a class of crucial peptidyl hydrolases within the ubiquitin system, playing a significant role in reversing and strictly regulating ubiquitination, which is essential for various biological processes such as protein stability and cellular signal transduction. Ubiquitin-specific protease 39 (USP39) is an important member of the DUBs family. Recent studies have revealed that USP39 is involved in the regulation of multiple cellular activities including cell proliferation, migration, invasion, apoptosis, and DNA damage repair. USP39 also plays a significant role in the development and progression of various cancers. It is believed that USP39 is a unique enzyme that controls the ubiquitin process and is closely associated with the occurrence and progression of many cancers, including hepatocellular, lung, gastric, breast, and ovarian cancer. This review summarizes the structural and functional aspects of USP39 and its research advancements in tumors, investigates the key molecular mechanisms related to USP39, and provides references for tumor diagnosis and treatment.

Knockout of the V-ATPase interacting protein Tldc2 in B-type kidney intercalated cells impairs urine alkalinization.

Intercalated cells (ICs) are acid-base regulatory cells in the kidney collecting duct that excrete either acid or base into the urine in response to systemic cues. A-ICs deliver protons into the tubule lumen via an apical proton pump (V-ATPase) and reabsorb base (bicarbonate) using the AE1 anion exchanger. B-ICs function in the opposite direction. They have basolateral V-ATPase and secrete bicarbonate into the lumen via the anion exchange protein, pendrin. The function of a third IC subtype, the non-A non-B IC which has apical pendrin and apical V-ATPase, is less well understood. We previously reported that members of the TLDc protein family interact with the V-ATPase and may regulate its function. TLDc proteins exhibit a distinct expression pattern in the kidney with RNAseq showing high, differential expression of Tldc2 in B-ICs. Here, we show by RNAscope imaging that Tldc2 is indeed expressed in B-ICs, but also in some non-A, non-B ICs. Using Tldc2 knockout (Tldc2-/-) mice, we found that males and females had significantly lower urine pH than wild-type littermates, and their ability to increase urine pH in response to a bicarbonate load was impaired. In addition, Tldc2-/- males developed hyperbicarbonatemia. Tldc2-/- kidneys contained fewer B-ICs than wild-type mice, but they were replaced by more non-A, non-B ICs; the number of A-ICs was unchanged. Finally, there was decreased basolateral accumulation of V-ATPase in Tldc2-/- B-ICs. These findings suggest that Tldc2 is a novel gene involved in renal acid-base regulation and in addition, may serve as a differentiation marker for B-ICs.

Therapeutic applications of exercise in neurodegenerative diseases: focusing on the mechanism of SIRT1.

Neurodegenerative diseases comprise a group of central nervous system disorders marked by progressive neuronal degeneration and dysfunction. Their pathogenesis is multifactorial, involving oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Recent research has highlighted the potential of exercise as a non-pharmacological intervention for both the prevention and treatment of these disorders. In particular, exercise has received growing attention for its capacity to upregulate the expression and activity of SIRT1, a critical mediator of neuroprotection via downstream signaling pathways. SIRT1, a key member of the Sirtuin family, is a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase. It plays an essential role in regulating cellular metabolism, energy homeostasis, gene expression, and cellular longevity. In the context of neurodegenerative diseases, SIRT1 confers neuroprotection by modulating multiple signaling cascades through deacetylation, suppressing neuronal apoptosis, and promoting neural repair and regeneration. Exercise enhances SIRT1 expression and activity by increasing NAD + synthesis and utilization, improving intracellular redox balance, alleviating oxidative stress-induced inhibition of SIRT1, and thereby promoting its activation. Moreover, exercise may indirectly modulate SIRT1 function by influencing interacting molecular networks. This review summarizes recent advances in the therapeutic application of exercise for neurodegenerative diseases, with a focus on SIRT1 as a central mechanism. It examines how exercise mediates neuroprotection through the regulation of SIRT1 and its associated molecular mechanisms and signaling pathways. Finally, the paper discusses the potential applications and challenges of integrating exercise and SIRT1-targeted strategies in the management of neurodegenerative diseases, offering novel perspectives for the development of innovative treatments and improvements in patients' quality of life.

