Regulation of YAP and Wnt signaling by the endosomal protein MAMDC4.

Maintenance of the intestinal epithelium requires constant self-renewal and regeneration. Tight regulation of proliferation and differentiation of intestinal stem cells within the crypt region is critical to maintaining homeostasis. The transcriptional co-factors ß-catenin and YAP are required for proliferation during normal homeostasis as well as intestinal regeneration after injury: aberrant signaling activity results in over proliferation and tumorigenesis. Although both YAP and ß-catenin activity are controlled along canonical pathways, it is becoming increasingly clear that non-canonical regulation of these transcriptional regulators plays a role in fine tuning their activity. We have shown previously that MAMDC4 (Endotubin, AEGP), an integral membrane protein present in endosomes, regulates both YAP and ß-catenin activity in kidney epithelial cells and in the developing intestinal epithelium. Here we show that MAMDC4 interacts with members of the signalosome and mediates cross-talk between YAP and ß-catenin. Interestingly, this cross-talk occurs through a non-canonical pathway involving interactions between AMOT:YAP and AMOT:ß-catenin.

Effects of amyloid-ß-mimicking peptide hydrogel matrix on neuronal progenitor cell phenotype.

Self-assembling peptide-based hydrogels have become a highly attractive scaffold for three-dimensional (3D) in vitro disease modeling as they provide a way to create tunable matrices that can resemble the extracellular matrix (ECM) of various microenvironments. Alzheimer's disease (AD) is an exceptionally complex neurodegenerative condition; however, our understanding has advanced due to the transition from two-dimensional (2D) to 3D in vitro modeling. Nonetheless, there is a current gap in knowledge regarding the role of amyloid structures, and previously developed models found long-term difficulty in creating an appropriate model involving the ECM and amyloid aggregates. In this report, we propose a multi-component self-assembling peptide-based hydrogel scaffold to mimic the amyloid-beta (ß) containing microenvironment. Characterization of the amyloid-ß-mimicking hydrogel (Col-HAMA-FF) reveals the formation of ß-sheet structures as a result of the self-assembling properties of phenylalanine (Phe, F) through π-π stacking of the residues, thus mimicking the amyloid-ß protein nanostructures. We investigated the effect of the amyloid-ß-mimicking microenvironment on healthy neuronal progenitor cells (NPCs) compared to a natural-mimicking matrix (Col-HAMA). Our results demonstrated higher levels of neuroinflammation and apoptosis markers when NPCs were cultured in the amyloid-like matrix compared to a natural brain matrix. Here, we provided insights into the impact of amyloid-like structures on NPC phenotypes and behaviors. This foundational work, before progressing to more complex plaque models, provides a promising scaffold for future investigations on AD mechanisms and drug testing. STATEMENT OF SIGNIFICANCE: In this study, we engineered two multi-component hydrogels: one to mimic the natural extracellular matrix (ECM) of the brain and one to resemble an amyloid-like microenvironment using a self-assembling peptide hydrogel. The self-assembling peptide mimics ß-amyloid fibrils seen in amyloid-ß protein aggregates. We report on the culture of neuronal progenitor cells within the amyloid-mimicking ECM scaffold to study the impact through marker expressions related to inflammation and DNA damage. This foundational work, before progressing to more complex plaque models, offers a promising scaffold for future investigations on AD mechanisms and drug testing.

Fish responses to underwater sounds depend on auditory adaptations: An experimental test of the effect of motorboat sounds on the fish community of a large fluvial lake.

Freshwater fishes exhibit a wide range of auditory adaptations and capabilities, which are assumed to help them navigate their environment, avoid predators, and find potential mates. Yet, we know very little about how freshwater environments sound to fish, or how fish with different auditory adaptations respond to different soundscapes. We first compiled data on fish hearing acuity and adaptations and provided a portrait of how anthropogenic sounds compare to natural sounds in different freshwater soundscapes. We then conducted a sound-enrichment field experiment at Lake Saint Pierre, a large fluvial lake in Canada, to evaluate the effect of motorboat sound exposure on the fish community by looking at the extent to which changes in species abundances were linked to auditory adaptations. Data compilation showed that the hearing acuity of most species overlaps with a wide range of ambient and anthropogenic underwater sounds while the field experiment showed that species with more specialized auditory structures were captured less often in sound-enriched traps, indicating avoidance behavior. Our findings highlight the importance of considering species' sensorial adaptations when evaluating the community-scale effects of anthropogenic sounds on the fish community, especially at low levels of anthropogenic activity.

