Immunization with excretory-secretory molecules of intestinal nematodes induces antigen-specific protective memory Th2 cell responses.

Parasitic nematodes infect more than 1 billion people in the global south. The development of effective antihelminthic vaccines is a crucial tool for their future elimination. Protective immune responses to nematodes depend on Gata3+ Th2 cells, which can also be induced by nematode-released products. Whether these nematode products induce antigen-specific long-lived memory T cells and thereby confer protection against a challenge infection is not known yet. Hence, we set out to characterize the formation of memory Th2 cells induced by immunization with Heligmosomoides polygyrus excretory-secretory (HES) products, infection-induced versus immunization-induced recall responses to a challenge infection, and whether HES-induced memory T cells show protective properties following adoptive transfer. Our results show that 8 weeks postimmunization, HES induces long-lived functional memory Th2 cells at the site of immunization in the peritoneal cavity. Following a H. polygyrus challenge infection, HES-immunized mice display MHC-II-dependent antigen-specific Th2 cytokine responses in the gut-draining lymph nodes, comparable to those induced by a prior natural infection. Moreover, adoptive transfer of sorted memory CD4+ T cells from HES-immunized donors reduces female worm fecundity following a challenge H. polygyrus infection in recipient mice, highlighting a protective role for immunization-induced memory T cells.

Changes in wider field swept-source OCT angiography vascular metrics with anti-vascular endothelial growth factor therapy in central retinal vein occlusion.

PURPOSE: To investigate the impact of anti-VEGF therapy on vascular metrics in eyes with macular edema secondary to central retinal vein occlusion (CRVO) using wider field swept-source OCT angiography (WF SS-OCTA). METHODS: We included 23 eyes with macular edema associated with non-ischemic CRVO from 22 patients treated with anti-VEGF therapy (median number of injections: 5 [2-9]). Changes in vessel density (VD), vessel skeletonized density (VSD), and foveal avascular zone (FAZ) parameters were measured using WF SS-OCTA. Visual acuity (VA) and central subfield thickness (CST) were also measured. RESULTS: Median CST decreased significantly from 369 µm (305-531) to 267 µm (243-300, p < 0.001). VD and VSD parameters in 12 × 12 mm images showed significant reductions. For instance, VSD in the whole retina decreased from a median of 13.37 (11.22-13.74) to 11.29 (9.36-12.97, p = 0.013). Additionally, a significant increase in FAZ circularity was found, suggesting improved microvascular integrity. Significant inverse correlations were found between the number of anti-VEGF injections and all VSD and VD parameters on the 12 × 12 mm images (p < 0.05). Notably, the reductions in VSD and VD on 12 × 12 mm angiograms in the deep capillary plexus (DCP) after each injection significantly correlated with increased logMAR VA (worse VA). CONCLUSION: Anti-VEGF therapy in CRVO patients not only mitigates macular edema but also alters the overall microvascular morphology and functionality as revealed by WF SS-OCTA.

Utility of multimodal molecular imaging in the diagnosis and decision-making in arterial diseases.

Arterial diseases are prevalent in the general population, particularly in the elderly, and they are among the main causes of morbidity and mortality worldwide. Nuclear imaging is a useful tool in diagnosis and follow-up in different areas of medicine, and over the last 2 decades, these study modalities have become more relevant in the field of angiology and vascular surgery due to their potential benefit in the interpretation of pathophysiological mechanisms associated with the natural history and severity of diseases that affect the circulation such as vasculitis, degenerative aortic aneurysms (AA), peripheral arterial disease (PAD), and complications following reconstructive procedures such as graft infections. The literature has shown evidence of an important number of radiotracers for specific molecules involved in the activity of these entities and their utility as predictors during surveillance and possible therapeutic targets. The present narrative review aims to describe the use of nuclear medicine, imaging methods, and radiotracers that have been applied in arterial diseases, as well as the advantages and considerations, their importance in the diagnosis and follow-up of these complex groups of patients, and future perspectives.

