Microglia regulate central nervous system myelin growth and integrity.

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFß1-TGFßR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.

Cerebral Vascular Dysfunctions Detected in Human Small Vessel Disease and Implications for Preclinical Studies.

Cerebral small vessel disease (SVD) is highly prevalent and a common cause of ischemic and hemorrhagic stroke and dementia, yet the pathophysiology is poorly understood. Its clinical expression is highly varied, and prognostic implications are frequently overlooked in clinics; thus, treatment is currently confined to vascular risk factor management. Traditionally, SVD is considered the small vessel equivalent of large artery stroke (occlusion, rupture), but data emerging from human neuroimaging and genetic studies refute this, instead showing microvessel endothelial dysfunction impacting on cell-cell interactions and leading to brain damage. These dysfunctions reflect defects that appear to be inherited and secondary to environmental exposures, including vascular risk factors. Interrogation in preclinical models shows consistent and converging molecular and cellular interactions across the endothelial-glial-neural unit that increasingly explain the human macroscopic observations and identify common patterns of pathology despite different triggers. Importantly, these insights may offer new targets for therapeutic intervention focused on restoring endothelial-glial physiology.

The antimicrobial peptide cathelicidin drives development of experimental autoimmune encephalomyelitis in mice by affecting Th17 differentiation.

Multiple sclerosis (MS) is a highly prevalent demyelinating autoimmune condition; the mechanisms regulating its severity and progression are unclear. The IL-17-producing Th17 subset of T cells has been widely implicated in MS and in the mouse model, experimental autoimmune encephalomyelitis (EAE). However, the differentiation and regulation of Th17 cells during EAE remain incompletely understood. Although evidence is mounting that the antimicrobial peptide cathelicidin profoundly affects early T cell differentiation, no studies have looked at its role in longer-term T cell responses. Now, we report that cathelicidin drives severe EAE disease. It is released from neutrophils, microglia, and endothelial cells throughout disease; its interaction with T cells potentiates Th17 differentiation in lymph nodes and Th17 to exTh17 plasticity and IFN-γ production in the spinal cord. As a consequence, mice lacking cathelicidin are protected from severe EAE. In addition, we show that cathelicidin is produced by the same cell types in the active brain lesions in human MS disease. We propose that cathelicidin exposure results in highly activated, cytokine-producing T cells, which drive autoimmunity; this is a mechanism through which neutrophils amplify inflammation in the central nervous system.

Altered human oligodendrocyte heterogeneity in multiple sclerosis.

Oligodendrocyte pathology is increasingly implicated in neurodegenerative diseases as oligodendrocytes both myelinate and provide metabolic support to axons. In multiple sclerosis (MS), demyelination in the central nervous system thus leads to neurodegeneration, but the severity of MS between patients is very variable. Disability does not correlate well with the extent of demyelination1, which suggests that other factors contribute to this variability. One such factor may be oligodendrocyte heterogeneity. Not all oligodendrocytes are the same-those from the mouse spinal cord inherently produce longer myelin sheaths than those from the cortex2, and single-cell analysis of the mouse central nervous system identified further differences3,4. However, the extent of human oligodendrocyte heterogeneity and its possible contribution to MS pathology remain unknown. Here we performed single-nucleus RNA sequencing from white matter areas of post-mortem human brain from patients with MS and from unaffected controls. We identified subclusters of oligodendroglia in control human white matter, some with similarities to mouse, and defined new markers for these cell states. Notably, some subclusters were underrepresented in MS tissue, whereas others were more prevalent. These differences in mature oligodendrocyte subclusters may indicate different functional states of oligodendrocytes in MS lesions. We found similar changes in normal-appearing white matter, showing that MS is a more diffuse disease than its focal demyelination suggests. Our findings of an altered oligodendroglial heterogeneity in MS may be important for understanding disease progression and developing therapeutic approaches.

ß-importin Tnpo-SR promotes germline stem cell maintenance and oocyte differentiation in female Drosophila.