Support needs of young people caring for their parents with cancer.

Family members play an essential role in cancer care, but greater attention is needed on how young people who are providing this care for their parents with cancer can be supported. The aim of this qualitative study was to identify strategies for allied healthcare providers to support young caregivers caring for parents with cancer. We conducted semi-structured interviews with 56 participants, including young caregivers (n = 10), parent survivor (n = 12), and allied healthcare providers (n = 34). Interviews were audio-taped, transcribed verbatim, and analyzed using a qualitative content analysis approach. Findings illuminate that young people are giving care with limited or no training and are not receiving intervention, support, or assistance from allied healthcare providers. Participants recognized that greater support is needed to meet young caregivers' needs, and the nature of the support needed changes over the course of cancer treatment. Allied healthcare providers could support young people through skills training, social and emotional support, and connecting to community resources. Findings reveal the unique and dynamic needs of young caregivers and underscore the need for healthcare systems to expand their support models to include these young, often invisible, caregivers. Given the chronic nature of cancer, the number of young caregivers is likely to increase; therefore, allied health professionals need to be better at identifying and supporting them as part of the family-centered cancer care provided.

Patient-Reported Social Determinants of Health in Patients With Heart Failure.

Social determinants of health (SDOH) complicate medical care and affect clinical outcomes, but the lack of a reliable structured interview for medical patients has impeded clinical assessment and research on SDOH. We assessed the reliability and validity of a newly developed SDOH Patient Interview Form and investigated SDOH in patients with heart failure. The SDOH Patient Interview Form was administered to recently hospitalized patients with heart failure between January 2021 and April 2024. The interviews were recorded, and 50 were randomly selected for the interrater reliability analysis. The sample included 367 participants (mean age, 61.2±12.1 years; 42.5% women; 57.7% minorities). The interrater reliability of SDOH Patient Interview Form categories (eg, Legal and Social Problems) was 100%. The κ reliability coefficients for individual items were ≥0.94. Higher lifetime SDOH counts were associated with lower age and income and higher New York Heart Association class and body mass index. Two distinct sets of problems were found to contribute to relatively high burdens of SDOH. The first originates with abuse in childhood and presents as severe socioeconomic deprivation in adulthood. The second includes losses of family members and occupational, financial, and caregiver stress along with difficulty affording medical care. The SDOH Patient Interview Form is a reliable instrument for assessing patient-reported SDOH in patients with heart failure. It is suitable for use in research and clinical contexts but requires further testing in other medical patient populations. This study revealed 2 distinct patterns of stressful problems that can contribute to a high overall burden of SDOH. URL: https://clinicaltrials.gov; Unique identifier: NCT04637776.

MiR-99 Family of Exosomes Targets Myotubularin-related Protein 3 to Regulate Autophagy in Trophoblast Cells and Influence Insulin Resistance.

The global incidence of gestational diabetes mellitus (GDM) continues to rise and is associated with negative outcomes in pregnancy. This study aims to investigate how the miR-99 family of exosomes derived from the placenta targets myotubularin-related protein 3 (MTMR3) to trigger autophagy and alter insulin resistance (IR) in trophoblast cells. In this study, placenta-derived exosomes from plasma samples of patients with GDM and normal pregnant women were isolated to evaluate the expression levels of miR-99 family members (miR-99a, miR-99b, and miR-100) by quantitative real-time polymerase chain reaction. Furthermore, we used Targeted Scan prediction and dual luciferase reporter assays to identify a potential target of the miR-99 family. Finally, Western blotting, CCK8 assay, and glucose level measurement were used to confirm that the miR-99 family regulates autophagy in trophoblast cells through targeting potential targets, thereby affecting IR. Through comprehensive molecular biology techniques, our analysis revealed that, in contrast to normal pregnant women, the placenta-derived exosomes of women with GDM exhibited a significant downregulation of the miR-99 family. Moreover, MTMR3 emerged as a potential target of the miR-99 family, revealing a negative correlation with the levels of miR-99. An increase in MTMR3 expression impaired cellular autophagy and contributed to IR. Conversely, augmenting the miR-99 family can lead to a downregulation of MTMR3, promotion of cellular autophagy, and mitigation of IR. This research demonstrated that the expression of the miR-99 family was reduced in plasma exosomes of GDM. The miR-99 family can directly target MTMR3, leading to its downregulation. This process activated autophagy in trophoblast cells and enhances insulin sensitivity. Consequently, the miR-99 family holds potential as a therapeutic strategy for patients with GDM.