Bioengineered in vitro three-dimensional tumor models in endocrine cancers.

Abstract: Endocrine tumors are a heterogeneous cluster of malignancies that originate from cells that can secrete hormones. Examples include, but are not limited to, thyroid cancer, adrenocortical carcinoma, and neuroendocrine tumors. Many endocrine tumors are relatively slow to proliferate, and as such, they often do not respond well to common antiproliferative chemotherapies. Therefore, increasing attention has been given to targeted therapies and immunotherapies in these diseases. However, in contrast to other cancers, many endocrine tumors are relatively rare, and as a result, less is understood about their biology, including specific targets for intervention. Our limited understanding of such tumors is in part due to a limitation in model systems that accurately recapitulate and enable mechanistic exploration of these tumors. While mouse models and 2D cell cultures exist for some endocrine tumors, these models often may not accurately model nuances of human endocrine tumors. Mice differ from human endocrine physiology and 2D cell cultures fail to recapitulate the heterogeneity and 3D architectures of in vivo tumors. To complement these traditional cancer models, bioengineered 3D tumor models, such as organoids and tumor-on-a-chip systems, have advanced rapidly in the past decade. However, these technologies have only recently been applied to most endocrine tumors. In this review we provide descriptions of these platforms, focusing on thyroid, adrenal, and neuroendocrine tumors and how they have been and are being applied in the context of endocrine tumors.

Breast cancer therapies reduce risk of Alzheimer's disease and promote estrogenic pathways and action in brain.

Worldwide, an ever-increasing number of women are prescribed estrogen-modulating therapies (EMTs) for the treatment of breast cancer. In parallel, aging of the global population of women will contribute to risk of both breast cancer and Alzheimer's disease. To address the impact of anti-estrogen therapies on risk of Alzheimer's and neural function, we conducted medical informatic and molecular pharmacology analyses to determine the impact of EMTs on risk of Alzheimer's followed by determination of EMT estrogenic mechanisms of action in neurons. Collectively, these data provide both clinical and mechanistic data indicating that select EMTs exert estrogenic agonist action in neural tissue that are associated with reduced risk of Alzheimer's disease while simultaneously acting as effective estrogen receptor antagonists in breast.

A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity.

Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture. Organoids and other small 3D in vitro models of tissues or tumors can model certain complexities of human in vivo biology; however, this technology has largely yet to be applied to ACC. In this study, we describe the generation of 3D tumor constructs from an established ACC cell line, NCI-H295R. NCI-H295R cells were encapsulated to generate 3D ACC constructs. Tumor constructs were assessed for biomarker expression, viability, proliferation, and cortisol production. In addition, matrix metalloproteinase (MMP) functionality was assessed directly using fluorogenic MMP-sensitive biosensors and through infusion of NCI-H295R cells into a metastasis-on-a-chip microfluidic device platform. ACC tumor constructs showed expression of biomarkers associated with ACC, including SF-1, Melan A, and inhibin α. Treatment of ACC tumor constructs with chemotherapeutics demonstrated decreased drug sensitivity compared to 2D cell culture. Since most tumor cells migrate through tissue using MMPs to break down extracellular matrix, we validated the utility of ACC tumor constructs by integrating fluorogenic MMP-sensitive peptide biosensors within the tumor constructs. Lastly, in our metastasis-on-a-chip device, NCI-H295R cells successfully engrafted in a downstream lung cell line-based construct, but invasion distance into the lung construct was decreased by MMP inhibition. These studies, which would not be possible using 2D cell cultures, demonstrated that NCI-H295R cells secreted active MMPs that are used for invasion in 3D. This work represents the first evidence of a 3D tumor constructs platform for ACC that can be deployed for future mechanistic studies as well as development of new targets for intervention and therapies.