Germ cell development requires interplay between factors that balance cell fate and division. Early in their development, germ cells in many organisms divide mitotically with incomplete cytokinesis. Key regulatory events then lead to the specification of mature gametes, marked by the switch to a meiotic cell cycle program. Though the regulation of germ cell proliferation and meiosis are well understood, how these events are coordinated during development remains incompletely described. Originally characterized in their role as nucleo-cytoplasmic shuttling proteins, ß-importins exhibit diverse functions during male and female gametogenesis. Here, we describe novel, distinct roles for the ß-importin, Transportin-Serine/Arginine rich (Tnpo-SR), as a regulator of the mitosis to meiosis transition in the Drosophila ovary. We find that Tnpo-SR is necessary for germline stem cell (GSC) establishment and self-renewal, likely by controlling the response of GSCs to bone morphogenetic proteins. Depletion of Tnpo-SR results in germ cell counting defects and loss of oocyte identity. We show that in the absence of Tnpo-SR, proteins typically suppressed in germ cells when they exit mitosis fail to be down-regulated, and oocyte-specific factors fail to accumulate. Together, these findings provide new insight into the balance between germ cell division and differentiation and identify novel roles for ß-importins in germ cell development.

AimSeg: A machine-learning-aided tool for axon, inner tongue and myelin segmentation.

Electron microscopy (EM) images of axons and their ensheathing myelin from both the central and peripheral nervous system are used for assessing myelin formation, degeneration (demyelination) and regeneration (remyelination). The g-ratio is the gold standard measure of assessing myelin thickness and quality, and traditionally is determined from measurements made manually from EM images-a time-consuming endeavour with limited reproducibility. These measurements have also historically neglected the innermost uncompacted myelin sheath, known as the inner tongue. Nonetheless, the inner tongue has been shown to be important for myelin growth and some studies have reported that certain conditions can elicit its enlargement. Ignoring this fact may bias the standard g-ratio analysis, whereas quantifying the uncompacted myelin has the potential to provide novel insights in the myelin field. In this regard, we have developed AimSeg, a bioimage analysis tool for axon, inner tongue and myelin segmentation. Aided by machine learning classifiers trained on transmission EM (TEM) images of tissue undergoing remyelination, AimSeg can be used either as an automated workflow or as a user-assisted segmentation tool. Validation results on TEM data from both healthy and remyelinating samples show good performance in segmenting all three fibre components, with the assisted segmentation showing the potential for further improvement with minimal user intervention. This results in a considerable reduction in time for analysis compared with manual annotation. AimSeg could also be used to build larger, high quality ground truth datasets to train novel deep learning models. Implemented in Fiji, AimSeg can use machine learning classifiers trained in ilastik. This, combined with a user-friendly interface and the ability to quantify uncompacted myelin, makes AimSeg a unique tool to assess myelin growth.

Haemorrhage of human foetal cortex associated with SARS-CoV-2 infection.

Maternal viral infection and immune response are known to increase the risk of altered development of the foetal brain. Given the ongoing global pandemic of coronavirus disease 2019 (COVID-19), investigating the impact of SARS-CoV-2 on foetal brain health is of critical importance. Here, we report the presence of SARS-CoV-2 in first and second trimester foetal brain tissue in association with cortical haemorrhages. SARS-CoV-2 spike protein was sparsely detected within progenitors and neurons of the cortex itself, but was abundant in the choroid plexus of haemorrhagic samples. SARS-CoV-2 was also sparsely detected in placenta, amnion and umbilical cord tissues. Cortical haemorrhages were linked to a reduction in blood vessel integrity and an increase in immune cell infiltration into the foetal brain. Our findings indicate that SARS-CoV-2 infection may affect the foetal brain during early gestation and highlight the need for further study of its impact on subsequent neurological development.

Lessons from Peru to reduce under-5 mortality: understanding program implementation and context.

