Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis.

One of the hallmarks of intractable psoriasis is neutrophil infiltration in skin lesions. However, detailed molecular mechanisms of neutrophil chemotaxis and activation remain unclear. Here, we demonstrate a significant upregulation of epidermal fatty acid binding protein (E-FABP, FABP5) in the skin of human psoriasis and psoriatic mouse models. Genetic deletion of FABP5 in mice by global knockout and keratinocyte conditional (Krt6a-Cre) knockout, but not myeloid cell conditional (LysM-Cre) knockout, attenuates psoriatic symptoms. Immunophenotypic analysis shows that FABP5 deficiency specifically reduces skin recruitment of Ly6G+ neutrophils. Mechanistically, activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis and activation in an FABP5-dependent manner. Proteomic analysis further identifies that FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling activation. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Collectively, these data demonstrate dysregulated FABP5 as a molecular mechanism promoting NF-κB signaling and neutrophil infiltration in psoriasis pathogenesis.

Sexual Function and Help-Seeking Behaviors following Childbirth: A Cross-Sectional Study.

This study examined 573 postpartum women's perceptions of changes in their sexual function and their help-seeking behaviors. Women residing in Ohio, Michigan, or Pennsylvania, USA, completed an online survey. Most women reported decreased postpartum sexual desire and/or arousal. Among women reporting decreased sexual function, most did not seek help from informal sources of support or health care professions (HCPs). Of those who did seek help from an HCP, in each domain of sexual function, only around half received helpful treatment. Women who did not seek help for their decreased sexual desire or arousal reported greater negative perceived impact of pregnancy/childbirth on their sexual function than women who did seek help.

Continuing perioperative estrogen therapy does not increase venous thromboembolic events in transgender patients: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study is to compare the risk of venous thromboembolic events (VTE) between patients suspending and continuing estrogen therapy perioperatively, in male to female gender-affirming surgery (vaginoplasty). MATERIALS AND METHODS: The authors conducted a systematic review and meta-analysis of existing research on male to female gender-affirming study, which compared the risk of VTE among the usage of estrogen perioperatively. RESULTS: A total of 209 studies were identified as potentially eligible among PubMed, Embase, and Cochrane library databases. Among the studies, 191 studies were excluded due to their abstract inappropriateness. Out of the remaining 18 studies, only 3 articles were eligible and were finally included. Meta-analysis was performed and showed odds ratio of 0.77 (95% CI: 0.04, 14.01). CONCLUSIONS: Perioperative estrogen therapy does not increase VTE risk on male to female gender-affirming surgery. Therefore, estrogen therapy may be continued perioperatively in vaginoplasty. More prospective studies are needed.

Tyrosine phosphorylation of NLRP3 by the Src family kinase Lyn suppresses the activity of the NLRP3 inflammasome.

In response to microbes and other danger signals, the NLRP3 inflammasome in immune cells triggers the activation of the protease caspase-1, which mediates the maturation of the inflammatory cytokine IL-1ß. Here, we investigated how the NLRP3 inflammasome is regulated. We found that its activation in primary mouse macrophages induced the Src family kinase Lyn to phosphorylate NLRP3 at Tyr918, which correlated with a subsequent increase in its ubiquitination that facilitated its proteasome-mediated degradation. NLRP3 tyrosine phosphorylation and ubiquitination was abrogated in Lyn-deficient macrophages, which produced increased amounts of IL-1ß. Furthermore, mice lacking Lyn were more susceptible to LPS-induced septic shock in an NLRP3-dependent manner. Our data demonstrate that Lyn-mediated tyrosine phosphorylation is a prerequisite for the ubiquitination that dampens NLRP3 inflammasome activity.

Deliberating Performance Targets: Follow-on workshop discussing PM10, NO2, CO, and SO2 air sensor targets.