Dupilumab Treatment Leads to Rapid and Consistent Improvement of Atopic Dermatitis in All Anatomical Regions in Patients Aged 6 Months to 5 Years.

INTRODUCTION: Atopic dermatitis (AD) is heterogeneous in distribution pattern and clinical features. This analysis assessed the effect of dupilumab on the extent and severity of AD across various signs (erythema, edema/papulation, excoriation, lichenification) in different anatomical regions (head and neck, trunk, upper extremities, lower extremities) in patients aged 6 months to 5 years. METHODS: In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo with concomitant low-potency topical corticosteroids (TCS) every 4 weeks for 16 weeks. Changes in AD signs across anatomical regions were assessed using unweighted Eczema Area and Severity Index (EASI) body region scores. RESULTS: Overall, 162 patients were randomized to dupilumab (n = 83) or placebo (n = 79). A significant improvement in least squares mean EASI area score was seen by week 2 in all four anatomical regions (P < 0.0001 for dupilumab vs. placebo) and sustained throughout treatment. Least squares mean EASI sign scores in erythema, excoriations, and infiltration/papulation showed significant improvement by week 2 in all regions (P < 0.001), while lichenification showed significant improvement in all regions by week 4 (P < 0.001). CONCLUSION: Dupilumab use with concomitant low-potency TCS treatment resulted in rapid and consistent improvement in AD signs in all anatomical regions, in patients aged 6 months to 5 years with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03346434 Part B.

Finding Well-Coupled Optical Fiber Locations for Railway Monitoring Using Distributed Acoustic Sensing.

Distributed acoustic sensors (DAS) utilize optical fibers to monitor vibrations across thousands of independent locations. However, the measured acoustic waveforms experience significant variations along the sensing fiber. These differences primarily arise from changes in coupling between the fiber and its surrounding medium as well as acoustic interferences. Here, a correlation-based method is proposed to automatically find the spatial locations of DAS where temporal waveforms are repeatable. Signal repeatability is directly associated with spatial monitoring locations with both good coupling and low acoustic interference. The DAS interrogator employed is connected to an over 30-year-old optical fiber installed alongside a railway track. Thus, the optical fiber exhibits large coupling changes and different installation types along its path. The results indicate that spatial monitoring locations with good temporal waveform repeatability can be automatically discriminated using the proposed method. The correlation between the temporal waveforms acquired at locations selected by the algorithm proved to be very high considering measurements taken for three days, the first two on consecutive days and the third one a month after the first measurement.

Surgical Treatment of a Supratentorial Extraventricular Ependymoma: A Case Report.

Supratentorial extraventricular ependymomas (STEE) are very rare primary tumors of the central nervous system (CNS). A 19-year-old man complained of headache, hemiparesis and seizures and was admitted to our hospital. Magnetic resonance imaging (MRI) revealed a right frontal intra-axial lesion. The patient underwent surgical treatment, and the tumor was resected successfully. A diagnosis of World Health Organization (WHO) grade 3 STEE was based on microscopic examination and immunohistochemical analysis. The patient was discharged without a neurological deficit.

Musculoeskeletal injuries and illnesses in the Spanish team the month prior to the WMTRC 2022

Introduction: The recent professionalization of trail running has focussed the interest in this sport. The aim is to describe the epidemiology of musculoskeletal injuries and illnesses among professional Spanish trail runners team during the month of training prior to the World Mountain and Trail Running Championship 2022.Material and Methods33 professional athletes from Spanish National Team that competed in the World Championship participated in the study. They completed a pre-participation health questionnaire based on the specific questionnaire "Oslo Sport Trauma Research Center - Health 2″.Results55% of the athletes suffered a musculoeskeletal injury or health problem during the last month. 12% had to modify their performance in a moderate or severe way. By anatomic location the foot was the most affected with 33% of the cases, followed by the ankle in 25%. Among the diagnoses, chronic overuse musculoskeletal injuries represented 80% with tendinopathy being the most frequent. Regarding the symptons 53% affected upper respiratory tract and 23% gastrointestinal problems.ConclusionsThere is a high risk for the professional trail runners who carry out a continued practice of trail running to suffer an injury or health problem, although most of such injuries or health problems have little impact on their sports performance. The foot and the upper respiratory system are the most affected. (AU)

A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity.

Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture. Organoids and other small 3D in vitro models of tissues or tumors can model certain complexities of human in vivo biology; however, this technology has largely yet to be applied to ACC. In this study, we describe the generation of 3D tumor constructs from an established ACC cell line, NCI-H295R. NCI-H295R cells were encapsulated to generate 3D ACC constructs. Tumor constructs were assessed for biomarker expression, viability, proliferation, and cortisol production. In addition, matrix metalloproteinase (MMP) functionality was assessed directly using fluorogenic MMP-sensitive biosensors and through infusion of NCI-H295R cells into a metastasis-on-a-chip microfluidic device platform. ACC tumor constructs showed expression of biomarkers associated with ACC, including SF-1, Melan A, and inhibin alpha. Treatment of ACC tumor constructs with chemotherapeutics demonstrated decreased drug sensitivity compared to 2D cell culture. Since most tumor cells migrate through tissue using MMPs to break down extracellular matrix, we validated the utility of ACC tumor constructs by integrating fluorogenic MMP-sensitive peptide biosensors within the tumor constructs. Lastly, in our metastasis-on-a-chip device, NCI-H295R cells successfully engrafted in a downstream lung cell line-based construct, but invasion distance into the lung construct was decreased by MMP inhibition. These studies, which would not be possible using 2D cell cultures, demonstrated that NCI-H295R cells secreted active MMPs that are used for invasion in 3D. This work represents the first evidence of a 3D tumor constructs platform for ACC that can be deployed for future mechanistic studies as well as development of new targets for intervention and therapies.

Assessment of progress toward regional haze rule visibility goals using United States anthropogenic emissions rate of progress.

The U.S. EPA developed the Regional Haze Rule to address Section 7491 of the 1977 Clean Air Act Amendments to prevent any future and remedy any existing visibility impairment due to manmade air pollution at Federal Class I areas (CIAs). The rule addresses this national goal by requiring states to show they are making progress toward estimated natural conditions by 2064 for the 20% anthropogenically Most Impaired Days (MID). For the MID, days that have high haze contributions from wildfires and windblown dust tend to be excluded using haze contributions from Carbon and crustal material as surrogates. To show progress toward natural conditions in 2064, a Uniform Rate of Progress Glidepath is defined as a straight line from measured 2000-2004 IMPROVE MID Baseline to natural conditions in 2064. Photochemical modeling is used to project the observed IMPROVE 2014-2018 MID visibility to 2028 that is compared to the Glidepath at 2028 to determine whether the MID visibility at a CIA is on a path toward natural visibility conditions in 2064. This paper discusses an alternative approach for showing progress toward no manmade impairment by using modeling results to generate a U.S. Anthropogenic Emissions Rate of Progress (RoP). The CAMx photochemical grid model was run for a current year (representing 2014-2018), 2028 future year and a 2002 past year and source apportionment was used to isolate the contributions of U.S. anthropogenic emissions to PM concentrations and visibility extinction. A RoP slope line is drawn from the 2002 visibility extinction due to U.S. anthropogenic emissions to zero in 2064 and the CAMx 2028 visibility for U.S. anthropogenic emissions is compared with the RoP slope line at 2028 to determine whether visibility due to U.S. anthropogenic emissions is on a path toward no U.S. manmade impairment in 2064.Implications: The U.S. EPA Regional Haze Rule guidance to show progress toward no U.S. manmade visibility impairment at Class I Areas by 2064 backs into the U.S. manmade impairment contribution by using total atmospheric haze based on measured PM concentrations and subtracting uncertain estimates of routine natural and episodic (i.e. wildfires and windblown dust) natural conditions. The guidance also recommends accounting for visibility contributions due to international anthropogenic and prescribed fire emissions that are also uncertain. This paper presents an alternative approach that models the contributions of U.S. anthropogenic emissions to visibility for past, current and future years using source apportionment to show that U.S. anthropogenic emissions visibility impairment at Class I areas are on a path toward no contribution in 2064. Many U.S. anthropogenic emissions (e.g. power plants with continuous emissions monitoring systems) are better known and characterized than international, fire and natural emissions so the alternative approach should provide a better assessment of whether U.S. anthropogenic emissions are on a path toward no manmade impairment in 2064 than using trends in the measured visibility most impaired days that rely on uncertain estimates of haze due to wildfire, windblown dust, and international emissions and uncertain estimates of natural conditions in 2064.