BACKGROUND: Health policymakers aiming to reduce under-5 mortality (U5M) often lack data regarding how successful interventions in other countries were implemented. The Exemplars in U5M Study identified countries that achieved significant reductions in amenable U5M. This case study in Peru used implementation research to explore the contextual factors and strategies that contributed to the successful implementation of key evidence-based interventions (EBIs). METHODS: This research utilized a hybrid implementation research framework and a mixed-methods approach to understand the factors associated with EBI implementation and the successful reduction of U5M between 2000-2015. A desk review of existing literature on EBIs and U5M in Peru was completed, and in-depth interviews were performed with key Peruvian informants to understand the implementation strategies employed and the contextual factors that facilitated or were barriers to success. For the purposes of this analysis, three EBIs were selected and evaluated: antenatal care visits (ANC), facility-based deliveries, and infant vaccination. RESULTS: Between 2000-2015, the percent of mothers attending at least four antenatal care visits rose from 69% to 96.9%, and the percent of facility-based deliveries increased from 56 to 91%. Three doses of the tetanus/diphtheria/pertussis vaccine, widely acknowledged as a key global health indicator, reached 90% by 2015. Key informants noted that economic growth, financial reforms, strong national commitment to reduce poverty in Peru, and national prioritization of maternal and child health, were important contextual factors that contributed to the successful reduction of U5M. They noted key strategies that helped achieve success during the implementation of EBIs, including utilization of data for decision-making, adaptation driven by cultural sensitivity to address gaps in coverage, and a focus on equity and anti-poverty initiatives with the participation of government, civil society, and political parties to assure continuity of policies. CONCLUSION: Several EBIs contributed to the successful reduction of U5M in Peru between 2000-2015. Strategies such as the focus on equity throughout the study period contributed to an increase in coverage of EBIs like ANC visits, facility-based deliveries and infant vaccination which worked to reduce U5M. Understanding how Peru successfully implemented programs that reduced preventable infant and child deaths could be useful to replicating this substantial public health success in other low- and middle-income countries.

Challenges and opportunities of English as the medium of instruction in diploma midwifery programs in Bangladesh: a mixed-methods study.

BACKGROUND: English is generally recognized as the international language of science and most research on evidence-based medicine is produced in English. While Bangla is the dominant language in Bangladesh, public midwifery degree programs use English as the medium of instruction (EMI). This enables faculty and student access to the latest evidence-based midwifery content, which is essential for provision of quality care later. Yet, it also poses a barrier, as limited English mastery among students and faculty limits both teaching and learning. METHODS: This mixed-methods study investigates the challenges and opportunities associated with the implementation of EMI in the context of diploma midwifery education in Bangladesh. Surveys were sent to principals at 38 public midwifery education institutions, and 14 English instructors at those schools. Additionally, ten key informant interviews were held with select knowledgeable stakeholders with key themes identified. RESULTS: Surveys found that English instructors are primarily guest lecturers, trained in general or business English, without a standardized curriculum or functional English language laboratories. Three themes were identified in the key informant interviews. First, in addition to students' challenges with English, faculty mastery of English presented challenges as well. Second, language labs were poorly maintained, often non-functional, and lacked faculty. Third, an alternative education model, such as the English for Specific Purposes (ESP) curriculum,  has potential to strengthen English competencies within midwifery schools. CONCLUSIONS: ESP, which teaches English for application in a specific discipline, is one option available in Bangladesh for midwifery education. Native language instruction and the middle ground of multilingualism are also useful options. Although a major undertaking, investing in an ESP model and translation of technical midwifery content into relevant mother tongues may provide faster and more complete learning. In addition, a tiered system of requirements for English competencies tied to higher levels of midwifery education could build bridges to students to help them access global evidence-based care resources. Higher levels might emphasize English more heavily, while the diploma level would follow a multilingualism approach, teach using an ESP curriculum, and have complementary emphasis on the mother tongue.

Novel roles for RNA binding proteins squid, hephaesteus, and Hrb27C in Drosophila oogenesis.