Th2 and metabolic responses to nematodes are independent of prolonged host microbiota abrogation.

Antibiotic treatment can lead to elimination of both pathogenic bacteria and beneficial commensals, as well as to altered host immune responses. Here, we investigated the influence of prolonged antibiotic treatment (Abx) on effector, memory and recall Th2 immune responses during the primary infection, memory phase and secondary infection with the small intestinal nematode Heligmosomoides polygyrus. Abx treatment significantly reduced gut bacterial loads, but neither worm burdens, nor worm fecundity in primary infection were affected, only worm burdens in secondary infection were elevated in Abx treated mice. Abx mice displayed trends for elevated effector and memory Th2 responses during primary infection, but overall frequencies of Th2 cells in the siLP, PEC, mLN and in the spleen were similar between Abx treated and untreated groups. Gata3+ effector and memory Th2 cytokine responses also remained unimpaired by prolonged Abx treatment. Similarly, the energy production and defence mechanisms of the host tissue and the parasite depicted by NAD(P)H fluorescence lifetime imaging (FLIM) did not change by the prolonged use of antibiotics. We show evidence that the host Th2 response to intestinal nematodes, as well as host and parasite metabolic pathways are robust and remain unimpaired by host microbiota abrogation.

Supervised Machine-Learning Methodology for Industrial Robot Positional Health Using Artificial Neural Networks, Discrete Wavelet Transform, and Nonlinear Indicators.

Robotic systems are a fundamental part of modern industrial development. In this regard, they are required for long periods, in repetitive processes that must comply with strict tolerance ranges. Hence, the positional accuracy of the robots is critical, since degradation of this can represent a considerable loss of resources. In recent years, prognosis and health management (PHM) methodologies, based on machine and deep learning, have been applied to robots, in order to diagnose and detect faults and identify the degradation of robot positional accuracy, using external measurement systems, such as lasers and cameras; however, their implementation is complex in industrial environments. In this respect, this paper proposes a method based on discrete wavelet transform, nonlinear indices, principal component analysis, and artificial neural networks, in order to detect a positional deviation in robot joints, by analyzing the currents of the actuators. The results show that the proposed methodology allows classification of the robot positional degradation with an accuracy of 100%, using its current signals. The early detection of robot positional degradation, allows the implementation of PHM strategies on time, and prevents losses in manufacturing processes.

Rac inhibition as a novel therapeutic strategy for EGFR/HER2 targeted therapy resistant breast cancer.

BACKGROUND: Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy. METHODS: To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins. RESULTS: Gefitinib and lapatinib treatments reduced mammosphere formation in the sensitive cells, but not in the therapy resistant variants, indicating enhanced mesenchymal and cancer stem cell-like characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in known therapy resistant pathways of AKT and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested, and found to inhibit viability and induce apoptosis of therapy resistant cells. CONCLUSIONS: Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer.

Antagonistic regulation of trafficking to Caenorhabditis elegans sensory cilia by a Retinal Degeneration 3 homolog and retromer.

Sensory neurons often possess cilia with elaborate membrane structures that are adapted to the sensory modality of the host cell. Mechanisms that target sensory transduction proteins to these specialized membrane domains remain poorly understood. Here, we show that a homolog of the human retinal dystrophy gene Retinal Degeneration 3 (RD3) is a Golgi-associated protein required for efficient trafficking of a sensory receptor, the receptor-type guanylate cyclase GCY-9, to cilia in chemosensory neurons of the nematode Caenorhabditis elegans The trafficking defect caused by mutation of the nematode RD3 homolog is suppressed in vivo by mutation of key components of the retromer complex, which mediates recycling of cargo from endosomes to the Golgi. Our data show that there exists a critical balance in sensory neurons between the rates of anterograde and retrograde trafficking of cargo destined for the sensory cilium and this balance requires molecular specialization at an early stage of the secretory pathway.