Exogenous Antioxidants in Remyelination and Skeletal Muscle Recovery.

Inflammatory, oxidative, and autoimmune responses cause severe damage to the nervous system inducing loss of myelin layers or demyelination. Even though demyelination is not considered a direct cause of skeletal muscle disease there is extensive damage in skeletal muscles following demyelination and impaired innervation. In vitro and in vivo evidence using exogenous antioxidants in models of demyelination is showing improvements in myelin formation alongside skeletal muscle recovery. For instance, exogenous antioxidants such as EGCG stimulate nerve structure maintenance, activation of glial cells, and reduction of oxidative stress. Consequently, this evidence is also showing structural and functional recovery of impaired skeletal muscles due to demyelination. Exogenous antioxidants mostly target inflammatory pathways and stimulate remyelinating mechanisms that seem to induce skeletal muscle regeneration. Therefore, the aim of this review is to describe recent evidence related to the molecular mechanisms in nerve and skeletal muscle regeneration induced by exogenous antioxidants. This will be relevant to identifying further targets to improve treatments of neuromuscular demyelinating diseases.

Diacutaneous Fibrolysis Intervention in Patients with Mild to Moderate Carpal Tunnel Syndrome May Avoid Severe Cases in Elderly: A Randomized Controlled Trial.

BACKGROUND: Carpal Tunnel Syndrome (CTS) mainly affects adults of working age. The prevalence of severe cases is higher in elderly patients (>65 years old). Clinical guidelines recommend conservative treatment as the best option in the initial stages of CTS to avoid severe cases. Diacutaneous Fibrolysis (DF) has demonstrated to improve nerve conduction studies and mechanosensitivity. The main purpose was to quantify changes in the cross-sectional area (CSA) of the median nerve, transversal carpal ligament (TCL) thickness, numbness intensity, and the subjective assessment of clinical change after DF treatment in patients with CTS. METHODS: a double-blind, randomized, placebo-controlled trial was designed. A number of 44 patients (60 wrists) with CTS were randomized to the DF group or the sham group. CSA and TCL thickness variables were registered by ultrasound. Clinical variables were assessed by the visual analogue scale and GROC scale. SPSS version 24.0 for MAC was used for statistical analysis. The group by time interaction between groups was analyzed using two-way repeated measures analysis of variance. RESULTS: The DF group reduced CSA with a mean of 0.45 mm2 (IC 95% 0.05 to 0.86) and TCL thickness with a mean reduction of 0.4 mm (IC 95% 0.6 to 2.1) compared to the sham group (p < 0.01, p < 0,03, respectively). Additionally, the DF group decreased the numbness intensity with a mean reduction of 3.47 (IC 95% 2.50 to 4.44, p < 0.01) and showed a statistically significant improvement on the GROC scale (p < 0.01). CONCLUSIONS: DF treatment may significantly reduce CSA and TCL thickness, numbness intensity, and improved clinical perspective. DF applied in patients with mild to moderate CTS may prevent the progression of the disease as they age.

Preliminary tribological results of a new total temporary hip joint prosthesis spacer.