BACKGROUND: Reproductive capacity in many organisms is maintained by germline stem cells (GSCs). A complex regulatory network influences stem cell fate, including intrinsic factors, local signals, and hormonal and nutritional cues. Posttranscriptional regulatory mechanisms ensure proper cell fate transitions, promoting germ cell differentiation to oocytes. As essential RNA binding proteins with constitutive functions in RNA metabolism, heterogeneous nuclear ribonucleoproteins (hnRNPs) have been implicated in GSC function and axis specification during oocyte development. HnRNPs support biogenesis, localization, maturation, and translation of nascent transcripts. Whether and individual hnRNPs specifically regulate GSC function has yet to be explored. RESULTS: We demonstrate that hnRNPs are expressed in distinct patterns in the Drosophila germarium. We show that three hnRNPs, squid, hephaestus, and Hrb27C are cell-autonomously required in GSCs for their maintenance. Although these hnRNPs do not impact adhesion of GSCs to adjacent cap cells, squid and hephaestus (but not Hrb27C) are necessary for proper bone morphogenetic protein signaling in GSCs. Moreover, Hrb27C promotes proper GSC proliferation, whereas hephaestus promotes cyst division. CONCLUSIONS: We find that hnRNPs are independently and intrinsically required in GSCs for their maintenance in adults. Our results support the model that hnRNPs play unique roles in stem cells essential for their self-renewal and proliferation.

First in Human Subjects Testing of the UroMonitor: A Catheter-free Wireless Ambulatory Bladder Pressure Monitor.

PURPOSE: Urodynamics is the standard method of diagnosing bladder dysfunction, but involves catheters and retrograde bladder filling. With these artificial conditions, urodynamics cannot always reproduce patient complaints. We have developed a wireless, catheter-free intravesical pressure sensor, the UroMonitor, which enables catheter-free telemetric ambulatory bladder monitoring. The purpose of this study was twofold: to evaluate accuracy of UroMonitor pressure data, and assess safety and feasibility of use in humans. MATERIALS AND METHODS: Eleven adult female patients undergoing urodynamics for overactive bladder symptoms were enrolled. After baseline urodynamics, the UroMonitor was transurethrally inserted into the bladder and position was confirmed cystoscopically. A second urodynamics was then performed with the UroMonitor simultaneously transmitting bladder pressure. Following removal of urodynamics catheters, the UroMonitor transmitted bladder pressure during ambulation and voiding in private. Visual analogue pain scales (0-5) were used to assess patient discomfort. RESULTS: The UroMonitor did not significantly alter capacity, sensation, or flow during urodynamics. The UroMonitor was also easily inserted and removed in all subjects. The UroMonitor reproduced bladder pressure, capturing 98% (85/87) of voiding and nonvoiding urodynamic events. All subjects voided with only the UroMonitor in place with low post-void residual volume. Median ambulatory pain score with the UroMonitor was rated 0 (0-2). There were no post-procedural infections or changes to voiding behavior. CONCLUSIONS: The UroMonitor is the first device to enable catheter-free telemetric ambulatory bladder pressure monitoring in humans. The UroMonitor appears safe and well tolerated, does not impede lower urinary tract function, and can reliably identify bladder events compared to urodynamics.

Hiding in plain sight: genetics of childhood steroid-resistant nephrotic syndrome in Sub-Saharan Africa.

Steroid-resistant nephrotic syndrome (SRNS) is the most severe form of childhood nephrotic syndrome with an increased risk of progression to chronic kidney disease stage 5. Research endeavors to date have identified more than 80 genes that are associated with SRNS. Most of these genes regulate the structure and function of the podocyte, the visceral epithelial cells of the glomerulus. Although individuals of African ancestry have the highest prevalence of SRNS, especially those from Sub-Saharan Africa (SSA), with rates as high as 30-40% of all cases of nephrotic syndrome, studies focusing on the characterization and understanding of the genetic basis of SRNS in the region are negligible compared with Europe and North America. Therefore, it remains unclear if some of the variants in SRNS genes that are deemed pathogenic for SRNS are truly disease causing, and if the leading causes of monogenic nephrotic syndrome in other populations are the same for children in SSA with SRNS. Other implications of this lack of genetic data for SRNS in the region include the exclusion of children from the region from clinical trials aimed at identifying potential novel therapeutic agents for this severe form of nephrotic syndrome. This review underlines a need for concerted efforts to advance the genetic basis of SRNS in children in SSA. Such endeavors will complement global efforts at understanding the genetic basis of nephrotic syndrome.