The use of air sensor technology is increasing worldwide for a variety of applications, however, with significant variability in data quality. The United States Environmental Protection Agency held a workshop in July 2019 to deliberate possible performance targets for air sensors measuring particles with aerodynamic diameters of 10 µm or less (PM10), nitrogen dioxide (NO2), carbon monoxide (CO), and sulfur dioxide (SO2). These performance targets were discussed from the perspective of non-regulatory applications and with the sensors operating primarily in a stationary mode in outdoor environments. Attendees included representatives from multiple levels of government organizations, sensor developers, environmental nonprofits, international organizations, and academia. The workshop addressed the current lack of sensor technology requirements, discussed fit-for-purpose data quality needs, and debated transparency issues. This paper highlights the purpose and key outcomes of the workshop. While more information on performance and applications of sensors is available than in past years, the performance metrics, or parameters used to describe data quality, vary among the studies reports and there is a need for more clear and consistent approaches for evaluating sensor performance. Organizations worldwide are increasingly considering, or are in the process of developing, sensor performance targets and testing protocols. Workshop participants suggested that these new guidelines are highly desirable, would help improve data quality, and would give users more confidence in their data. Given the wide variety of uses for sensors and user backgrounds, as well as varied sensor design features (e.g., communication approaches, data tools, processing/adjustment algorithms and calibration procedures), the need for transparency was a key workshop theme. Suggestions for increasing transparency included documenting and sharing testing and performance data, detailing best practices, and sharing data processing and correction approaches.

Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia.

Aberrant NLRP3 inflammasome activation contributes to the development of endotoxemia. The importance of negative regulation of NLRP3 inflammasomes remains poorly understood. Here, we show that the E3 ubiquitin ligase Cbl-b is essential for preventing endotoxemia induced by a sub-lethal dose of LPS via a caspase-11/NLRP3-dependent manner. Further studies show that NLRP3 undergoes both K63- and K48-linked polyubiquitination. Cbl-b binds to the K63-ubiquitin chains attached to the NLRP3 leucine-rich repeat domain (LRR) via its ubiquitin-associated region (UBA) and then targets NLRP3 at K496 for K48-linked ubiquitination and proteasome-mediated degradation. We also identify RNF125 as an additional E3 ubiquitin ligase that initiates K63-linked ubiquitination of the NLRP3 LRR domain. Therefore, NLRP3 is sequentially ubiquitinated by K63- and K48-linked ubiquitination, thus keeping the NLRP3 inflammasomes in check and restraining endotoxemia.

Baseline renal function and renal ultrasound findings in patients with obstetric fistulas (RENFRU): a prospective cohort study.

OBJECTIVE: To describe and compare baseline renal anatomy and renal function in patients with obstetric fistulas, and to evaluate whether preoperative renal testing and imaging may aid with operative decision making. DESIGN: A prospective cohort study. SETTING: Fistula Care Centre in Malawi. POPULATION: Women with an obstetric fistula. METHODS: Baseline creatinine testing and renal ultrasounds were performed. Surgeons completed a short questionnaire on the usefulness of creatinine and renal ultrasound on operative decision making. MAIN OUTCOME MEASURES: Baseline creatinine and renal ultrasound findings. RESULTS: Four surgeons performed operations on 85 patients. The mean creatinine in patients with vesicovaginal fistulas (VVF) was 0.60 ng/ml versus patients with uretero-vaginal fistulas (UVF) (0.79 ng/ml, P = 0.012). When a grade 3 or more hydronephrosis is absent on renal ultrasound, the negative predictive value of the presence of UVF is 93.3% (95% confidence interval [CI] 88.6-96.2) with a specificity of 97.2% (95% CI 90.3-99.6). In cases of UVF, surgeons found the renal ultrasound results useful or very useful 87.5% of the time, and the creatinine useful or very useful 75% of the time. CONCLUSION: In this pilot study, most patients with obstetric fistulas presented with a normal creatinine. In the absence of a grade 3 hydronephrosis or above on renal ultrasound, the probability of not having a UVF is 93.3%. Surgeons should consider performing preoperative renal ultrasound testing in all patients with an obstetric fistula, particularly in women with a prior laparotomy, as this population has risk factors for ureterovaginal fistula. TWEETABLE ABSTRACT: Most patients with obstetric fistulas have normal renal function. Preoperative renal ultrasounds should be performed.

