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Cohesin mediates chromatin loop formation across the genome by extruding chromatin between convergently oriented CTCF-binding elements. Recent studies indicate that cohesin-mediated loop extrusion in developing B cells presents immunoglobulin heavy chain (Igh) variable (V), diversity (D) and joining (J) gene segments to RAG endonuclease through a process referred to as RAG chromatin scanning. RAG initiates V(D)J recombinational joining of these gene segments to generate the large number of different Igh variable region exons that are required for immune responses to diverse pathogens. Antigen-activated mature B cells also use chromatin loop extrusion to mediate the synapsis, breakage and end joining of switch regions flanking Igh constant region exons during class-switch recombination, which allows for the expression of different antibody constant region isotypes that optimize the functions of antigen-specific antibodies to eliminate pathogens. Here, we review recent advances in our understanding of chromatin loop extrusion during V(D)J recombination and class-switch recombination at the Igh locus., (© 2022. Springer Nature Limited.)

Pulmonary fibrosis (PF) is a feared outcome of many pulmonary diseases which results in a reduction in lung compliance and capacity. The development of PF is relatively rare, but it can occur secondary to viral pneumonia, especially COVID-19 infection. While COVID-19 infection and its complications are still under investigation, we can look at a similar outbreak in the past to gain better insight as to the expected long-term outcomes of COVID-19 patient lung function. In the current article, we review the literature relative to PF via PubMed. We also performed a literature search for COVID-related pathological changes in the lungs. Finally, the paper was reviewed and summarized based on the studies' integrity, relative, or power calculations. This article provides a narrative review that endeavors to elucidate the current understanding of the pathophysiological mechanisms underlying PF and therapeutic strategies. We also discussed the potential for preventing progression to the fibrotic state within the context of the COVID-19 pandemic. With the massive scale of the COVID-19 pandemic, we expect there should more instances of PF due to COVID-19 infection. Patients who survive severe COVID-19 infection may suffer from a high incidence of PF.

Background: Homebound individuals with advanced Parkinson disease (PD) require intensive caregiving, the majority of which is provided by informal, family caregivers. PD caregiver strain is an independent risk factor for institutionalization. There are currently no effective interventions to support advanced PD caregivers. Studies in other neurologic disorders, however, have demonstrated the potential for peer mentoring interventions to improve caregiver outcomes. In the context of an ongoing trial of interdisciplinary home visits, we designed and piloted a nested trial of caregiver peer mentoring for informal caregivers of individuals with advanced PD., Objective: The aim of this study was to test the feasibility of peer mentoring for caregivers of homebound individuals with advanced PD and to evaluate its effects on anxiety, depression, and caregiver strain., Methods: This was a single-center, 16-week pilot study of caregiver peer mentoring nested within a year-long controlled trial of interdisciplinary home visits. We recruited 34 experienced former or current family caregivers who completed structured mentor training. Caregivers enrolled in the larger interdisciplinary home visit trial consented to receive 16 weeks of weekly, one-to-one peer mentoring calls with a trained peer mentor. Weekly calls were guided by a curriculum on advanced PD management and caregiver support. Fidelity to and satisfaction with the intervention were gathered via biweekly study diaries. Anxiety, depression, and caregiver strain were measured pre- and postmentoring intervention at home visits 2 and 3., Results: Enrollment and peer-mentor training began in 2018, and 65 caregivers enrolled in the overarching trial. The majority of mentors and mentees were White, female spouses or partners of individuals with PD; mentors had a mean of 8.7 (SD 6.4) years of caregiving experience, and 33 mentors were matched with at least 1 mentee., Conclusions: This is the first study of caregiver peer mentoring in PD and may establish an adaptable and sustainable model for disease-specific caregiver interventions in PD and other neurodegenerative diseases., Trial Registration: ClinicalTrials.gov NCT03189459; http://clinicaltrials.gov/ct2/show/NCT03189459., International Registered Report Identifier (irrid): DERR1-10.2196/34750., (©Jori E Fleisher, Faizan Akram, Jeanette Lee, Ellen C Klostermann, Serena P Hess, Erica Myrick, Melissa Levin, Bichun Ouyang, Jayne Wilkinson, Deborah A Hall, Joshua Chodosh. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.05.2022.)