Midwife-led pandemic telemedicine services for maternal health and gender-based violence screening in Bangladesh: an implementation research case study.

BACKGROUND: The COVID-19 pandemic disrupted maternal and newborn health services in Bangladesh, exacerbating the large gaps in service utilization that existed prior to the pandemic. As part of its response, Bangladesh initiated remote antenatal and postnatal care telemedicine services led by midwives in 36 sub-district hospitals across five of Bangladesh's 64 districts. Gender-based violence screening and referral were integrated into the service to address a reported rise in violence following the country's pandemic lockdown. METHODS: Mixed-methods implementation research was used to develop an intrinsic case study describing the design and implementation of the telemedicine program. Qualitative analysis comprised document review, key informant interviews, and focus group discussions. Quantitative analysis employed an interrupted time series analysis with segmented multi-variate regression to compare maternity care service use trends before and after implementation. Poisson regression analysis was used to examine the trend in number of gender-based violence remote screenings, sessions held, and cases identified. RESULTS: A statistically significant change in trend for onsite antenatal and postpartum care as well as women seeking care at the hospital as a result of postpartum hemorrhage arising in the community was observed following the introduction of telemedicine. Facility births and cases of eclampsia appropriately identified and managed also had significant increases. In addition, over 6917 women were screened for GBV, 223 received counseling and 34 referrals were made, showing a statistically significant increase in frequency over time following the implementation of the telemedicine program. Challenges included that not all midwives adopted GBV screening, some women were reluctant to discuss GBV, there was an unanticipated need to introduce a patient visit scheduling system in all intervention hospitals, and many women were not reachable by phone due to lack of access or network coverage. CONCLUSIONS: Maternal health and gender-based violence telemedicine led by midwives was an effective, low-cost intervention in Bangladesh for addressing pandemic and pre-pandemic gaps in service use. Other low and middle-income countries planning to implement remote maternal health interventions via midwives should consider whether a patient visit scheduling system needs to be introduced, as well as limitations around mobile phone access and connectivity. Future research should include care quality oversight and improvement, and a more well-informed strategy for facilitating effective GBV screening.

To support the continuation of sexual and reproductive health services following pandemic lockdowns, Bangladesh introduced a midwife-led telemedicine program. Through the program, midwives who were already employed within the health system delivered remote antenatal and postnatal care, including gender-based violence screening and referral. The program operated in 36 sub-district hospitals across five of Bangladesh's 64 districts. Intrinsic implementation research was used to develop a case study describing the design and implementation of the telemedicine program. Qualitative and quantitative methods comprised document review, key informant interviews, focus group discussions, and service use trends. Analysis of the data identified a statistically significant trend increase for most maternity care services. Although they did increase significantly over time, referrals for GBV were less than expected, which may have been related to some midwives not screening for GBV, and/or that many women were reluctant to discuss GBV. In addition, there was an unanticipated need to introduce a patient visit scheduling system in all intervention hospitals, and many women were not reachable by phone due to lack of access or network coverage. In spite of this, 6197 women were screened for GBV. Of those, 223 received counseling and 34 received referrals. Overall, telemedicine led by midwives was an effective, low-cost intervention for maternal health, and a step toward stronger GBV response in Bangladesh. Other low and middle-income countries planning to implement remote maternal health interventions via midwives should consider what is needed to facilitate comfort for both providers and women as related to GBV screening, as well as practical issues regarding introducing scheduling systems and limitations of mobile phone access and connectivity.

Expert Consensus Guidelines for Assessing Students on the Social Determinants of Health.