The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease.

Inherited retinal degenerations (IRDs) are a diverse group of conditions that are often characterized by the loss of photoreceptors and blindness. Recent innovations in molecular biology and genomics have allowed us to identify the causative defects behind these dystrophies and to design therapeutics that target specific mechanisms of retinal disease. Recently, the FDA approved the first in vivo gene therapy for one of these hereditary blinding conditions. Current clinical trials are exploring new therapies that could provide treatment for a growing number of retinal dystrophies. While the field has had early success with gene augmentation strategies for treating retinal disease based on loss-of-function mutations, many novel approaches hold the promise of offering therapies that span the full spectrum of causative mutations and mechanisms. Here, we provide a comprehensive review of the approaches currently in development including a discussion of retinal neuroprotection, gene therapies (gene augmentation, gene editing, RNA modification, optogenetics), and regenerative stem or precursor cell-based therapies. Our review focuses on technologies that are being developed for clinical translation or are in active clinical trials and discusses the advantages and limitations for each approach.

COVID-19 pandemic lessons to facilitate future engagement in the global climate crisis.

The COVID-19 pandemic was declared a Public Health Emergency of International Concern (PHEIC) in January 2020. As of November 2020, over 54 million cases and over 1 million deaths have been reported globally. The sudden coronavirus global pandemic has also pointed to the importance of tackling the global climate crisis even more urgently. This article discusses six lessons drawn from the COVID-19 pandemic that can inform and facilitate greater future engagement in the global climate crisis. These lessons were identified through monitoring and analyzing media coverage of COVID-19 related events during the initial onset of COVID-19 in late January 2020 to June 30, 2020. The key lessons included the potentiality of reducing fossil fuel consumption and greenhouse emissions, the significance of responding late, a case for strong sustainability, the limits of rugged individualism, a (mis)trust in science, and the possibility of large-scale change. The insights put forward point to the fact that, like the COVID-19 pandemic, people need to continue to attach their health to expectations of government action in the context of the global climate crisis.

Evaluation of aquafitness exercise on the physical and mental health of older women: a pilot study.

Physical activity is a priority to improve health. However, a sedentary lifestyle is increasingly becoming the norm. For example, in Mexico, sedentarism has increased, especially among older women. This study evaluated the effects of aquafitness on the health of older women in Mexico. Healthy older women performed aquafitness exercise and were compared to a control group of comparable women. Outcome assessments performed at baseline and after 17-weeks included psychological and physical/anthropometric measures. Participants in aquafitness became more optimistic, lost more weight, body fat, and a subsequent decrease in BMI, compared to controls. The results suggest important avenues for future research.

Paenibacillus ottowii sp. nov. isolated from a fermentation system processing bovine manure.

Strain MS2379T was isolated from a pasteurized solution sample from a predominantly anaerobic fermentation system processing bovine manure in Pilot Point, Texas. Phylogenetic analyses based on both 16S rRNA gene and rpoB gene sequences showed that MS2379T was most closely related to Paenibacillus polymyxa (DSM 36T), P. jamilae (DSM 13815T), and P. peoriae (DSM 8320T), yet DNA-DNA relatedness through DNA-DNA hybridization revealed only 22.6, 32.0 and 24.7 % relatedness to these three species respectively. Rod-shaped cells of strain MS2379T are Gram-stain variable with sub-terminal, ellipsoidal, deforming endospores. The peptidoglycan contains meso-diaminopimelic acid (mDAP) and the predominant fatty acids are anteiso-C15 : 0 (61.9 %) and anteiso-C17 : 0 (11.6 %), confirming that strain MS2379T has diagnostic features of other Paenibacillus species. The G+C content of MS2379T is 45.9 mol%. Fermentation of glucose yields acid and gas end-products. The polar lipids found were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, and glycolipids, but also included some unidentified lipids, aminolipids, aminoglycolipid, and phosphatidylmethylethanolamine. The growth range of MS2379T was observed from 10-45 °C with optimal growth temperature at 30 °C. Growth was observed between pH 6-10 and up to 3 % NaCl. Unlike the most closely related Paenibacillus species, strain MS2379T was negative in the Voges-Proskauer reaction. Nucleic acid, chemotaxonomic and biochemical features support the distinctiveness of strain MS2379T. Thus, strain MS2379T represents a novel species of the genus Paenibacillus for which the name Paenibacillus ottowii sp. nov. is proposed with the type strain MS2379T (=DSM 107750T=ATCC TSD-165T).