Aiming for survival: a qualitative single case study of support for family members across the care process in outpatient colorectal cancer care

BackgroundAt times of cancer, also family members may need support from healthcare professionals. For support to be relevant it needs to be tailored to a person’s needs. Tailored support is recognized as support co-created through an intangible interaction between the supporter and the supported. Despite this, studies primarily focus on the supporter (healthcare professionals) or the supported (family members). As a result, the co-created dimension is lost. Therefore, the purpose was to describe and compare family members´ supportive care needs with support from cancer nurses across the care process in outpatient colorectal cancer care.MethodsThis study is designed as a qualitative single case study with two embedded units: family members and Contact Nurses. Data consisted of transcribed semi-structured interviews from 23 family members and 21 Contact Nurses. Both within and across units, analyses were undertaken using conventional qualitative content analysis. Reporting adheres to the Consolidated Criteria for Reporting Qualitative Research checklist.ResultsAnalysis generated a main category: Aiming for survival illustrating the common goal of the two units and its implications for support for family members in routine colorectal cancer care. Three subcategories describe family members´ supportive care needs in relation to Contact Nurses´ support for family members across the colorectal cancer care process: (1) The diagnostic phase: Narrowed sight in treatment preparation; (2) The treatment phase: Foregrounding family caregiving while backgrounding family support; and (3) The surveillance phase: An enduring cancer experience despite being considered a co-survivor.ConclusionsSupport tailored to family members’ supportive care needs should derive from the family members’ cancer experiences and include strategies for bringing their needs to light. This could possibly be achieved by strengthening the collaboration between contact nurses and clinical social workers. In addition, family members require preparation for and support during their entire cancer trajectory to enable a healthy family recovery post-treatment. In addition, they need guidance on where and whom to turn to at each stage of the care process.

Understanding Community-Level Determinants and Navigating Care for Psychosis: The Experiences of Black Service Users and Their Family Members.

Prior research on the experiences of individuals in the early stages of psychosis have primarily focused on identifying facilitators and barriers at individual and interpersonal level determinants on the pathway to care, with very few studies focused on Black individuals and their family members. The purpose of this study is to explore and understand perceived community-level determinants that support or hinder the experiences of Black service users in the early stages of psychosis and their family members/support persons as they navigate care. In-depth semi-structured interviews were conducted with six Black young adults in the early stages of psychosis and 11 Black family members of individuals enrolled in early intervention services for psychosis. Qualitative data was thematically analyzed, and five core themes emerged from the analysis: (1) access to social networks, resources, and opportunities; (2) combating racism and discrimination; (3) stigma in the Black community; (4) diverse representation and cultural relevancy; and (5) public education and awareness on psychosis. Findings explored how community and societal factors hinder access to resources, shape experiences navigating care, and identify facilitators to support services and improve the experiences of Black individuals in the early stages of psychosis and family members.

Reactions and Engagement of Individuals with Dementia Toward Humanoid Assistive Robots: A Study Using the Pepper Robot.

While robot acceptance in different populations is well-studied, little is known about how individuals with dementia perceive and respond to humanoid assistive robots. This paper explores how individuals affected by dementia react to and engage with such robots, focusing on interactions with Pepper, a humanoid robot. Conducted in an all-dementia nursing home with residents experiencing varying stages of dementia, the study has collected direct observations and participant feedback. A common concern among clinicians, family members, and caregivers is that individuals with dementia may find robots frightening or unsettling, raising questions about their suitability for caregiving roles. However, the findings of this study suggest otherwise. Residents consistently identified the robots as "cute" and "child-like," with many expressing comfort and interest in interacting with them. These results highlight the potential for humanoid robots like Pepper to serve as non-threatening, engaging companions for individuals with dementia, addressing caregiving needs while enhancing their well-being. This study provides a foundation for further exploration into the acceptance and application of assistive robotics in dementia care settings.