Advancements in reprogramming somatic cells into induced pluripotent stem cells (iPSCs) have provided a strong framework for in vitro disease modeling, gene correction and stem cell-based regenerative medicine. In cases of skeletal muscle disorders, iPSCs can be used for the generation of skeletal muscle progenitors to study disease mechanisms, or implementation for the treatment of muscle disorders. We have recently developed an improved directed differentiation method for the derivation of skeletal myogenic progenitors from hiPSCs. This method allows for a short-term (2 weeks) and efficient skeletal myogenic induction (45-65% of the cells) in human pluripotent stem cells (ESCs/iPSCs) using small molecules to induce mesoderm and subsequently myotomal progenitors, without the need for any gene integration or modification. After initial differentiation, skeletal myogenic progenitors can be purified from unwanted cells using surface markers (CD10 + CD24 - ). These myogenic progenitors have been extensively characterized using in vitro gene expression/differentiation profiling as well as in vivo engraftment studies in dystrophic (mdx) and muscle injury (VML) rodent models and have been proven to be able to engraft and form mature myofibers as well as seeding muscle stem cells. The current protocol describes a detailed, step-by-step guide for this method and outlines important experimental details and troubleshooting points for its application in any human pluripotent stem cells.

In this perspective, the potential application of stem cells for the treatment of COVID-19 related pneumonia and their potential mechanism of action have been overviewed., (© 2020 Wiley Periodicals LLC.)

Background: Tuberculosis (TB) is an uncommon disease in the Western hemisphere that can present with peritoneal involvement, as tuberculous peritonitis(TBP) causing abdominal pain and fever. The healthcare and economic burden of TBP in the United States remains unknown., Methods: The National Inpatient Sample database was utilized to investigate TBP hospitalizations from 2002 to 2014. Economic expenditures, patient and hospital demographics, and associations of certain comorbidities with TBP were analyzed., Results: A total of 5878 hospitalizations for TBP occurred over the 12-year duration, with $420 million in-hospital charges. The median patient age was 45 years (interquartile range: 31.1-61.7), with the majority being Hispanic (27.15%). Hospitalizations occurred primarily in the Western (31.3%) and Southern (31.7%) United States. Patient comorbidities and the respective odds ratio associated with TBP included HIV (33.56), continuous peritoneal dialysis (10.49), malnutrition (7.38), liver cirrhosis (6.87), and liver cirrhosis sequelae (6.91). Nearly 6.37% of TBP hospitalizations also had active pulmonary TB., Conclusion: Although TBP is uncommon in the United States, it should be considered in patients presenting with abdominal pain and fever and a history of HIV, continuous peritoneal dialysis, malnutrition, liver cirrhosis, or liver cirrhosis sequelae., Competing Interests: None

Hebbian plasticity is widely considered to be the mechanism by which information can be coded and retained in neurons in the brain. Homeostatic plasticity moves the neuron back towards its original state following a perturbation, including perturbations produced by Hebbian plasticity. How then does homeostatic plasticity avoid erasing the Hebbian coded information? To understand how plasticity works in the brain, and therefore to understand learning, memory, sensory adaptation, development and recovery from injury, requires development of a theory of plasticity that integrates both forms of plasticity into a whole. In April 2016, a group of computational and experimental neuroscientists met in London at a discussion meeting hosted by the Royal Society to identify the critical questions in the field and to frame the research agenda for the next steps. Here, we provide a brief introduction to the papers arising from the meeting and highlight some of the themes to have emerged from the discussions.This article is part of the themed issue 'Integrating Hebbian and homeostatic plasticity'., (© 2017 The Author(s).)

Purpose: Hodgkin lymphoma (HL) is the commonest cancer in adolescents and young adults (AYAs), aged 15-29 years. While the survival rate is high, many survivors experience adverse late effects of therapy. Yet, this age group in general makes limited use of health services. This study sought to determine whether the need for health services by HL survivors was mismatched to their health service utilization, as hypothesized a priori., Methods: A population-based cohort of survivors (N = 43) younger than 39 years of age was sent a mailed survey for self-assessment of need, as expressed in health-related quality of life (HRQOL), and utilization of health services by validated instruments; the Health Utilities Index and Health and Social Service Utilization Survey, respectively. Survivors who were AYAs at diagnosis were compared to children and older adults., Results: AYAs had the lowest mean HRQOL score (0.79 on a scale of 0.00-1.00) compared to children (0.86) and older adults (0.94)-clinically meaningful differences. The difference in the single attribute score for cognition reached statistical significance (0.89 vs. 0.99 vs. 1.00, p = 0.02). AYAs also had lower mean overall annual costs for health services (CAN$601) than children (CAN$753) and older adults (CAN$936) did., Conclusions: Survivors of HL who were AYAs at diagnosis had a mismatch between high need for and low utilization of health services. Providers of healthcare to this population should be made aware of this discrepancy, and the survivors should be encouraged to seek the health services they need.