PHENOMENON: Assessment and evaluation guidelines inform programmatic changes necessary for educational effectiveness. Presently, no widely accepted guidelines exist for educators to assess learners and evaluate programs regarding social determinants of health (SDOH) during physician and physician assistant (PA) education. We sought to garner expert consensus about effective SDOH learner assessment and program evaluation, so as to make recommendations for best practices related to SDOH education. APPROACH: We used a Delphi approach to conduct our study (September 2019 to December 2020). To administer our Delphi survey, we followed a three-step process: 1) literature review, 2) focus groups and semi-structured interviews, 3) question development and refinement. The final survey contained 72 items that addressed SDOH content areas, assessment methods, assessors, assessment integration, and program evaluation. Survey participants included 14 SDOH experts at US medical schools and PA programs. The survey was circulated for three rounds seeking consensus, and when respondents reached consensus on a particular question, that question was removed from subsequent rounds. FINDINGS: The geographically diverse sample of experts reached consensus on many aspects of SDOH assessment and evaluation. The experts selected three important areas to assess learners' knowledge, skills, and attitudes about SDOH. They identified assessment methods that were "essential", "useful, but not essential", and "not necessary." The essential assessment methods are performance rating scales for knowledge and attitudes and skill-based assessments. They favored faculty and patients as assessors, as well as learner self-assessment, over assessments conducted by other health professionals. Questions about separation versus incorporation of SDOH assessment with other educational assessment did not yield consensus opinion. The experts reached consensus on priority outcome measures to evaluate a school's SDOH program which included student attitudes toward SDOH, Competence-Based Assessment Scales, and the percentage of graduates involved in health equity initiatives. INSIGHTS: Based on the Delphi survey results, we make five recommendations that medical and PA educators can apply now when designing learner assessments and evaluating SDOH programming. These recommendations include what should be assessed, using what methods, who should do the assessments, and how they should be incorporated into the curriculum. This expert consensus should guide future development of an assessment and evaluation toolkit to optimize SDOH education and clinical practice.Supplemental data for this article is available online at https://doi.org/10.1080/10401334.2022.2045490 .

Evolution in Health and Medical Humanities education: a proposal for accreditation.

The growth of Health and Medical Humanities baccalaureate and master's degrees in recent decades makes the present moment ideal for initiating field-defining conversations among health humanities constituents about the boundaries of this transdisciplinary field. Focusing on accreditation at the programme level rather than the individual level, we explore four models with different advantages for Health and Medical Humanities: a certification for practice; a network (umbrella organisation); a programme of merit (POM) model; and consultancy. We conclude that for a young field like health humanities that is transdisciplinary, does not have an established canon and does not lead to entry to a specific professional path (ie, gatekeeping), the POM model is the best fit. In contrast to a full accreditation model, POM credentialling leaves room for creativity, expansiveness, and diversity of approaches and will not restrict programmes from calling themselves health humanities programmes; POM enhances visibility rather than decides who can teach in the field and what they must teach. To implement this model, we suggest the creation of a semi-independent Health and Medical Humanities Program Accreditation Commission (HMHPAC) that would be administered by the Health Humanities Consortium. The HMHPAC should have three goals: ensure that health humanities educational programmes are of the highest quality, assist programmes in acquiring the resources they need from their institutions and help programmes attract potential students.

Exploring the Use of Living Shorelines for Stabilization and Nutrient Mitigation in New England.

As salt marsh habitats face challenges due to sea level rise, storm events, and coastal development, there is an effort to use nature-based approaches such as living shorelines to enhance salt marshes and provide coastal protection. A living shoreline restoration and seasonal monitoring was conducted between July 2016 and October 2018 at an eroding salt marsh on Martha's Vineyard, Massachusetts, Northeastern USA to assess changes in two essential ecosystem services: shoreline stabilization and nitrogen removal. Neither the living shoreline nor unaltered sites demonstrated significant sediment deposition at the marsh edge or on the marsh platform between 2017 and 2018. While we expected nitrogen removal via denitrification to improve at the living shoreline sites over time as abiotic and biotic conditions became more favorable, we found limited support for this hypothesis. We found higher rates of denitrification enzyme activity (DEA) at the living shoreline sites when compared to unaltered sites, but these rates did not increase over time. This study also provides a qualitative assessment of our living shoreline structural integrity through the years, particularly following storm events that greatly challenged our restoration efforts. We demonstrate that living shorelines fortified solely with natural materials may not be the most effective approach to maintain these ecosystem services for Northeastern USA salt marshes exposed to intense northeasterly storms. We suggest the restoration of salt marshes to improve major functions be a priority among managers and restoration practitioners. Initiatives promoting the use of nature-based restoration solution where environmental conditions permit should be encouraged.