Temporary antibiotic-loaded cement spacers are widely used for treating chronic periprosthetic hip infections. The aim of this study is to evaluate the short-term tribological performance of ultra-high-molecular-weight polyethylene (UHMWPE) and (60Co) gamma-irradiated cross-linked UHMWPE (XLPE) self-mated systems as frictional pairs for temporary total hip spacers. A three-axial hip joint simulator, FIME II, was used to test the UHMWPE and XLPE self-mated systems under variable load profiles. A fetal bovine serum solution was used as a lubricant. After simulation tests, wear measurements of damaged coupled surfaces were made with a coordinate measuring machine. Finally, surfaces were characterized with scanning electron microscopy, Raman spectroscopy, Fourier transform infrared spectroscopy, and nanoindentation tests. The mass loss test results for UHMWPE were 11.91 ± 3.43 mg for the cups and 4.57 ± 0.92 mg for the heads. Whereas, the results for XLPE showed a significant reduction, with mean mass loss values of 6.59 ± 0.14 mg for the cups and 2.82 ± 0.59 mg for the heads, suggesting the viability of the self-mated XLPE contact pair for a temporary total hip spacer.

WhatsApp as a facilitator of expressions of gratitude for palliative care professionals.

INTRODUCTION: Family members significantly value the professional and humane support that medical teams provide in the process of caring for patients with advanced diseases. Communication is currently changing, making it of interest to explore technology's possible influence on communication and on the care relationship. It remains unknown whether this can vary based on increased use of technology in patient care. Using communication technologies can facilitate recognition of professional support through the expression of gratitude aimed at healthcare professionals. The objective here is to describe expressions of gratitude sent via WhatsApp messages by patients who receive treatment from a palliative care team and their relatives. METHOD: A generic qualitative methodology was used. The palliative care service studied used WhatsApp in the patient/family-professional relationship. A content analysis of 130 WhatsApp messages sent to the professionals and containing expressions of gratitude was carried out. Two researchers inductively performed the analysis. Analysis included aspects for which senders were most grateful and others, such as who the messages came from, whether they were reactive or spontaneous and to whom they were directed. RESULTS: Almost all of the patients treated transmitted their gratitude via WhatsApp. It was also observed that family members were most grateful for features of the care received (i.e., affection, availability), the professional's support (i.e., accompaniment, comfort) and the professional's qualities (i.e., professionalism, kindness). They also appreciated symptom control and attempts to resignify loss; these aspects received the most expressions of gratitude in the messages. In turn, all the messages contain expressions of support for palliative care professionals, evidencing a patient/family-professional relationship. CONCLUSION: The use of communication technologies like WhatsApp can contribute to the perception of professionals' availability and closeness and become a facilitator of expressions of gratitude that specify the aspects that family members most appreciate from the palliative care team, such as skills related to humane care and availability.

Optimized in vitro three-dimensional invasion assay for quantifying a wide range of cancer cell invasive behavior.

We describe a three-dimensional (3D) in vitro assay for quantifying cancer cell invasion into a 3D microenvironment with defined biochemical and biophysical properties. Researchers can quantify invasion dynamics (e.g., cell motility and directionality) and examine morphological changes during invasion, using live-cell and confocal imaging techniques. Together, these advantages over existing in vitro invasion assays, such as transwell-based assays, provide researchers with a valuable tool to gain insight into the mechanisms regulating cancer cell invasion. For complete details on the use and execution of this protocol, please refer to Padilla-Rodriguez et al. (2018) and Watson et al. (2021).

Class I MHC Polymorphisms Associated with Type 2 Diabetes in the Mexican Population.

Type 2 diabetes (T2D) has been linked to the expression of Human Leukocyte Antigens, principally to the Major Histocompatibility Complex Class II, with only scarce reports of Major Histocompatibility Complex Class I in specific populations. The objective of the present work was to explore the presence of polymorphisms in the MHC Class I related to T2D in the Mexican population using the Genome-Wide Association Studies Slim Initiative in Genomic Medicine of the Americas (GWAS SIGMA) database. This database contains information on 3848 Mexican individuals with T2D and 4366 control individuals from the same population without a clinical or hereditary history of the disease. The searching criteria considered a p-value of <0.005 and an odds ratio (OR) of >1.0. Ten novel, statistically significant nucleotide variants were identified: four polymorphisms associated with HLA-A (A*03:01:01:01) and six with HLA-C (C*01:02:01:01). These alleles have a high prevalence in Latin American populations and could potentially be associated with autoimmunity mechanisms related to the development of T2D complications.