Synaptic vesicle clustering requires a distinct MIG-10/Lamellipodin isoform and ABI-1 downstream from Netrin.

The chemotrophic factor Netrin can simultaneously instruct different neurodevelopmental programs in individual neurons in vivo. How neurons correctly interpret the Netrin signal and undergo the appropriate neurodevelopmental response is not understood. Here we identify MIG-10 isoforms as critical determinants of individual cellular responses to Netrin. We determined that distinct MIG-10 isoforms, varying only in their N-terminal motifs, can localize to specific subcellular domains and are differentially required for discrete neurodevelopmental processes in vivo. We identified MIG-10B as an isoform uniquely capable of localizing to presynaptic regions and instructing synaptic vesicle clustering in response to Netrin. MIG-10B interacts with Abl-interacting protein-1 (ABI-1)/Abi1, a component of the WAVE complex, to organize the actin cytoskeleton at presynaptic sites and instruct vesicle clustering through SNN-1/Synapsin. We identified a motif in the MIG-10B N-terminal domain that is required for its function and localization to presynaptic sites. With this motif, we engineered a dominant-negative MIG-10B construct that disrupts vesicle clustering and animal thermotaxis behavior when expressed in a single neuron in vivo. Our findings indicate that the unique N-terminal domains confer distinct MIG-10 isoforms with unique capabilities to localize to distinct subcellular compartments, organize the actin cytoskeleton at these sites, and instruct distinct Netrin-dependent neurodevelopmental programs.

Bidirectional thermotaxis in Caenorhabditis elegans is mediated by distinct sensorimotor strategies driven by the AFD thermosensory neurons.

The nematode Caenorhabditis elegans navigates toward a preferred temperature setpoint (Ts) determined by long-term temperature exposure. During thermotaxis, the worm migrates down temperature gradients at temperatures above Ts (negative thermotaxis) and performs isothermal tracking near Ts. Under some conditions, the worm migrates up temperature gradients below Ts (positive thermotaxis). Here, we analyze positive and negative thermotaxis toward Ts to study the role of specific neurons that have been proposed to be involved in thermotaxis using genetic ablation, behavioral tracking, and calcium imaging. We find differences in the strategies for positive and negative thermotaxis. Negative thermotaxis is achieved through biasing the frequency of reorientation maneuvers (turns and reversal turns) and biasing the direction of reorientation maneuvers toward colder temperatures. Positive thermotaxis, in contrast, biases only the direction of reorientation maneuvers toward warmer temperatures. We find that the AFD thermosensory neuron drives both positive and negative thermotaxis. The AIY interneuron, which is postsynaptic to AFD, may mediate the switch from negative to positive thermotaxis below Ts. We propose that multiple thermotactic behaviors, each defined by a distinct set of sensorimotor transformations, emanate from the AFD thermosensory neurons. AFD learns and stores the memory of preferred temperatures, detects temperature gradients, and drives the appropriate thermotactic behavior in each temperature regime by the flexible use of downstream circuits.

A chemoreceptor that detects molecular carbon dioxide.

