The goal of this study was to compare dysphagia phenotypes in low and high copy number (LCN and HCN) transgenic superoxide dismutase 1 (SOD1) mouse models of ALS to accelerate the discovery of novel and effective treatments for dysphagia and early amyotrophic lateral sclerosis (ALS) diagnosis. Clinicopathological features of dysphagia were characterized in individual transgenic mice and age-matched controls utilizing videofluoroscopy in conjunction with postmortem assays of the tongue and hypoglossal nucleus. Quantitative PCR accurately differentiated HCN-SOD1 and LCN-SOD1 mice and nontransgenic controls. All HCN-SOD1 mice developed stereotypical paralysis in both hindlimbs. In contrast, LCN-SOD1 mice displayed wide variability in fore- and hindlimb involvement. Lick rate, swallow rate, inter-swallow interval, and pharyngeal transit time were significantly altered in both HCN-SOD1 and LCN-SOD1 mice compared to controls. Tongue weight, tongue dorsum surface area, total tongue length, and caudal tongue length were significantly reduced only in the LCN-SOD1 mice compared to age-matched controls. LCN-SOD1 mice with lower body weights had smaller/lighter weight tongues, and those with forelimb paralysis and slower lick rates died at a younger age. LCN-SOD1 mice had a 32% loss of hypoglossal neurons, which differed significantly when compared to age-matched control mice. These novel findings for LCN-SOD1 mice are congruent with reported dysphagia and associated tongue atrophy and hypoglossal nucleus pathology in human ALS patients, thus highlighting the translational potential of this mouse model in ALS research.

China is the largest producer and consumer of tobacco products worldwide. While direct marketing and advertisement of tobacco products is restricted, indirect marketing still exists under the guise of sponsorship and corporate social responsibility (CSR). This case study is focused on tobacco industry-sponsored elementary schools in Chinese rural areas.

To show the characteristics and outcomes of patients with neovascular age-related macular degeneration (nAMD) who had extended remission (ER) while on a pro re nata (PRN) treatment protocol.

The acute respiratory distress syndrome (ARDS) is a multifaceted lung disorder in which no specific therapeutic intervention is able to effectively improve clinical outcomes. Despite an improved understanding of molecular mechanisms and advances in supportive care strategies, ARDS remains associated with high mortality, and survivors usually face long-term morbidity. In recent years, preclinical studies have provided mounting evidence of the potential of mesenchymal stem cell (MSC)-based therapies in lung diseases and critical illnesses. In several models of ARDS, MSCs have been demonstrated to induce anti-inflammatory and anti-apoptotic effects, improve epithelial and endothelial cell recovery, and enhance microbial and alveolar fluid clearance, thus resulting in improved lung and distal organ function and survival. Early-stage clinical trials have also demonstrated the safety of MSC administration in patients with ARDS, but further, large-scale investigations are required to assess the safety and efficacy profile of these therapies. In this review, we summarize the main mechanisms whereby MSCs have been shown to exert therapeutic effects in experimental ARDS. We also highlight questions that need to be further elucidated and barriers that must be overcome in order to efficiently translate MSC research into clinical practice.

In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZ-induced seizures in mice. Thus, AS-1 may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM).

The dysregulation of ROS production and osteoclastogenesis is involved in the progress of osteoporosis. To identify novel and effective targets to treat this disease, it is important to explore the underlying mechanisms. In our study, we firstly tested the effect of the Nrf2 activator RTA-408, a novel synthetic triterpenoid under clinical investigation for many diseases, on osteoclastogenesis. We found that it could inhibit osteoclast differentiation and bone resorption in a time- and dose-dependent manner. Further, RTA-408 enhanced the expression and activity of Nrf2 and significantly suppressed RANKL-induced reactive oxygen species (ROS) production. Nrf2 regulates the STING expression and STING induces the production of IFN-β. Here, we found that RTA-408 could suppress STING expression, but that it does not affect Ifnb1 expression. RANKL-induced degradation of IκBα and the nuclear translocation of P65 was suppressed by RTA-408. Although this compound was not found to influence STING-IFN-β signaling, it suppressed the RANKL-induced K63-ubiquitination of STING via inhibiting the interaction between STING and the E3 ubiquitin ligase TRAF6. Further, adenovirus-mediated STING overexpression rescued the suppressive effect of RTA-408 on NF-κB signaling and osteoclastogenesis. In vivo experiments showed that this compound could effectively attenuate ovariectomy (OVX)-induced bone loss in C57BL/6 mice by inhibiting osteoclastogenesis. Collectively, we show that RTA-408 inhibits NF-κB signaling by suppressing the recruitment of TRAF6 to STING, in addition to attenuating osteoclastogenesis and OVX-induced bone loss in vivo, suggesting that it could be a promising candidate for treating osteoporosis in the future.

