Age of the oldest known Homo sapiens from eastern Africa.

Efforts to date the oldest modern human fossils in eastern Africa, from Omo-Kibish1-3 and Herto4,5 in Ethiopia, have drawn on a variety of chronometric evidence, including 40Ar/39Ar ages of stratigraphically associated tuffs. The ages that are generally reported for these fossils are around 197 thousand years (kyr) for the Kibish Omo I3,6,7, and around 160-155 kyr for the Herto hominins5,8. However, the stratigraphic relationships and tephra correlations that underpin these estimates have been challenged6,8. Here we report geochemical analyses that link the Kamoya's Hominid Site (KHS) Tuff9, which conclusively overlies the member of the Omo-Kibish Formation that contains Omo I, with a major explosive eruption of Shala volcano in the Main Ethiopian Rift. By dating the proximal deposits of this eruption, we obtain a new minimum age for the Omo fossils of 233 ± 22 kyr. Contrary to previous arguments6,8, we also show that the KHS Tuff does not correlate with another widespread tephra layer, the Waidedo Vitric Tuff, and therefore cannot anchor a minimum age for the Herto fossils. Shifting the age of the oldest known Homo sapiens fossils in eastern Africa to before around 200 thousand years ago is consistent with independent evidence for greater antiquity of the modern human lineage10.

Dysregulation of the Long Noncoding RNA X-Inactive-Specific Transcript Expression in Male Patients with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a sex-biased disease with female sex as a significant risk factor. Increased expression of the long noncoding RNA X-inactive-specific transcript (Xist), as induced by an intersectin-1s protein fragment with proliferative potential (EHITSN), may explain the sexual dimorphism of female pulmonary artery endothelial cells (ECs) and at least in part, the imbalance sex/ratio of PAH. Xist is essential for X-chromosome inactivation and dosage compensation of X-linked genes. Herein, increased Xist expression was detected in a subset of ECs and lung tissue samples of male patients with PAH. The role of different Xist expression levels in ECs of male patients with PAH (ECPAH) was studied in several lines of male ECPAH in conjunction with molecular, biochemical, morphologic, and functional approaches. Male ECPAH showed on average 10.3-fold increase in high Xist versus low Xist, a significant association between Xist levels and their proliferative potential, and a heterogeneous methylation of the Xist/XIST antisense RNA (Tsix) locus. Interestingly, Xist up-regulation in male ECPAH decreased the expression of Krueppel-like factor 2 (Klf2), via EHITSN interaction with enhancer of zeste polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of the polycomb repressive complex 2. Moreover, the studies demonstrate that EHITSN-triggered p38/ETS domain-containing protein Elk1/AP-1 transcription factor subunit (c-Fos) signaling is a pathologic mechanism central to ECPAH proliferation and the dynamic crosstalk with cell cycle regulatory proteins cyclin A1/cyclin D2 and Xist-EZH2-Klf2 interaction participate directly and differentially in establishing the proliferative profile of male ECPAH.

The Impact of Sex Chromosomes in the Sexual Dimorphism of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a sex-biased disease with a poorly understood female prevalence. Emerging research suggests that nonhormonal factors, such as the XX or XY sex chromosome complement and sex bias in gene expression, may also lead to sex-based differences in PAH incidence, penetrance, and progression. Typically, one of females' two X chromosomes is epigenetically silenced to offer a gender-balanced gene expression. Recent data demonstrate that the long noncoding RNA X-inactive specific transcript, essential for X chromosome inactivation and dosage compensation of X-linked gene expression, shows elevated levels in female PAH lung specimens compared with controls. This molecular event leads to incomplete inactivation of the females' second X chromosome, abnormal expression of X-linked gene(s) involved in PAH pathophysiology, and a pulmonary artery endothelial cell (PAEC) proliferative phenotype. Moreover, the pathogenic proliferative p38 mitogen-activated protein kinase/ETS transcription factor ELK1 (Elk1)/cFos signaling is mechanistically linked to the sexually dimorphic proliferative response of PAECs in PAH. Apprehending the complicated relationship between long noncoding RNA X-inactive specific transcript and X-linked genes and how this relationship integrates into a sexually dimorphic proliferation of PAECs and PAH sex paradox remain challenging. We highlight herein new findings related to how the sex chromosome complement and sex-differentiated epigenetic mechanisms to control gene expression are decisive players in the sexual dimorphism of PAH. Pharmacologic interventions in the light of the newly elucidated mechanisms are discussed.

