Plectin ensures intestinal epithelial integrity and protects colon against colitis

Plectin, a highly versatile cytolinker protein, provides tissues with mechanical stability through the integration of intermediate filaments (IFs) with cell junctions. Here, we hypothesize that plectin-controlled cytoarchitecture is a critical determinant of the intestinal barrier function and homeostasis. Mice lacking plectin in an intestinal epithelial cell (IEC; Ple^ΔIEC) spontaneously developed colitis characterized by extensive detachment of IECs from the basement membrane (BM), increased intestinal permeability, and inflammatory lesions. Moreover, plectin expression was reduced in the colons of ulcerative colitis (UC) patients and negatively correlated with the severity of colitis. Mechanistically, plectin deficiency in IECs led to aberrant keratin filament (KF) network organization and the formation of dysfunctional hemidesmosomes (HDs) and intercellular junctions. In addition, the hemidesmosomal α6β4 integrin (Itg) receptor showed attenuated association with KFs, and protein profiling revealed prominent downregulation of junctional constituents. Consistent with the effects of plectin loss in the intestinal epithelium, plectin-deficient IECs exhibited remarkably reduced mechanical stability and limited adhesion capacity in vitro. Feeding mice with a low-residue liquid diet that reduced mechanical stress and antibiotic treatment successfully mitigated epithelial damage in the Ple^ΔIEC colon.     

Identification of B cell epitopes of Per a 5 allergen using bioinformatic approach

BackgroundImmune epitopes of allergens are pivotal for development of novel diagnostic and therapeutic modalities. Present study aims to identify antigenic determinants of Per a 5, a clinically relevant cross reactive cockroach allergen.MethodsThe three dimensional structure of Per a 5 was modelled using Modeller 9v11 software. A combination of sequence and structure based computational tools were employed for predicting B cell epitopes. Epitopes were synthesized and immunoreactivity was assessed by ELISA using cockroach hypersensitive patient’s sera. Cross-reactivity potential of predicted epitopes was assessed with SDAP and ConSurf and validated by IgE ELISA with fungal and mite hypersensitive patient’s sera.ResultsPer a 5 structure exhibited good quality factor in ERRAT and high stereochemical stability. In silico analysis revealed six B cell epitopes (BC-P1 to P6). BC-P3 demonstrated significant IgE binding followed by BC-P2 and BC-P1 with cockroach hypersensitive patient’s sera. Per a 5 epitopes demonstrate considerable similarity with broad spectrum of allergens from fungal, mites, helminths, fruits and nuts. Analysis of PD values indicate BC-P4 to be well conserved among dust mite and helminth GSTs (8.89, 10.63 and 10.69 with D. pteronyssinus, W. bancrofti and F. hepatica respectively). ConSurf analysis of Per a 5 revealed specific enrichment of evolutionarily similar amino acid residues in BC-P2 (with fungal and mite GSTs) and BC-P4 (with mite and helminth GSTs). Further, IgE binding analysis of epitopes demonstrate BC-P2, BC-P3 and BC-P5 as high IgE binders in fungal hypersensitive sera while BC-P1, BC-P2, BC-P4 and BC-P5 demonstrated significant IgE binding with mite hypersensitive sera.ConclusionsAmong the predicted epitopes, BC-P3 demonstrates maximal IgE binding ability. Computational analysis suggests strong evolutionary conservation and cross reactive potential of BC-P4 with allergens in dust mite and helminths. ELISA highlights predictive potential of analysing evolutionarily conserved residues for uncovering potentially cross reactive antigenic determinants.General significanceImmune epitopes of Per a 5 were identified for aiding molecular diagnosis and potential cross reactivity.     

The roles of prostaglandin E2 and D2 in lipopolysaccharide-mediated changes in sleep

When living organisms become sick as a result of a bacterial infection, a suite of brain-mediated responses occur, including fever, anorexia and sleepiness. Systemic administration of lipopolysaccharide (LPS), a common constituent of bacterial cell walls, increases body temperature and non-rapid eye movement (NREM) sleep in animals and induces the production of pro-inflammatory prostaglandins (PGs). PGE₂ is the principal mediator of fever, and both PGE₂ and PGD₂ regulate sleep–wake behavior. The extent to which PGE₂ and PGD₂ are involved in the effect of LPS on NREM sleep remains to be clarified. Therefore, we examined LPS-induced changes in body temperature and NREM sleep in mice with nervous system-specific knockouts (KO) for the PGE₂ receptors type EP₃ or EP₄, in mice with total body KO of microsomal PGE synthase-1 or the PGD₂ receptor type DP, and in mice treated with the cyclooxygenase (COX) inhibitor meloxicam. We observed that LPS-induced NREM sleep was slightly attenuated in mice lacking EP₄ receptors in the nervous system, but was not affected in any of the other KO mice or in mice pretreated with the COX inhibitor. These results suggest that the effect of LPS on NREM sleep is partially dependent on PGs and is likely mediated mainly by other pro-inflammatory substances. In addition, our data show that the main effect of LPS on body temperature is hypothermia in the absence of nervous system EP₃ receptors or in the presence of a COX inhibitor.     

Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations).MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards.ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients.ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms.SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.     

Human epididymis protein 4 (HE4) levels inversely correlate with lung function improvement (delta FEV1) in cystic fibrosis patients receiving ivacaftor treatment

Background

We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy.

Spatial dispersion modeling of 90Sr by point cumulative semivariogram at Keban Dam Lake, Turkey.