BFGF alleviates diabetic endothelial dysfunction by downregulating Endoplasmic reticulum stress.

Diabetes is a chronic metabolic disorder characterized by hyperglycemia, resulting from absolute or relative insufficiency in insulin secretion and disorder in insulin utilization. Diabetes has emerged as a global public health issue, with its incidence rate escalating year on year. Its vascular complications pose a severe challenge in clinical practice and constitute one of the principal causes of death among diabetes patients. Basic fibroblast growth factor, a member of the fibroblast growth factor family, exhibits a robust protective effect on numerous diseases. Consequently, it has become a research focus in the treatment of vascular complications related to diabetes. Nevertheless, the specific mechanism underlying basic fibroblast growth factor's vascular protective effect remains unclear. This study aims to explore whether basic fibroblast growth factor can alleviate endothelial dysfunction in diabetes by inhibiting endoplasmic reticulum stress. The research outcomes demonstrated that basic fibroblast growth factor significantly decreased the production of endoplasmic reticulum stress in db/db mice and endothelial cells incubated with high glucose and palmitic acid, augmented nitric oxide production, and reduced endothelial cell apoptosis. Treatment with the endoplasmic reticulum stress inducer Tunicamycin nullified the basic fibroblast growth factor mediated reduction in endoplasmic reticulum stress generation and endothelial protective effects. In conclusion, these discoveries imply that the endothelial protective effect of basic fibroblast growth factor in diabetes can be partially ascribed to its inhibition of endoplasmic reticulum stress.

An Engineered RNase P Ribozyme Effectively Reduces Human Coronavirus 229E Gene Expression and Growth in Human Cells

The human coronavirus 229E (HCoV-229E) is a member of the human coronavirus family that includes SARS-CoV-2, the causative agent of COVID-19. Developing antiviral strategies and compounds is crucial to treat and prevent HCoV-229E infections and the associated diseases. Ribozymes derived from ribonuclease P (RNase P) catalytic RNA represent a novel class of promising gene-targeting agents by cleaving their target mRNA and knocking down the expression of the target mRNA. However, it has not been reported whether RNase P ribozymes block the infection and replication of HCoV-229E. We report here the engineering of an anti-HCoV-229E RNase P ribozyme to target an overlapping region of viral genomic RNA and the mRNA encoding the nucleocapsid (N) protein, which is vital for viral replication and growth. The engineered ribozyme actively hydrolyzed the viral RNA target in vitro. HCoV-229E-infected cells expressing the engineered, catalytically active ribozyme exhibited a reduction of about 85% in viral RNA levels and N protein expression, and a reduction of about 750-fold in infectious particle production, compared to cells expressing no ribozymes or a control, catalytically inactive ribozyme. Our study provides the first direct evidence of the therapeutic potential of RNase P ribozymes against human coronaviruses such as HCoV-229E.

Prognostic Implications and Therapeutic Potential of MXD Genes in Gastric Cancer.