The nucleoskeleton as a genome-associated dynamic 'network of networks'.

In the cytosol, actin polymers, intermediate filaments and microtubules can anchor to cell surface adhesions and interlink to form intricate networks. This cytoskeleton is anchored to the nucleus through LINC (links the nucleoskeleton and cytoskeleton) complexes that span the nuclear envelope and in turn anchor to networks of filaments in the nucleus. The metazoan nucleoskeleton includes nuclear pore-linked filaments, A-type and B-type lamin intermediate filaments, nuclear mitotic apparatus (NuMA) networks, spectrins, titin, 'unconventional' polymers of actin and at least ten different myosin and kinesin motors. These elements constitute a poorly understood 'network of networks' that dynamically reorganizes during mitosis and is responsible for genome organization and integrity.

Atrial tachyarrhythmias after lung transplantation in children: A common occurrence.

BACKGROUND: Atrial arrhythmia's (AA) following lung transplant in adults are a well-described clinical finding. In pediatrics, however, there are limited data with some reports suggesting that arrhythmias are rare. METHODS: We performed a single-center retrospective review of lung transplant recipients from January 2013 to June 2020. A detailed evaluation of clinical characteristics, presence of arrhythmias, and outcomes was completed. Arrhythmias were documented based on inpatient telemetry or remote Holter monitoring. Analyses assessing risk factors for arrhythmias and associations with clinical outcomes were performed. RESULTS: Ninety-one lung transplants were performed in 90 patients. Post-operative AA occurred following 19% transplants. Ectopic atrial tachycardia was seen in 14%, atrial flutter in 2%, and a combination in 2%. The majority of these arrhythmias occurred within the first 45 days post-operatively. Antiarrhythmic treatment was required in 59%, but none required ablation or electrical cardioversion. In patients followed for a year or more, 88% had resolution of their arrhythmia. Arrhythmias were not associated with mortality. In further analysis, however, the presence of arrhythmia was associated with an increased length of ICU stay (median of 12 days (IQR 6, 23) versus 5 days (IQR 4, 9); p = .019) and overall length of hospital stay (median of 26 days (IQR 19, 36) versus 17 days (IQR 19, 36); p = .043). CONCLUSIONS: Atrial tachyarrhythmias after lung transplantation are common in the pediatric population and usually occur early. Although they frequently require medical therapy and are associated with longer stays, there is no associated increased mortality. In addition, the arrhythmias typically self-resolve.

Decreased Heart Rate Variability in Children with Acute Decompensated Heart Failure is Associated with Poor Outcomes.

Heart rate variability (HRV) is a noninvasive indicator of the health of neurocardiac interactions of the autonomic nervous system. In adults, decreased HRV correlates with increased cardiovascular mortality. However, the relationship between HRV and outcomes in children with acute decompensated heart failure (ADHF) has not been described. Patients < 21 years old hospitalized with ADHF from 2013 to 2019 were included (N = 79). Primary outcome was defined as death, heart transplant, or mechanical circulatory support (MCS). The median standard deviation of the R-to-R interval in 5-min intervals (SDNN) was calculated from telemetry data obtained across the first 24 h of admission. Patients who met the primary outcome had significantly lower median SDNN (13.8 [7.8, 29.1]) compared to those who did not (24.6 [15.3, 84.4]; p = 0.004). A median SDNN of 20 ms resulted in a sensitivity of 68% and specificity of 69%. Median SDNN < 20 ms represented decreased freedom from primary outcome (p = 0.043) and a hazard ratio of 2.2 in multivariate analysis (p = 0.016). Pediatric patients with ADHF who died, underwent heart transplant, or required MCS had significantly decreased HRV at presentation compared to those that did not. This supports HRV as a noninvasive tool to improve prognostication in children in ADHF.

Sex differences in the proliferation of pulmonary artery endothelial cells: implications for plexiform arteriopathy.