Unregulated stress during critical periods of development is proposed to drive deficits consistent with schizophrenia in adults. If accurate, reopening the critical period could make the adult susceptible to pathology. We evaluated the impact of early adolescent and adult stress exposure (combination of daily footshock for 10 days and 3 restraint sessions) on (1) midbrain dopamine (DA) neuron activity, (2) ventral hippocampal (vHipp) pyramidal neuron activity, and (3) the number of parvalbumin (PV) interneurons in the vHipp and their associated perineuronal nets (PNNs). Ventral tegmental area (VTA) DA neuron population activity and vHipp activity was increased 1-2 and 5-6 weeks post-adolescent stress, along with a decrease in the number of PV+, PNN+, PV + /PNN + cells in the vHipp, which are consistent with the MAM model of schizophrenia. In contrast, adult stress decreased VTA DA neuron population activity only at 1-2 weeks post stress, which is consistent with what has been observed in animal models of depression, without impacting vHipp activity and PV/PNN expression. Administration of valproate (VPA), which can re-instate the critical period of plasticity via histone deacetylase (HDAC) inhibition, caused adult stress to produce changes similar to those induced by adolescent stress, presumably by increasing stress vulnerability to early adolescent levels. Our findings indicate that timing of stress is a critical determinant of the pathology produced in the adult: adolescent stress led to circuit deficits that recapitulates schizophrenia, whereas adult stress induced a depression-like hypodopaminergic state. Reopening the critical period in the adult restores vulnerability to stress-induced pathology resembling schizophrenia.

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.

Loss of inner ear hair cells leads to incurable balance and hearing disorders because these sensory cells do not effectively regenerate in humans. A potential starting point for therapy would be the stimulation of quiescent progenitor cells within the damaged inner ear. Inner ear progenitor/stem cells, which have been described in rodent inner ears, would be principal candidates for such an approach. Despite the identification of progenitor cell populations in the human fetal cochlea and in the adult human spiral ganglion, no proliferative cell populations with the capacity to generate hair cells have been reported in vestibular and cochlear tissues of adult humans. The present study aimed at filling this gap by isolating colony-forming progenitor cells from surgery- and autopsy-derived adult human temporal bones in order to generate inner ear cell types in vitro. Sphere-forming and mitogen-responding progenitor cells were isolated from vestibular and cochlear tissues. Clonal spheres grown from adult human utricle and cochlear duct were propagated for a limited number of generations. When differentiated in absence of mitogens, the utricle-derived spheres robustly gave rise to hair cell-like cells, as well as to cells expressing supporting cell-, neuron-, and glial markers, indicating that the adult human utricle harbors multipotent progenitor cells. Spheres derived from the adult human cochlear duct did not give rise to hair cell-like or neuronal cell types, which is an indication that human cochlear cells have limited proliferative potential but lack the ability to differentiate into major inner ear cell types. Anat Rec, 303:461-470, 2020. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Showing how engagement adds value for all stakeholders can be an effective motivator for broader implementation of patient engagement. However, it is unclear what methods can best be used to evaluate patient engagement. This paper is focused on ways to evaluate patient engagement at three decision-making points in the medicines research and development process: research priority setting, clinical trial design and early dialogues with regulators and health technology assessment bodies.