MAX dimerization (MXD) genes play integral roles in various types of tumors. The expression patterns, prognostic value, potential mechanisms, and roles in immunotherapy of MXD genes in gastric cancer (GC) remain not fully elucidated. We aimed to explore the role of MXDs in GC. The Wilcoxon rank sum test and t-test were employed to evaluate the differential expression of the MXD gene family members in GC tissues compared to non-paired normal gastric tissues. cBioPortal was utilized for examining genetic alterations within the MXD gene family. R software, specifically version 3.6.3, was used to scrutinize the expression patterns of MXD genes in GC, their correlation with clinical parameters, and to generate a correlation heat map. The survival package (v3.2-10) and the Cox regression model were implemented to evaluate the prognostic significance of the MXD gene family. The pROC package (v1.17.0.1) was applied to assess the diagnostic potential of the MXD gene family. R software (v3.6.3) was also used to explore potential regulatory networks involving members of the MXD gene family and related genes. The GSVA package (v1.34.0) was leveraged to investigate the link between the expression of the MXD gene family and immune cell infiltration. Visualization was facilitated by the ggplot2 (v3.3.3), survminer (v0.4.9), and clusterProfiler (v3.14.3) packages. Gene Set Cancer Analysis (GSCA) was employed to determine the sensitivity of the MXD gene family's expression to drugs from the GDSC database. The expression levels of MXD genes were validated across various cell lines using quantitative real-time PCR (qRT-PCR). MXD1 was significantly upregulated in GC, while MXD3 and MXD4 were significantly downregulated. Significant correlations were identified between the expression levels of MXD3 and the T stage (p = 0.041) and age (p = 0.001) of GC patients. Additionally, a notable association was observed between MXD4 expression and the histologic grade (p = 0.006) in GC patients. Low MXD3 expression was associated with a poor prognosis in GC. Low MXD3 expression was an independent prognostic factor for poor outcomes in GC patients. MXD3 demonstrated some accuracy in predicting tumor and normal tissue outcomes (AUC = 0.884). MXDs mediate gastric carcinogenesis and progression by regulating immune cells and pathways, including endocytosis, cell cycle, and apoptosis. The expression of the MXD gene family was associated with immune cell infiltration and drug sensitivity. MXD3 and MXD4 expression levels were significantly downregulated in GC cell lines, while MXD1 expression was significantly upregulated. The MXD gene family may serve as novel biomarkers of poor prognosis and as potential immunotherapeutic targets for GC.

Excess of death and the experiential disruption of death and mourning rituals during the COVID-19 pandemic in South Africa.

In the context of South Africa's quadruple burden of disease, which includes a high prevalence of both infectious (particularly AIDS and tuberculosis) and non-communicable diseases, the COVID-19 pandemic has been signified by excess deaths. Although never officially acknowledged by the State, communities across the country have witnessed and experienced this excess. Departing from a syndemics approach, this paper focuses on the experiences of black African communities from low-resourced urban areas in selected central regions of South Africa.The paper delves into participants' experiences of the losing family and community members, as well as the disruption of their grief work resulting from the changes effected by the COVID-19 restrictive procedures on funerals and burials. Death and mourning practices, among the 20 participants in this study, are otherwise guided by the intertwining of Christian and African cultural traditions. Based on participant interviews, the paper reflects on the incompleteness of ritual associated with the disruption of COVID-19 restrictions and its impact on mourning in a context of excess death resulting in unaccomplished grief work In so doing, this paper raises critical issues regarding physical, emotional and mental health alongside pandemic responsibility, cultural diversity and human rights.

Determinants of Farmers’ Motivation for Litchi Cultivation in Kapasia, Bangladesh: An Analysis Based on Maslow’s Hierarchy of Needs

Litchi cultivation is highly profitable business in Gazipur District, Bangladesh specially in Kapasia upazila. This study aimed to assess the motivation of litchi farmers using Maslow’s Hierarchy of Needs Theory, identify their socio-economic characteristics, and explore the major constraints they face in litchi cultivation. Data were collected randomly from 110 litchi farmers through a semi structured interview schedule. The results indicated that farmers primarily motivated to fulfil physiological and safety needs like, fulfilling familys’ food requirements, ensuring shelter and cloth to the family members. It was observed that farmers safety needs and esteem needs were high in comparison to aesthetic, esteem and self-actualization needs. However, farmers showed lower interest to fulfil some aspects of self-actualization needs such as teaching or motivating farmers. Key obstacles reported by farmers included inflorescence drop, irrigation issues, drying of flower clusters and inadequate support from agricultural extension officers. The study recommends increasing training opportunities, enhancing the role of extension services and conducting need-based research to further motivate farmers.