The sex-biased disease pulmonary arterial hypertension (PAH) is characterized by the proliferation and overgrowth of dysfunctional pulmonary artery endothelial cells (PAECs). During inflammation associated with PAH, granzyme B cleaves intersectin-1 to produce N-terminal (EHITSN) and C-terminal (SH3A-EITSN) protein fragments. In a murine model of PAH, EHITSN triggers plexiform arteriopathy via p38-ELK1-c-Fos signaling. The SH3A-EITSN fragment also influences signaling, having dominant-negative effects on ERK1 and ERK2 (also known as MAPK3 and MAPK1, respectively). Using PAECs engineered to express tagged versions of EHITSN and SH3A-EITSN, we demonstrate that the two ITSN fragments increase both p38-ELK1 activation and the ratio of p38 to ERK1 and ERK2 activity, leading to PAEC proliferation, with female cells being more responsive than male cells. Furthermore, expression of EHITSN substantially upregulates the expression and activity of the long non-coding RNA Xist in female PAECs, which in turn upregulates the X-linked gene ELK1 and represses expression of krüppel-like factor 2 (KLF2). These events are recapitulated by the PAECs of female idiopathic PAH patients, and may account for their proliferative phenotype. Thus, upregulation of Xist could be an important factor in explaining sexual dimorphism in the proliferative response of PAECs and the imbalanced sex ratio of PAH.

Ripple mapping: A precise tool for atrioventricular nodal reentrant tachycardia ablation.

INTRODUCTION: Ablation for atrioventricular nodal reentrant tachycardia (AVNRT) classically utilizes evaluation of signal morphology within the anatomic region of the slow pathway (SP), which involves subjectivity. Ripple mapping (RM; CARTO-3© Biosense Webster Inc) displays each electrogram at its three-dimensional coordinate as a bar changing in length according to its voltage-time relationship. This allows prolonged, low-amplitude signals to be displayed in their entirety, helping identify propagation in low-voltage areas. We set out to evaluate the ability of RM to locate the anatomic site of the SP and assess its use in guiding ablation for AVNRT. METHODS: Patients ≤18 years with AVNRT in the EP laboratory between 2017 and 2021 were evaluated. RM was performed to define region of SP conduction in patients from 2019 to 2021, whereas standard electro-anatomical mapping was used from 2017 to 2019. All ablations were performed using cryotherapy. Demographics, outcomes, and analysis of variance in number of test lesions until success was compared between groups. RESULTS: A total of 115 patients underwent AVRNT ablation during the study; 46 patients were in the RM group and 69 were in the control group. There were no demographic differences between groups. All procedures, in both groups, were acutely successful. In RM group, 89% of first successful lesions were within 4 mm of the predicted site. There was significantly reduced variability in number of test lesions until success in the RM group (p = .01). CONCLUSION: RM is a novel technique that can help identify SP location, allowing for successful ablation of AVNRT with decreased variability.

Considerations to Support Use of Patient-Reported Outcomes Measurement Information System Pediatric Measures in Ambulatory Clinics.

OBJECTIVE: To identify challenges to the use of Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric measures in the ambulatory pediatric setting and possible solutions to these challenges. STUDY DESIGN: Eighteen semistructured telephone interviews of health system leaders, measurement implementers, and ambulatory pediatric clinicians were conducted. Five coders used applied thematic analysis to iteratively identify and refine themes in interview data. RESULTS: Most interviewees had roles in leadership or the implementation of patient-centered outcomes; 39% were clinicians. Some had experience using PROMIS clinically (44%) and 6% were considering this use. Analyses yielded 6 themes: (1) selection of PROMIS measures, (2) method of administration, (3) use of PROMIS Parent Proxy measures, (4) privacy and confidentiality of PROMIS responses, (5) interpretation of PROMIS scores, and (6) using PROMIS scores clinically. Within the themes, interviewees illuminated specific unique considerations for using PROMIS with children, including care transitions and privacy. CONCLUSIONS: Real-world challenges continue to hamper PROMIS use. Ongoing efforts to disseminate information about the integration of PROMIS measures in clinical care is critical to impacting the health of children.

Supply-chain strategies for essential medicines in rural western Kenya during COVID-19.