Animals from diverse phyla possess neurons that are activated by the product of aerobic respiration, CO2. It has long been thought that such neurons primarily detect the CO2 metabolites protons and bicarbonate. We have determined the chemical tuning of isolated CO2 chemosensory BAG neurons of the nematode Caenorhabditis elegans. We show that BAG neurons are principally tuned to detect molecular CO2, although they can be activated by acid stimuli. One component of the BAG transduction pathway, the receptor-type guanylate cyclase GCY-9, suffices to confer cellular sensitivity to both molecular CO2 and acid, indicating that it is a bifunctional chemoreceptor. We speculate that in other animals, receptors similarly capable of detecting molecular CO2 might mediate effects of CO2 on neural circuits and behavior.

Diagnostic performance of CT esophagography in patients with suspected esophageal rupture.

Esophageal rupture is a surgical catastrophe. The gold standard for diagnosing is iodine, water-soluble contrast medium esophagography. CT esophagography has shown promising results. This study aimed to assess the diagnostic performance of CT esophagography in patients with a suspicion of esophageal rupture. This prospective study assessed the performance of a diagnostic test and was approved by local IRB committee. Patients who presented with a clinical suspicion of esophageal rupture were included. CT esophagography findings were described by the emergency radiologist. Clinical outcomes (presence or absence of esophageal rupture) were reported by surgeons. The operative characteristics were calculated. A final predictive scale for rupture was built. A total of 64 patients were recruited (age 26.5 years, 90 % male, 82 % trauma). Sensitivity, specificity, and positive and negative likelihood ratios (LRs) were 77.7 % (95 % confidence interval (CI) 45-100), 94.3 % (87.2-100), 14 (9.81-19.9), and 0.24 (0.05-1.22), respectively. The final model for predicting rupture included five variables: age (odds ratio (OR) 1.03; 95 % CI, 0.95-1.11; p=0.04), leakage of contrast media into the mediastinum or pleural space (OR 10.0; 95 % CI, 0.64-156.9; p=0.10), extraluminal air or fluid collections (OR 43.1; 95 % CI, 1.52-1217.3; p=0.027), esophageal wall thickening (OR 10.1; 95 % CI, 0.50-202.8; p=0.12), and left pneumothorax or pleural effusion (OR 6.5; 95 % CI, 0.31-132.7; p=0.2). The overall agreement was 0.40 (95 % CI, 0.09-0.72) for the predictive model. The model sensitivity was 50.0 %, and the specificity was 98.4 %. CT esophagography shows a good diagnostic performance in patients with a suspected esophageal rupture.

Environmental impacts of medium-scale pig farming at technical and economic optimum production weight in Mexico.

Medium-scale pig production systems, which make up 30 % of Mexico's pig farms, face two key obstacles impacting their economic and financial performance. The first is the absence of a sales plan based on pigs' weight, which negatively affects both profitability and resource management. The second obstacle is inadequate waste management, which hampers efforts to mitigate environmental impacts generated by pig farms. Based on this criterion, this study aims to determine technical and economic optimum levels of a medium-scale pig farm and evaluate its associated environmental impacts. Based on the last farm sale weight (116.3 kg - base scenario), technical and economic optimum levels were estimated using a production function, resulting in a technical optimum of 155 kg and an economic optimum of 127 kg. An environmental assessment of the pig fattening process was carried out following the principles of the Life Cycle Analysis methodological framework. Using a cradle-to-farm gate perspective, and establishing 1 kg of live-weight pig as the functional unit. The results indicated that production at maximum weight level (155 kg), increased environmental impacts by 60 % to 75 % compared to the base scenario. In contrast, at the maximum economic benefit level (127 kg), environmental impacts increased by 5 % to 10 %. Feed production represented the largest contribution (over 74 %) in six impact categories. The results provide valuable information for medium-scale pig farms to mitigate the environmental burdens associated with the optimal production weight and to direct efforts towards achieving future economic and environmental efficiency.

Vaginal peritoneum fistula through pouch of Douglas during peritoneal dialysis: Case report and literature review.