Neuronal loss is the best neuropathological substrate that correlates with cortical atrophy and dementia in Alzheimer's disease (AD). Defective GABAergic neuronal functions may lead to cortical network hyperactivity and aberrant neuronal oscillations and in consequence, generate a detrimental alteration in memory processes. In this study, using immunohistochemical and stereological approaches, we report that the two major and non-overlapping groups of inhibitory interneurons (SOM-cells and PV-cells) displayed distinct vulnerability in the perirhinal cortex of APP/PS1 mice and AD patients. SOM-positive neurons were notably sensitive and exhibited a dramatic decrease in the perirhinal cortex of 6-month-old transgenic mice (57% and 61% in areas 36 and 35, respectively) and, most importantly, in AD patients (91% in Braak V-VI cases). In addition, this interneuron degenerative process seems to occur in parallel, and closely related, with the progression of the amyloid pathology. However, the population expressing PV was unaffected in APP/PS1 mice while in AD brains suffered a pronounced and significant loss (69%). As a key component of cortico-hippocampal networks, the perirhinal cortex plays an important role in memory processes, especially in familiarity-based memory recognition. Therefore, disrupted functional connectivity of this cortical region, as a result of the early SOM and PV neurodegeneration, might contribute to the altered brain rhythms and cognitive failures observed in the initial clinical phase of AD patients. Finally, these findings highlight the failure of amyloidogenic AD models to fully recapitulate the selective neuronal degeneration occurring in humans.

We present the results of a large-scale analysis of event-related responses based on raw EEG data from 17 studies performed at six experimental sites associated with four different institutions. The analysis corpus represents 1,155 recordings containing approximately 7.8 million event instances acquired under several different experimental paradigms. Such large-scale analysis is predicated on consistent data organization and event annotation as well as an effective automated preprocessing pipeline to transform raw EEG into a form suitable for comparative analysis. A key component of this analysis is the annotation of study-specific event codes using a common vocabulary to describe relevant event features. We demonstrate that Hierarchical Event Descriptors (HED tags) capture statistically significant cognitive aspects of EEG events common across multiple recordings, subjects, studies, paradigms, headset configurations, and experimental sites. We use representational similarity analysis (RSA) to show that EEG responses annotated with the same cognitive aspect are significantly more similar than those that do not share that cognitive aspect. These RSA similarity results are supported by visualizations that exploit the non-linear similarities of these associations. We apply temporal overlap regression, reducing confounds caused by adjacent event instances, to extract time and time-frequency EEG features (regressed ERPs and ERSPs) that are comparable across studies and replicate findings from prior, individual studies. Likewise, we use second-level linear regression to separate effects of different cognitive aspects on these features across all studies. This work demonstrates that EEG mega-analysis (pooling of raw data across studies) can enable investigations of brain dynamics in a more generalized fashion than single studies afford. A companion paper complements this event-based analysis by addressing commonality of the time and frequency statistical properties of EEG across studies at the channel and dipole level.

Premature senescence, a death escaping pathway for cells experiencing stress, is conducive to aging and cardiovascular diseases. The molecular switch between senescent and apoptotic fate remains, however, poorly recognized. Nrf2 is an important transcription factor orchestrating adaptive response to cellular stress. Here, we show that both human primary endothelial cells (ECs) and murine aortas lacking Nrf2 signaling are senescent but unexpectedly do not encounter damaging oxidative stress. Instead, they exhibit markedly increased S-nitrosation of proteins. A functional role of S-nitrosation is protection of ECs from death by inhibition of NOX4-mediated oxidative damage and redirection of ECs to premature senescence. S-nitrosation and senescence are mediated by Keap1, a direct binding partner of Nrf2, which colocalizes and precipitates with nitric oxide synthase (NOS) and transnitrosating protein GAPDH in ECs devoid of Nrf2. We conclude that the overabundance of this "unrestrained" Keap1 determines the fate of ECs by regulation of S-nitrosation and propose that Keap1/GAPDH/NOS complex may serve as an enzymatic machinery for S-nitrosation in mammalian cells.