Histologically resolved small RNA maps in primary focal segmental glomerulosclerosis indicate progressive changes within glomerular and tubulointerstitial regions.

Pathological heterogeneity is common in clinical tissue specimens and complicates the interpretation of molecular data obtained from the specimen. As a typical example, a kidney biopsy specimen often contains glomeruli and tubulointerstitial regions with different levels of histological injury, including some that are histologically normal. We reasoned that the molecular profiles of kidney tissue regions with specific histological injury scores could provide new insights into kidney injury progression. Therefore, we developed a strategy to perform small RNA deep sequencing analysis for individually scored glomerular and tubulointerstitial regions in formalin-fixed, paraffin-embedded kidney needle biopsies. This approach was applied to study focal segmental glomerulosclerosis (FSGS), the leading cause of nephrotic syndrome in adults. Large numbers of small RNAs, including microRNAs, 3'-tRFs, 5'-tRFs, and mitochondrial tRFs, were differentially expressed between histologically indistinguishable tissue regions from patients with FSGS and matched healthy controls. A majority of tRFs were upregulated in FSGS. Several small RNAs were differentially expressed between tissue regions with different histological scores in FSGS. Notably, with increasing levels of histological damage, miR-21-5p was upregulated progressively and miR-192-5p was downregulated progressively in glomerular and tubulointerstitial regions, respectively. This study marks the first genome scale molecular profiling conducted in histologically characterized glomerular and tubulointerstitial regions. Thus, substantial molecular changes in histologically normal kidney regions in FSGS might contribute to initiating tissue injury or represent compensatory mechanisms. In addition, several small RNAs might contribute to subsequent progression of glomerular and tubulointerstitial injury, and histologically mapping small RNA profiles may be applied to analyze tissue specimens in any disease.

Interplay between Brain Pericytes and Endothelial Cells in Dementia.

Prevalence of dementia continues to increase because of the aging population and limited treatment options. Cerebral small vessel disease and Alzheimer disease are the two most common causes of dementia with vascular dysfunction being a large component of both their pathophysiologies. The neurogliovascular unit, in particular the blood-brain barrier (BBB), is required for maintaining brain homeostasis. A complex interaction exists among the endothelial cells, which line the blood vessels and pericytes, which surround them in the neurogliovascular unit. Disruption of the BBB in dementia precipitates cognitive decline. This review highlights how dysfunction of the endothelial-pericyte crosstalk contributes to dementia, and focuses on cerebral small vessel disease and Alzheimer disease. It also examines loss of pericyte coverage and subsequent downstream changes. Furthermore, it examines how disruption of the intimate crosstalk between endothelial cells and pericytes leads to alterations in cerebral blood flow, transcription, neuroinflammation, and transcytosis, contributing to breakdown of the BBB. Finally, this review illustrates how cumulation of loss of endothelial-pericyte crosstalk is a major driving force in dementia pathology.

Oligodendroglia heterogeneity in the human central nervous system.

It is the centenary of the discovery of oligodendrocytes and we are increasingly aware of their importance in the functioning of the brain in development, adult learning, normal ageing and in disease across the life course, even in those diseases classically thought of as neuronal. This has sparked more interest in oligodendroglia for potential therapeutics for many neurodegenerative/neurodevelopmental diseases due to their more tractable nature as a renewable cell in the central nervous system. However, oligodendroglia are not all the same. Even from the first description, differences in morphology were described between the cells. With advancing techniques to describe these differences in human tissue, the complexity of oligodendroglia is being discovered, indicating apparent functional differences which may be of critical importance in determining vulnerability and response to disease, and targeting of potential therapeutics. It is timely to review the progress we have made in discovering and understanding oligodendroglial heterogeneity in health and neuropathology.