PROBLEM: The coronavirus disease 2019 (COVID-19) pandemic has disrupted health systems worldwide and threatened the supply of essential medicines. Especially affected are vulnerable patients in low- and middle-income countries who can only afford access to public health systems. APPROACH: Soon after physical distancing and curfew orders began on 15 March 2020 in Kenya, we rapidly implemented three supply-chain strategies to ensure a continuous supply of essential medicines while minimizing patients' COVID-19 exposure risks. We redistributed central stocks of medicines to peripheral health facilities to ensure local availability for several months. We equipped smaller, remote health facilities with medicine tackle boxes. We also made deliveries of medicines to patients with difficulty reaching facilities. LOCAL SETTING: Τo implement these strategies we leveraged our 30-year partnership with local health authorities in rural western Kenya and the existing revolving fund pharmacy scheme serving 85 peripheral health centres. RELEVANT CHANGES: In April 2020, stocks of essential chronic and non-chronic disease medicines redistributed to peripheral health facilities increased to 835 140 units, as compared with 316 330 units in April 2019. We provided medicine tackle boxes to an additional 46 health facilities. Our team successfully delivered medications to 264 out of 311 patients (84.9%) with noncommunicable diseases whom we were able to reach. LESSONS LEARNT: Our revolving fund pharmacy model has ensured that patients' access to essential medicines has not been interrupted during the pandemic. Success was built on a community approach to extend pharmaceutical services, adapting our current supply-chain infrastructure and working quickly in partnership with local health authorities.

Association between post-hospital clinic and telephone follow-up provider visits with 30-day readmission risk in an integrated health system.

BACKGROUND: Follow-up visits with clinic providers after hospital discharge may not be feasible for some patients due to functional limitations, transportation challenges, need for physical distancing, or fear of exposure especially during the current COVID-19 pandemic. METHODS: The aim of the study was to determine the effects of post-hospital clinic (POSH) and telephone (TPOSH) follow-up provider visits versus no visit on 30-day readmission. We used a retrospective cohort design based on data from 1/1/2017 to 12/31/2019 on adult patients (n = 213,513) discharged home from 15 Kaiser Permanente Southern California hospitals. Completion of POSH or TPOSH provider visits within 7 days of discharge was the exposure and all-cause 30-day inpatient and observation stay readmission was the primary outcome. We used matching weights to balance the groups and Fine-Gray subdistribution hazard model to assess for readmission risk. RESULTS: Unweighted all-cause 30-day readmission rate was highest for patients who completed a TPOSH (17.3%) followed by no visit (14.2%), non-POSH (evaluation and management visits that were not focused on the hospitalization: 13.6%) and POSH (12.6%) visits. The matching weighted models showed that the effects of POSH and TPOSH visits varied across patient subgroups. For high risk (LACE 11+) medicine patients, both POSH (HR: 0.77, 95% CI: 0.71, 0.85, P < .001) and TPOSH (HR: 0.91, 95% CI: 0.83, 0.99, P = .03) were associated with 23 and 9% lower risk of 30-day readmission, respectively, compared to no visit. For medium to low risk medicine patients (LACE< 11) and all surgical patients regardless of LACE score or age, there were no significant associations for either visit type with risk of 30-day readmission. CONCLUSIONS: Post-hospital telephone follow-up provider visits had only modest effects on 30-day readmission in high-risk medicine patients compared to clinic visits. It remains to be determined if greater use and comfort with virtual visits by providers and patients as a result of the pandemic might improve the effectiveness of these encounters.

The Relationship Between Household Microfinance Group Participation and Vaccine Adherence Among Children in Rural Western Kenya.

INTRODUCTION: High childhood vaccine adherence is critical for disease prevention, and poverty is a key barrier to vaccine uptake. Interventions like microfinance programs that aim to lift individuals out of poverty could thus improve vaccine adherence of the children in the household. BIGPIC Family Program in rural Western Kenya provides group-based microfinance services while working to improve access to healthcare and health screenings for the local community. The aim of the present paper is to evaluate the association between household participation in BIGPIC's microfinance program and vaccine adherence among children in the household. We hypothesize that microfinance group participation will have a positive impact on vaccine adherence among children in the household. METHODS: From 2018 to 2019, we surveyed a sample of 300 participants from two rural communities in Western Kenya, some of whom were participants in the BIGPIC Family's microfinance program. The primary outcome of interest was vaccine adherence of children in the household. Log-binomial models were used to estimate the relationship between microfinance group participation and vaccine adherence, adjusted for key covariates. We also assessed whether the relationship differed by gender of the adult respondent. RESULTS: Microfinance group members were more likely to have all children in their households fully vaccinated [aPR (95% CI): 1.68 (1.20,2.35)] compared to non-microfinance group members. Further, the association was stronger when women were the microfinance members [PR (95% CI): 1.87 (1.27,2.76)] compared to men [PR (95% CI): 1.24 (0.81,1.90)]. CONCLUSIONS: Microfinance participation was associated with higher childhood vaccine adherence in rural Western Kenya. Microfinance interventions should be further explored as strategies to improve child health and well-being in low- and middle-income countries.