INTRODUCTION: Peritoneal dialysis is the preferred approach for kidney replacement therapy. A peritoneal-vaginal fistula is a rare complication associated with peritoneal dialysis. CASE PRESENTATION: A 69-year-old woman with a history of type two diabetes and systemic arterial hypertension for twenty years is scheduled to undergo the surgical placement of a Tenckoff catheter to begin renal replacement therapy. After having thirty dialysis sessions, she was discharged to continue therapy at home. Five days later, she observed a notable rise in vaginal discharge after peritoneal dialysis. This case report investigates the etiology, diagnosis, and management of peritoneal vaginal fistula and analyzes current medical literature. DISCUSSION: Factors associated with the formation of peritoneum-vaginal fistula include increased intra-abdominal pressure due to dialysis, anatomical predisposition, peritonitis, and malnutrition. CONCLUSIONS: Peritoneal vaginal fistula is an uncommon consequence of peritoneal dialysis. Diagnosis entails demonstrating the movement of dialysis fluid from the peritoneum to the vagina. Treatment should be customized according to the etiology of the fistula and the individual needs of each patient.

Widefield Swept-Source OCTA Findings in HELLP Syndrome: Choroidal Infarcts.

PURPOSE: Pre-eclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome have been previously implicated with ophthalmic complications including serous retinal detachments and disorders of the choroidal vasculature. Herein, we report a case of macular serous detachment associated with HELLP syndrome in which wide field swept-source optical coherence tomography angiography (WF SS-OCTA) was used. METHODS: Retrospective case report of a patient who developed HELLP syndrome. The patient underwent multimodal retinal imaging and wide field swept-source OCT angiography (WF SS-OCTA) (PLEX® Elite 9000, Carl Zeiss Meditec Inc.). RESULTS: A 36-year-old female patient diagnosed with HELLP syndrome presented with bilateral blurry vision. At presentation, dilated fundus exam revealed localized subretinal fluid in the macula. WF SS-OCTA showed areas of peripapillary and subfoveal flow signal attenuation in the choroid OD, consistent with choroidal infarction. CONCLUSIONS: These findings support the hypothesis that HELLP syndrome is associated with vascular changes that lead to choroidal dysfunction and subsequent serous retinal detachments. Furthermore, this case highlights a role for the non-invasive WF SS-OCTA technology in diagnosing and further characterizing the pathophysiology without the use of dye-based angiography.

Th2-biased immune responses to body migrating Ascaris larvae in primary infection are associated with pathology but not protection.

Helminth infections lead to an overdispersion of the parasites in humans as well as in animals. We asked whether early immune responses against migrating Ascaris larvae are responsible for the unequal distribution of worms in natural host populations and thus investigated a susceptible versus a resistant mouse strain. In mice, the roundworm larvae develop until the lung stage and thus early anti-Ascaris immune responses against the migrating larvae in the liver and lung can be deciphered. Our data show that susceptible C57BL/6 mice respond to Ascaris larval migration significantly stronger compared to resistant CBA mice and the anti-parasite reactivity is associated with pathology. Increased eosinophil recruitment was detected in the liver and lungs, but also in the spleen and peritoneal cavity of susceptible mice on day 8 post infection compared to resistant mice. In serum, eosinophil peroxidase levels were significantly higher only in the susceptible mice, indicating functional activity of the recruited eosinophils. This effect was associated with an increased IL-5/IL-13 production by innate lymphoid cells and CD4+ T cells and a pronounced type 2 macrophage polarization in the lungs of susceptible mice. Furthermore, a comparison of wildtype BALB/c and eosinophil-deficient dblGATA-1 BALB/c mice showed that eosinophils were not essential for the early control of migrating Ascaris larvae. In conclusion, in primary infection, a strong local and systemic type 2 immune response during hepato-tracheal helminth larval migration is associated with pathology rather than protection.