We examined metaproteome profiles from two Arctic microbiomes during 10-day shipboard incubations to directly track early functional and taxonomic responses to a simulated algal bloom and an oligotrophic control. Using a novel peptide-based enrichment analysis, significant changes (p-value < 0.01) in biological and molecular functions associated with carbon and nitrogen recycling were observed. Within the first day under both organic matter conditions, Bering Strait surface microbiomes increased protein synthesis, carbohydrate degradation, and cellular redox processes while decreasing C1 metabolism. Taxonomic assignments revealed that the core microbiome collectively responded to algal substrates by assimilating carbon before select taxa utilize and metabolize nitrogen intracellularly. Incubations of Chukchi Sea bottom water microbiomes showed similar, but delayed functional responses to identical treatments. Although 24 functional terms were shared between experimental treatments, the timing, and degree of the remaining responses were highly variable, showing that organic matter perturbation directs community functionality prior to alterations to the taxonomic distribution at the microbiome class level. The dynamic responses of these two oceanic microbial communities have important implications for timing and magnitude of responses to organic perturbations within the Arctic Ocean and how community-level functions may forecast biogeochemical gradients in oceans.

To develop an evidence-based decision aid for parents of children with cancer and to help guide them in the use of complementary and alternative medicine (CAM) for cancer care.

ZC4H2 encodes a C4H2 type zinc-finger nuclear factor, the mutation of which has been associated with disorders with various clinical phenotypes in human, including developmental delay, intellectual disability and dystonia. ZC4H2 has been suggested to regulate spinal cord patterning in zebrafish as a co-factor for RNF220, an ubiquitin E3 ligase involved in Gli signaling. Here we showed that ZC4H2 and RNF220 knockout animals phenocopy each other in spinal patterning in both mouse and zebrafish, with mispatterned progenitor and neuronal domains in the ventral spinal cord. We showed evidence that ZC4H2 is required for the stability of RNF220 and also proper Gli ubiquitination and signaling in vivo. Our data provides new insights into the possible etiology of the neurodevelopmental impairments observed in ZC4H2-associated syndromes.

This study aimed to research the understanding and knowledge of cervical cancer, human papilloma virus (HPV), and HPV vaccination, and the acceptance of HPV vaccination, among a population of women in northeastern China. A cross-sectional survey was carried out by questionnaire to investigate knowledge of cervical cancer, HPV, and HPV vaccination. The 230 female participants were native residents of northeastern China, and their ages ranged between 18 and 65 years. Questionnaires were randomly acquired by the respondents from online and paper questionnaire distribution. The questionnaire included questions on three major aspects to record people's perceptions of cervical cancer, HPV, and vaccines. Of the sample of 230 women surveyed, 80.9% had heard of cervical cancer, but understanding was only 15.7%; 38.3% knew about HPV; 20% knew about HPV vaccine; 39.6% agreed to receive HPV vaccination, and the remainder were mainly concerned about its safety and effectiveness. Data analysis showed that age, family income, and whether there was experience of screening all influenced knowledge of cervical cancer, but this was not statistically significant. The level of education had no obvious effect on the degree of knowledge about cervical cancer; however, with an improvement in education, women's awareness of HPV vaccine improved significantly (p < 0.05). Women who have received cervical cancer screening had significantly greater knowledge about cervical cancer and HPV than those with no screening (p < 0.05). Women in northeastern China have little knowledge of cervical cancer, HPV, and HPV vaccine, lack disease knowledge, and hold a skeptical attitude about HPV vaccination. Medical institutions are the main channel providing information to these women.

IgG4-related disease (IgG4-RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll-like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD.

Ambulatory ECG monitoring is typically achieved using portable devices with limited number of surface leads, autonomy, and length of recording. Smart garments with multiple conductive textile electrodes provide great promise to perform continuous and comfortable ECG monitoring.

We aimed to identify factors (child diet, physical activity; maternal BMI) associated with body composition of Ghanaian pre-school children.