Evaluating atrial fibrillations through strange attractors dynamics.

Nonlinear dynamics is nowadays widely employed in the study of biological phenomena. In such context, taking into account that abnormal heart rhythms display chaotic behaviours, in our opinion, the specific attractor dynamics can constitute a method for evaluating various cardiac afflictions. By using mathematical procedures specific to nonlinear dynamics we devise a new method for evaluating atrial fibrillations. Using data from ECG signals, we construct strange attractors corresponding to the phase space, specific to the analyzed signals. We show that their dynamics reflect abnormal heart rhythms. The skewness and kurtosis values are in accordance with pulse rate distributions from histograms of the analyzed signals. The Lyapunov exponent has positive values, close to zero for normal heart rhythm and with values over one order of magnitude higher in the case of fibrillation crises, highlighting a chaotic behavior for cardiac muscle dynamics. All the employed statistical parameters were calculated for a total of 5 cases (ECG signals) and statistical correlations were made using Python programming language. The presented results show that by applying nonlinear dynamics methods for analyzing the heart electrical activity we can obtain valuable information regarding fibrillation crises.

Plexiform Arteriopathy in Rodent Models of Pulmonary Arterial Hypertension.

As time progresses, our understanding of disease pathology is propelled forward by technological advancements. Much of the advancements that aid in understanding disease mechanics are based on animal studies. Unfortunately, animal models often fail to recapitulate the entirety of the human disease. This is especially true with animal models used to study pulmonary arterial hypertension (PAH), a disease with two distinct phases. The first phase is defined by nonspecific medial and adventitial thickening of the pulmonary artery and is commonly reproduced in animal models, including the classic models (ie, hypoxia-induced pulmonary hypertension and monocrotaline lung injury model). However, many animal models, including the classic models, fail to capture the progressive, or second, phase of PAH. This is a stage defined by plexogenic arteriopathy, resulting in obliteration and occlusion of the small- to mid-sized pulmonary vessels. Each of these two phases results in severe pulmonary hypertension that directly leads to right ventricular hypertrophy, decompensated right-sided heart failure, and death. Fortunately, newly developed animal models have begun to address the second, more severe, side of PAH and aid in our ability to develop new therapeutics. Moreover, p38 mitogen-activated protein kinase activation emerges as a central molecular mediator of plexiform lesions in both experimental models and human disease. Therefore, this review will focus on plexiform arteriopathy in experimental animal models of PAH.

The efficacy of onabotulinumtoxinA in patients with previous failed augmentation cystoplasty: Cohort series and literature review.

AIMS: To investigate the role of onabotulinumtoxinA (BTX-A) injections in patients with failed augmentation cystoplasty for neuropathic or idiopathic detrusor overactivity (NDO or IDO). METHODS: A retrospective review of all cystoplasty patients who underwent onabotulinumtoxinA injection at a tertiary center between 2008 and 2019 was performed. Details including indications and time from cystoplasty, video-urodynamic parameters, onabotulinumtoxinA dose, and clinical outcomes were analyzed. Telephone interview was performed for patients that requested repeat onabotulinumtoxinA injections. The interview included a modified PGIC7 and UDI6 questionnaires. A positive clinical response was considered improvement of overactive symptoms sufficient to merit repeat onabotulinumtoxinA injection and a modified PGIC7 of four or above. RESULTS: Thirty patients were identified (11 men and 19 women). The indications for augmentation were IDO (n = 18) or NDO (n = 12). Mean age at the time of cystoplasty was 42 years (range, 10-61). Interval between cystoplasty and initial onabotulinumtoxinA was 98 months (range, 3-271). Video-urodynamics before onabotulinumtoxinA revealed low compliance in 13 patients, DO in 22 patients, and combined low compliance/DO in 10. The median maximum cystometric bladder capacity was 338 mL (range, 77-570 mL). Thirteen patients responded to onabotulinumtoxinA injections. Higher peak DO pressure was associated with a significantly higher chance that the patient would experience benefit from the injections P = .026). The patients that responded to onabotulinumtoxin A underwent a total of 115 procedures (mean, 8.8 injections) over a mean 88 months (range, 20-157 months). CONCLUSIONS: Forty-three percent of patients responded well to intra-detrusor onabotulinumtoxinA injections. This avoided the need for more invasive surgery and had a positive impact on their quality of life.