Identification of a novel missense variant in the LMX1B gene associated with nail-patella syndrome in a Chinese family

BackgroundNail-patella syndrome (NPS) is an autosomal dominant disorder caused by the variants of the LMX1B gene, affecting several systems, including musculoskeletal, renal, and ocular systems. Despite the well-established genetic basis, the complicated relationship between genotype and phenotype still remains unclear. This study aimed to identify the genetic cause of NPS in a Chinese family and elucidate its potential contribution to the disease’s phenotypic spectrum.MethodsClinical data and peripheral blood samples were collected from the affected family. Whole-exome sequencing (WES) was conducted to identify potential pathogenic variants, followed by Sanger sequencing to validate the candidate variant. Bioinformatic tools were employed to predict the 3D structure alterations and pathogenicity of the variant. Wild-type and mutant LMX1B overexpression plasmids were constructed to investigate the functional consequences of the variant. Western blotting and immunofluorescence were conducted to measure the expression and localization of the protein.ResultsThe proband presented with clinical manifestations, including nail malformation, patella dysplasia, restricted elbow movement, and pes planus. Both his mother and sister exhibited symptoms related to the skeletal system. WES identified a novel c.812G>C (p.R271T) variant in the affected family members. Bioinformatic analyses revealed structural modification in the protein and predicted functional impairment. Western blotting showed no significant difference in the expression level between wild-type and mutant protein. However, immunofluorescence demonstrated distinct changes in the subcellular localization of c.812G>C mutant.ConclusionNPS is a rare multisystem disorder with variable clinical presentations. In this family, the skeletal system was mainly involved with variations among different members. Our study identified a novel c.812G > c variant in the LMX1B gene, changing the nuclear localization of the protein.

The Perspectives of Families in Decision-Making Conflicts Related to Palliative Care Patients With Mechanical Ventilation in Taiwan.

BackgroundFamily members experience decision-making conflicts regarding changes in patient care. If the medical team does not attempt to understand the family members' awareness of palliative care, family members may experience medical decision-making stress and dilemmas. This study examined the decision-making conflicts of the family members of patients dependent on prolonged mechanical ventilator regarding palliative care in Taiwan.MethodsA cross-sectional design was used in this study. Family members of such patients in the subacute respiratory care ward and the respiratory intensive care unit of a medical center in Taiwan were recruited. A structured questionnaire was used to collect data.ResultsAmong the family members of the 127 patients included, 57.5% hesitated to make palliative medical decisions and 61.4% experienced palliative medical decision conflicts. The absence of other chronic diseases, family members' inability to accept the movement of patients to palliative care, and family members' hesitation in palliative care medical decision-making resulted in decision-making conflicts. In this study, 127 prolonged mechanical ventilation-dependent patients (PMVDP) and their family members were examined. The results revealed that family members experienced palliative care medical decision-making difficulties (61.40% = <2.5). Predictors of palliative care decision-making conflict for PMVDP and their family members included the following: absence of other comorbid chronic diseases, the inability of family to accept palliative care on behalf of patients, and hesitation in palliative care medical decision-making by family members.ConclusionThe study results are able to help Taiwanese medical staff in evaluating such conflicts and palliative care medical decisions of PMVDP.

Uncovering the Molecular Interactions Underlying MBD2 and MBD3 Phase Separation.

Chromatin organization controls DNA's accessibility to regulatory factors to influence gene expression. Heterochromatin, or transcriptionally silent chromatin enriched in methylated DNA and methylated histone tails, self-assembles through multivalent interactions with its associated proteins into a condensed, but dynamic state. Liquid-liquid phase separation (LLPS) of key heterochromatin regulators, such as heterochromatin protein 1 (HP1), plays an essential role in heterochromatin assembly and function. Methyl-CpG-binding protein 2 (MeCP2), the most studied member of the methyl-CpG-binding domain (MBD) family of proteins, has been recently shown to undergo LLPS in the absence and presence of methylated DNA. These studies provide a new mechanistic framework for understanding the role of methylated DNA and its readers in heterochromatin formation. However, the details of the molecular interactions by which other MBD family members undergo LLPS to mediate genome organization and transcriptional regulation are not fully understood. Here, we focus on two MBD proteins, MBD2 and MBD3, that have distinct but interdependent roles in gene regulation. Using an integrated computational and experimental approach, we uncover the homotypic and heterotypic interactions governing MBD2 and MBD3 phase separation and DNA's influence on this process. We show that despite sharing the highest sequence identity and structural homology among all the MBD protein family members, MBD2 and MBD3 exhibit differing residue patterns resulting in distinct phase separation mechanisms. Understanding the molecular underpinnings of MBD protein condensation offers insights into the higher-order, LLPS-mediated organization of heterochromatin.