Monocular deprivation (MD) during a critical period of visual development triggers a rapid remodeling of cortical responses in favor of the open eye. We have previously shown that this process is enhanced by sleep and is inhibited when the sleeping cortex is reversibly inactivated. A related but distinct form of cortical plasticity is evoked when the originally deprived eye (ODE) is reopened, and the non-deprived eye is closed during the critical period (reverse monocular deprivation (RMD)). Recent studies suggest that different mechanisms regulate the initial loss of deprived eye responses following MD and the recovery of deprived eye responses following RMD. In this study we investigated whether sleep also enhances RMD plasticity in critical period cats. Using polysomnography combined with microelectrode recordings and intrinsic signal optical imaging in visual cortex we show that sleep does not enhance the recovery of ODE responses following RMD. These findings add to the growing evidence that different forms of plasticity in vivo are regulated by distinct mechanisms and that sleep has divergent roles upon different types of experience-dependent cortical plasticity.

The development of precise connections in the mammalian brain proceeds through refinement of initially diffuse patterns, a process that occurs largely within critical developmental windows. To elucidate the molecular pathways that orchestrate these early periods of circuit remodeling, we have examined the role of a calcium- and cAMP-regulated transcriptional pathway. We show that there is a window of CRE/CREB-mediated gene expression in the developing thalamus, which precedes neocortical expression. In the LGN, this wave of gene expression occurs prior to visual experience, but requires retinal function. Mutant mice with reduced CREB expression show loss of refinement of retinogeniculate projections. These results suggest an important role of the CRE/CREB transcriptional pathway in the coordination of experience-independent circuit remodeling during forebrain development.

Exogenous administration of the neurotrophins brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5 (NT-4/5), or blockade of their endogenous actions, have been reported to affect the anatomic organization and physiological responses of neurons in developing mammalian primary visual cortex. Experimental alteration of levels of these neurotrophic factors can also influence the morphology of the geniculocortical afferents that project from the lateral geniculate nucleus (LGN) to primary visual cortex. BDNF and NT-4/5 are ligands of the TrkB tyrosine kinase receptor. Although multiple populations of cortical neurons express TrkB, it is not known whether geniculocortical afferents express this receptor on their axon branches in visual cortex. We have anatomically labeled geniculocortical afferents of postnatal day 40 kittens with the anterograde neuronal tracer Phaseolus vulgaris leucoagglutinin (PHA-L) and performed double-label immunofluorescence with a panel of anti-TrkB antibodies. Confocal microscopy and object-based colocalization analysis were used to measure levels of TrkB-like immunoreactivity (IR) on geniculocortical afferents in layer IV of primary visual cortex. By using a conservative analysis involving a comparison of measured colocalization with the amount of colocalization expected based on random overlap of TrkB puncta and PHA-L--labeled afferents, 3 of 5 anti-TrkB antibodies tested showed significant colocalization with the geniculocortical axons. Results for the other two antibodies were indeterminate. The indices obtained for colocalization of TrkB and geniculocortical afferents were also compared with the equivalent index obtained for GAD65, a protein that has a similar overall expression pattern to that of TrkB but is not expressed on geniculocortical axons. This analysis indicated that TrkB was present on geniculocortical axons for all five TrkB antibodies tested. TrkB-like IR was also observed on neuronal somata in the LGN. These results indicate that TrkB receptors on geniculocortical afferents are potential mediators of the actions of BDNF and NT-4/5 in developing visual cortex., (Copyright 2001 Wiley-Liss, Inc.)

Experience can dramatically alter the responses of cortical neurons. During a critical period in the development of visual cortex, these changes are extremely rapid, taking place in 2 d or less. Anatomical substrates of these changes have long been sought, primarily in alterations in the principal visual input from the thalamus, but the significant changes that have been found take 1 week. Recent results indicate that the initial physiological changes in the cortical circuit take place outside of the primary input layer. We now find that rapid plasticity of binocular responses in the upper layers of cortex is mirrored by similarly rapid anatomical changes in the horizontal connections between ocular dominance columns in the upper layers, which reorganize within 2 d.

During a critical period of brain development, occluding the vision of one eye causes a rapid remodeling of the visual cortex and its inputs. Sleep has been linked to other processes thought to depend on synaptic remodeling, but a role for sleep in this form of cortical plasticity has not been demonstrated. We found that sleep enhanced the effects of a preceding period of monocular deprivation on visual cortical responses, but wakefulness in complete darkness did not do so. The enhancement of plasticity by sleep was at least as great as that produced by an equal amount of additional deprivation. These findings demonstrate that sleep and sleep loss modify experience-dependent cortical plasticity in vivo. They suggest that sleep in early life may play a crucial role in brain development.