Health-related quality of life, pain, and fatigue in young adults with cerebral palsy.

AIM: To describe health-related quality of life (HRQoL), pain, fatigue, and other health variables in young adults with cerebral palsy (CP), and to explore associations with the Gross Motor Function Classification System - Expanded and Revised (GMFCS-ER) and physical activity. METHOD: This was a cross-sectional study of 61 young adults at a mean age of 21 years 2 months (standard deviation 8mo, range 20-22y) with CP, from a geographically defined area. Data collection included: Short Form 36 version 2 for HRQoL, Brief Pain Inventory - Short Form, Fatigue Severity Scale, level of physical activity, medical history, and physical examination. RESULTS: Overall HRQoL equalled that of population norms; however self-reported physical health was lower in GMFCS-ER levels III to V compared to GMFCS-ER levels I to II. Self-reported mental health was, inversely, lower in GMFCS-ER levels I to II compared to GMFCS-ER levels III to V. Pain prevalence was 49%, and pain was present across all GMFCS-ER levels. Fatigue, as well as sleep problems, had 41% prevalence, with fatigue severity decreasing with increasing level of physical activity. INTERPRETATION: General HRQoL in young adults with CP was comparable to population norms. Pain and fatigue are important to address in high motor-functioning individuals also. Physical activity could be a possible protective factor against fatigue. WHAT THIS PAPER ADDS: Health-related quality of life in young adults with cerebral palsy (CP) was comparable to population norms. Pain, fatigue, and sleep problems occurred at all Gross Motor Function Classification System levels. There is a possible protective effect of physical activity on fatigue.

The relationship between a microfinance-based healthcare delivery platform, health insurance coverage, health screenings, and disease management in rural Western Kenya.

BACKGROUND: Structural barriers often prevent rural Kenyans from receiving healthcare and diagnostic testing. The Bridging Income Generation through grouP Integrated Care (BIGPIC) Family intervention facilitates microfinance groups, provides health screenings and treatment, and delivers education about health insurance coverage to address some of these barriers. This study evaluated the association between participation in BIGPIC microfinance groups and health screening/disease management outcomes. METHODS: From November 2018 to March 2019, we interviewed a sample of 300 members of two rural communities in Western Kenya, 100 of whom were BIGPIC microfinance members. We queried participants about their experiences with health screening and disease management for HIV, diabetes, hypertension, tuberculosis, and cervical cancer. We used log-binomial regression models to estimate the association between microfinance membership and each health outcome, adjusting for key covariates. RESULTS: Microfinance members were more likely to be screened for most of the health conditions we queried, including those provided by BIGPIC [e.g. diabetes: aPR (95% CI): 3.46 (2.60, 4.60)] and those not provided [e.g. cervical cancer: aPR (95% CI): 2.43 (1.21, 4.86)]. Microfinance membership was not significantly associated with health insurance uptake and disease management outcomes. CONCLUSIONS: In rural Kenya, a microfinance program integrated with healthcare delivery may be effective at increasing health screening. Interventions designed to thoughtfully and sustainably address structural barriers to healthcare will be critical to improving the health of those living in low-resource settings.

Endocytic deficiency induced by ITSN-1s knockdown alters the Smad2/3-Erk1/2 signaling balance downstream of Alk5.