Leishmania major degrades murine CXCL1 - An immune evasion strategy.

Leishmaniasis is a global health problem with an estimated report of 2 million new cases every year and more than 1 billion people at risk of contracting this disease in endemic areas. The innate immune system plays a central role in controlling L. major infection by initiating a signaling cascade that results in production of pro-inflammatory cytokines and recruitment of both innate and adaptive immune cells. Upon infection with L. major, CXCL1 is produced locally and plays an important role in the recruitment of neutrophils to the site of infection. Herein, we report that L. major specifically targets murine CXCL1 for degradation. The degradation of CXCL1 is not dependent on host factors as L. major can directly degrade recombinant CXCL1 in a cell-free system. Using mass spectrometry, we discovered that the L. major protease cleaves at the C-terminal end of murine CXCL1. Finally, our data suggest that L. major metalloproteases are involved in the direct cleavage and degradation of CXCL1, and a synthetic peptide spanning the CXCL1 cleavage site can be used to inhibit L. major metalloprotease activity. In conclusion, our study has identified an immune evasion strategy employed by L. major to evade innate immune responses in mice, likely reservoirs in the endemic areas, and further highlights that targeting these L. major metalloproteases may be important in controlling infection within the reservoir population and transmittance of the disease.

Quantifying Levels of Peste Des Petits Ruminants (PPR) Virus in Excretions from Experimentally Infected Goats and Its Importance for Nascent PPR Eradication Programme.

Following the successful eradication of rinderpest, the World Organization of Animal Health (OIE) and the Food and Agriculture Organisation (FAO) have set a goal to globally eradicate Peste des petits ruminants (PPR) by 2030. To support the eradication programme we have quantified the levels of PPR virus (PPRV) nucleic acid excreted in body fluids (blood, feces, saliva, nasal and eye swabs) of PPRV-infected goats to ascertain which days post-infection animals are potentially infectious, and hence direct quarantine activities. The data will also indicate optimal sample strategies to assess presence of PPR infection in the naturally infected herd. Peak PPRV nucleic acid detection in different bodily fluids was between 5 and 10 days post-infection. As such, this period must be considered the most infectious period for contact transmission, although high viral load was observed through RNA detection in nasal excretions from two days post-infection until at least two weeks post-infection. Percentage sample positivity was low both in eye swabs and saliva samples during the early stage of infection although RNA was detected as late as two weeks post-infection. From the individual animal data, PPRV was detected later post-infection in fecal material than in other body fluids and the detection was intermittent. The results from this study indicate that nasal swabs are the most appropriate to sample when considering molecular diagnosis of PPRV.

Prospective cohort study of ultrasound surveillance of regional lymph nodes in patients with intermediate-risk cutaneous melanoma.

BACKGROUND: For patients with intermediate-thickness melanoma, surveillance of regional lymph node basins by clinical examination alone has been reported to result in a larger number of lymph nodes involved by melanoma than if patients had initial sentinel node biopsy and completion dissection. This may result in worse regional control. A prospective study of both regular clinical examination and ultrasound surveillance was conducted to assess the effectiveness of these modalities. METHODS: Between 2010 and 2014, patients with melanoma of thickness 1·2-3·5 mm who had under-gone wide local excision but not sentinel node biopsy were recruited to a prospective observational study of regular clinical and ultrasound nodal surveillance. The primary endpoint was nodal burden within a dissected regional lymph node basin. Secondary endpoints included locoregional or distant relapse, progression-free and overall survival. RESULTS: Ninety patients were included in the study. After a median follow-up of 52 months, ten patients had developed nodal relapse as first recurrence, four had locoregional disease outside of an anatomical nodal basin as the first site of relapse and six had relapse with distant disease. None of the patients who developed relapse within a nodal basin presented with unresectable nodal disease. The median number of involved lymph nodes in patients undergoing lymphadenectomy for nodal relapse was 1 (range 1-2; mean 1·2). CONCLUSION: This study suggests that ultrasound surveillance of regional lymph node basins is safe for patients with melanoma who undergo a policy of nodal surveillance.