Spatial analysis of (90)Sr artificial radionuclide in consequence of global fallout and Chernobyl nuclear accident has been carried out by using the point cumulative semivariogram (PCSV) technique based on 40 surface water station measurements in Keban Dam Lake during March, April, and May 2006. This technique is a convenient tool in obtaining the regional variability features around each sampling point, which yields the structural effects also in the vicinity of the same point. It presents the regional effect of all the other sites within the study area on the site concerned. In order to see to change of (90)Sr, the five models are constituted. Additionally, it provides a measure of cumulative similarity of the regional variable, (90)Sr, around any measurement site and hence it is possible to draw regional similarity maps at any desired distance around each station. In this paper, such similarity maps are also drawn for a set of distances. (90)Sr activities in lake that distance approximately 4.5 km from stations show the maximum similarity.     

Acupoint stimulation for long COVID: A promising intervention: 穴位刺激治疗长新冠:一种有前景的干预措施

“Long COVID” is a sustained symptom following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). According to recent statistics, at least 65 million people have long COVID, which poses a long-term threat to human health. The pathogenic mechanisms of coronavirus disease 2019 (COVID-19) are complex and affect multiple organs and systems. Common symptoms include palpitations, breathing difficulties, attention and memory deficits, fatigue, anxiety, and depression. It is difficult to achieve satisfactory treatment effect with a single intervention. Currently, treatment strategies for long COVID are still in the exploratory stage, and there is an urgent need to find appropriate and effective methods for long COVID treatment. Traditional Chinese medicine is effective in treating the various phases of COVID-19. Previous studies have shown that acupoint stimulation therapy is effective in improving palpitations, dyspnea, cognitive impairment, anxiety, depression, and other symptoms in patients. According to previous studies, acupoint stimulation may improve various symptoms related to long COVID. This paper discusses the potential application value of acupoint stimulation in the treatment of long COVID-related symptoms, based on the common sequelae of various systems involved in long COVID, and the effect of acupoint stimulation in the treatment of similar symptoms and diseases in recent years.     

Low body mass index is associated with increased mortality in patients with pelvic and acetabular fractures

AimsFractures of the pelvis and acetabulum are often the consequence of high energy trauma in young individuals or fragility fractures in osteoporotic bone. They can be life-threatening or life changing injuries. No published data exists comparing body mass index (BMI) and mortality for this patient group. The aim of this study was to identify if low BMI (<18.5) was a predictor of morbidity and mortality for patients with these injuries.Patients and MethodsOf the 1033 patients with pelvic or acetabular fractures referred to a single level 1 major trauma centre (MTC) over a 4.5-year period (August 2015 - January 2020); we retrospectively analysed data for all admitted patients. Data was collected on demographics, injury pattern, operative intervention and complications. Comparison was made between patients that were underweight (BMI<18.5) and patients that were not. Both in-hospital and post discharge complications were recorded including pulmonary embolus (PE), deep venous thrombosis (DVT), ileus, infection, loss of reduction and mortality at 6 months.Results569 patients admitted to the MTC with a pelvic or acetabular fracture were included in our analysis. Underweight patients had a statistically significant increase in mortality both in-hospital (p = 0.019) and at 6 months post injury (p = 0.039) when compared to other BMI groups. No statistical significance was found between these BMI groups comparing morbidity: DVT (p = 0.712), PE (p = 0.736) nor ileus (p = 0.149). Covariate analysis showed that a low BMI was associated with triple the in-hospital mortality after correction for age and energy of injury (adjusted OR 3.028, 95% CI 1.059-8.659).ConclusionThis is the first published study that demonstrates a statistically significant increase in mortality in patients with pelvic or acetabular fractures who are underweight. Surgeons should carefully consider appropriate peri-operative optimisation for these patients. Further investigation into the effects of low BMI and response to trauma is required.     

A carbon fiber-reinforced polyetheretherketone intramedullary nail improves fracture site visibility on postoperative radiographic images

IntroductionTo evaluate the advantages of a carbon fiber-reinforced polyetheretherketone (CFR/PEEK) intramedullary nail on the diagnosis of fracture healing because of its radiolucency, we retrospectively reviewed radiographs and computed tomography (CT) images of trochanteric femoral fractures that underwent internal fixation with the CFR/PEEK intramedullary nail or a traditional metallic intramedullary nail.MethodsRadiographs and CT images from 20 patients with intertrochanteric femoral fractures treated with a CFR/PEEK intramedullary nail and 20 similar patients treated with a metallic intramedullary nail were reviewed. After division of the intertrochanteric region into three zones on anteroposterior and lateral views of the radiographs, the visibilities of the fracture site, fracture line, and bone formation were evaluated in each zone. A three-grade assessment for existence of scattering and effect of scattering on diagnosis of the surrounding bone was performed on three axial slices of the CT images.ResultsIn the CFR/PEEK group, the fracture site was visible in all zones for all cases except for the posterior zone on the lateral view in one case. In the cranial and middle zones on anteroposterior views and the middle zone on lateral views of the radiographs, the visible fracture site rates in the CFR/PEEK group were significantly higher than those in the metal group. The grades for existence of scattering and effect of scattering on diagnosis of surrounding bone on the CT images were significantly lower in the CFR/PEEK group compared with the metal group.ConclusionSuperior fracture site visibility on radiographs was demonstrated in cases treated with the CFR/PEEK intramedullary nail compared with cases treated with the traditional metallic intramedullary nail, thereby confirming the advantages of the CFR/PEEK intramedullary nail for evaluation of fracture reduction and bone formation. The CFR/PEEK nail evoked little scattering on CT images, leading to higher diagnostic values for the peri-prosthetic cancellous and cortical bone compared with the metallic nail.