Recently, we demonstrated in cultured endothelial cells and in vivo that deficiency of an isoform of intersectin-1, ITSN-1s, impairs caveolae and clathrin-mediated endocytosis and functionally upregulates compensatory pathways and their morphological carriers (i.e. enlarged endocytic structures, membranous rings or tubules) that are normally underrepresented. We now show that these endocytic structures internalize the broadly expressed transforming growth factor ß receptor I (TGFß-RI or TGFBR1), also known as Alk5, leading to its ubiquitylation and degradation. Moreover, the apoptotic or activated vascular cells of the ITSN-1s-knockdown mice release Alk5-bearing microparticles to the systemic circulation. These interact with and transfer Alk5 to endocytosis-deficient endothelial cells, resulting in lung endothelial cell survival and phenotypic alteration towards proliferation through activation of Erk1 and Erk2 (also known as MAPK3 and MAPK1, respectively). We also show that non-productive assembly of the Alk5-Smad-SARA (Smad anchor for receptor activation, also known as ZFYVE9) signaling complex and preferential formation of the Alk5-mSos-Grb2 complex account for Erk1/2 activation downstream of Alk5 and proliferation of pulmonary endothelial cells. Taken together, our studies demonstrate a functional relationship between the intercellular transfer of Alk5 by microparticles and endothelial cell survival and proliferation, and define a novel molecular mechanism for TGFß and Alk5-dependent Erk1/2(MAPK) signaling that is significant for proliferative signaling and abnormal growth.

[Comparative evaluation of dermoscopy and capillaroscopy in Raynaud's phenomenon]. / Évaluation comparative de la dermatoscopie et de la capillaroscopie dans le phénomène de Raynaud.

OBJECTIVE: Raynaud's phenomenon (RP) is a common cause for consultation. Capillaroscopy is a well-established technique to detect capillary abnormalities suggestive of a connective tissue disease, but it is sometimes unavailable. The aim of this study was to compare dermoscopy and capillaroscopy in the assessment of RP. METHODS: This was a prospective single-centre observational study in adult patients consulting for RP at the Hôpital Nord Franche-Comté between January 2014 and June 2015. Dermoscopy was performed at dermatological consultations and capillaroscopy was prescribed. For each capillaroscopy and dermoscopy, the following parameters were examined: normal appearance, giant capillaries, avascular areas, dystrophic capillaries or tortuosity and haemorrhages. Kappa coefficients were calculated. RESULTS: Twenty-six patients participated in this study. The kappa coefficient was 0.76 for "normal" status, 0.78 for tortuosity, 0.70 for giant capillaries, 0.48 for haemorrhage and 0.62 for avascular areas. The global kappa coefficient was 0.33. Detection of these abnormalities with capillaroscopy was significantly associated with abnormal dermoscopic status (P<0.05). The sensitivity of dermoscopy for the detection of "abnormal" capillaroscopic status was 0.87. CONCLUSION: The correlation coefficients were good. Despite poor global concordance, 80% of patients had the same status, normal or abnormal, for both capillaroscopy and dermoscopy, which resulted in the same clinical management. Dermoscopy is thus a valuable tool screening for periungual anomalies and provides support for clinical examination by the dermatologist, although the reference method continues to be capillaroscopy.

The molecular basis of emerin-emerin and emerin-BAF interactions.

Emerin is a conserved membrane component of nuclear lamina structure. Here, we report an advance in understanding the molecular basis of emerin function: intermolecular emerin-emerin association. There were two modes: one mediated by association of residues 170-220 in one emerin molecule to residues 170-220 in another, and the second involving residues 170-220 and 1-132. Deletion analysis showed residues 187-220 contain a positive element essential for intermolecular association in cells. By contrast, deletion of residues 168-186 inactivated a proposed negative element, required to limit or control association. Association of GFP-emerin with nuclear BAF in cells required the LEM domain (residues 1-47) and the positive element. Emerin peptide arrays revealed direct binding of residues 170-220 to residues 206-225 (the proposed positive element), residues 147-174 (particularly P(153)MYGRDSAYQSITHYRP(169)) and the LEM domain. Emerin residues 1-132 and 159-220 were each sufficient to bind lamin A or B1 tails in vitro, identifying two independent regions of molecular contact with lamins. These results, and predicted emerin intrinsic disorder, support the hypothesis that there are multiple 'backbone' and LEM-domain configurations in a proposed intermolecular emerin network at the nuclear envelope.