Extracellular release of virulence factor major surface protease via exosomes in Leishmania infantum promastigotes.

BACKGROUND: The Leishmania spp. protozoa are introduced into humans through a sand fly blood meal, depositing the infectious metacyclic promastigote form of the parasite into human skin. Parasites enter a variety of host cells, although a majority are found in macrophages where they replicate intracellularly during chronic leishmaniasis. Symptomatic leishmaniasis causes considerable human morbidity in endemic regions. The Leishmania spp. evade host microbicidal mechanisms partially through virulence-associated proteins such as the major surface protease (MSP or GP63), to inactivate immune factors in the host environment. MSP is a metalloprotease encoded by a tandem array of genes belonging to three msp gene classes, whose mRNAs are differentially expressed in different life stages of the parasite. Like other cells, Leishmania spp. release small membrane-bound vesicles called exosomes into their environment. The purpose of this study was to detect MSP proteins in exosomal vesicles of Leishmania spp. protozoa. METHODS: Using mass spectrometry data we determined the profile of MSP class proteins released in L. infantum exosomes derived from promastigotes in their avirulent procyclic (logarithmic) stage and virulent stationary and metacyclic stages. MSP protein isoforms belonging to each of the three msp gene classes could be identified by unique peptides. RESULTS: Metacyclic promastigote exosomes contained the highest, and logarithmic exosomes had the lowest abundance of total MSP. Among the MSP classes, MSPC class had the greatest variety of isoforms, but was least abundant in all exosomes. Nonetheless, all MSP classes were present at higher levels in exosomes released from stationary or metacyclic promastigotes than logarithmic promastigotes. CONCLUSIONS: The data suggest the efficiency of exosome release may be more important than the identity of MSP isoform in determining the MSP content of Leishmania spp. exosomes.

The perceived effects and comfort of various body armour systems on police officers while performing occupational tasks.

BACKGROUND: The nature of police work often necessitates use of Individual Light Armour Vests (ILAVs) for officer protection. Previous research has demonstrated various biomechanical and physical performance impacts of ILAVs, however, little knowledge exists on the individual officer's perceptions of ILAV. The aim of this study was to investigate officers' perceptions of the impacts of three different ILAVs and normal station wear whilst performing police occupational tasks. METHODS: A prospective, within subjects, repeated measures design was employed in which 11 serving police officers wore each of three different types of body armour (ILAV A, ILAV B or ILAV C) and normal station wear for a full day while performing tasks including a simulated victim drag, a patrol vehicle exit and a marksmanship shoot. Ratings of Perceived Exertion (RPE) and a Visual Analogue Scale (VAS; - 10 to + 10) were used to examine officer perceptions of each ILAV. Finally, officers were asked to indicate areas of both discomfort and comfort of each ILAV on a mannequin chart. RESULTS: Officers perceived less effort was required for the victim drag whilst wearing ILAV B (RPE = 3.6/10) when compared to ILAV A, ILAV C and even station wear (RPE = 4.7/10, 4.0/10, 3.8/10, respectively). A positive impact on performance was perceived for ILAV B (VAS = + 0.26) when performing a patrol vehicle exit and sprint task but not for the other two ILAVs (VAS = - 3.58, - 0.55, - 0.85, respectively). Officers perceived a positive impact of ILAV B (VAS = + 2.7) and station wear (VAS = + 1.4) and a negative impact of ILAVs A and C (VAS = - 2.1, - 1.7 respectively) on marksmanship. Despite all armour types being criticized for discomfort, ILAV B received lower ratings of discomfort overall, and some positive comments regarding both comfort and performance. CONCLUSIONS: Officers perceived ILAV B to have positive effects on task performance. It was also rated more comfortable than the other two, possibly due to a longer torso design which shifted load from the shoulders to the hips and pelvis. Officer perceptions of comfort and effects on occupational performance should be considered when designing and procuring armour systems. Although ILAVs may be similar, perceived impacts may vary between officers.

Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets.

RATIONALE: Classical interpretation of cystic fibrosis (CF) lung disease pathogenesis suggests that infection initiates disease progression, leading to an exuberant inflammatory response, excessive mucus, and ultimately bronchiectasis. Although symptomatic antibiotic treatment controls lung infections early in disease, lifelong bacterial residence typically ensues. Processes that control the establishment of persistent bacteria in the CF lung, and the contribution of noninfectious components to disease pathogenesis, are poorly understood. OBJECTIVES: To evaluate whether continuous antibiotic therapy protects the CF lung from disease using a ferret model that rapidly acquires lethal bacterial lung infections in the absence of antibiotics. METHODS: CFTR (cystic fibrosis transmembrane conductance regulator)-knockout ferrets were treated with three antibiotics from birth to several years of age and lung disease was followed by quantitative computed tomography, BAL, and histopathology. Lung disease was compared with CFTR-knockout ferrets treated symptomatically with antibiotics. MEASUREMENTS AND MAIN RESULTS: Bronchiectasis was quantified from computed tomography images. BAL was evaluated for cellular differential and features of inflammatory cellular activation, bacteria, fungi, and quantitative proteomics. Semiquantitative histopathology was compared across experimental groups. We demonstrate that lifelong antibiotics can protect the CF ferret lung from infections for several years. Surprisingly, CF animals still developed hallmarks of structural bronchiectasis, neutrophil-mediated inflammation, and mucus accumulation, despite the lack of infection. Quantitative proteomics of BAL from CF and non-CF pairs demonstrated a mucoinflammatory signature in the CF lung dominated by Muc5B and neutrophil chemoattractants and products. CONCLUSIONS: These findings implicate mucoinflammatory processes in the CF lung as pathogenic in the absence of clinically apparent bacterial and fungal infections.

The use of Singapore flaps for vaginal reconstruction in women with vaginal stenosis with obstetric fistula: a surgical technique.

Gynecologic and plastic surgeons collaborate to improve vaginal reconstruction for women with vaginal stenosis and obstetric fistula. As these cases occur typically in low-resource settings, the Singapore flap is a useful technique given its reliability, safety, ease of dissection, and minimal need for additional supplies. The fasciocutaneous flap maintains cutaneous innervation and vasculature and does not require stenting. The surgical collaboration has made it possible to provide functional vaginal reconstruction as a part of the overall care of obstetric fistula patients. The technique shows promise for improving sexual function for women with obstetric fistula and may also enhance healing. TWEETABLE ABSTRACT: Gynecologic & plastic surgeons collaborate to improve vaginal reconstruction for women with obstetric fistula.

Identifying errors in dust models from data assimilation.

Airborne mineral dust is an important component of the Earth system and is increasingly predicted prognostically in weather and climate models. The recent development of data assimilation for remotely sensed aerosol optical depths (AODs) into models offers a new opportunity to better understand the characteristics and sources of model error. Here we examine assimilation increments from Moderate Resolution Imaging Spectroradiometer AODs over northern Africa in the Met Office global forecast model. The model underpredicts (overpredicts) dust in light (strong) winds, consistent with (submesoscale) mesoscale processes lifting dust in reality but being missed by the model. Dust is overpredicted in the Sahara and underpredicted in the Sahel. Using observations of lighting and rain, we show that haboobs (cold pool outflows from moist convection) are an important dust source in reality but are badly handled by the model's convection scheme. The approach shows promise to serve as a useful framework for future model development.

Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity.

The CD4(+) and CD8(+) T cell dichotomy is essential for effective cellular immunity. How individual T cell identity is established remains poorly understood. Here we show that the high-mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4(+) lineage-associated genes including Cd4, Foxp3 and Rorc in CD8(+) T cells. Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutation of five conserved amino acids in the Tcf1 HDAC domain diminishes HDAC activity and the ability to suppress CD4(+) lineage genes in CD8(+) T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes.