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No abstract available. Article truncated after 150 words. Clinical Scenario: A 59-year-old woman with hypothyroidism presented to the emergency room with progressive shortness of breath for 2 weeks. Upon arrival, she was markedly hypoxic necessitating use of a non-rebreather to maintain her oxygen saturations above 88%. A chest radiograph demonstrated extensive, bilateral airspace disease. She was diagnosed with SARS-CoV-2 (COVID-19) pneumonia and started on the appropriate therapies. Approximately 48 hours into her hospitalization, she required intubation with mechanical ventilation due to her progressive hypoxemic respiratory failure. She was intubated for approximately 5 weeks with a gradual improvement in her respiratory status, but not to the point where she was a candidate for a tracheostomy. Despite being off sedation for an extended period, she remained unresponsive. A CT of the head without contrast did not demonstrate any significant abnormalities. An MRI of the brain was subsequently performed and demonstrated diffuse juxtacortical and callosal white matter microhemorrhages (Figure 1). Given …

SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.

High blood pressure (BP) is a risk factor for various health conditions, and dietary factors have been linked to the development of high blood pressure. Scientific studies have shown that consuming marine food, particularly oily fish, can be beneficial in reducing blood pressure levels. This study aims to investigate the relationship between traditional fish sauces and seafood consumption, and blood pressure levels in Bandar Kong Cohort study. Methods: Cross-sectional analyses were performed using data from 2823 volunteers, collected through questionnaires and BP measurements following a standardized protocol. Age-adjusted and multivariate associations between BP and seafood consumption were estimated using multiple linear regressions. Three models of analysis were used: model 1, daily energy intake; model 2, daily energy intake along with age; and model 3, daily energy intake, age, education, body mass index (BMI), residence, occupation, marital status, using hookah, socio-economic status, physical activity, and family history of hypertension. Results: Among 2823 participants (age; 46.88±8.94 yrs.), 1138(40.3%) men and 1685(59.7%) women, 693 (24.5%) individuals had hypertension, (n=288) accounting for 25.3% men and (n=405) 24.0% women. After adjusting for covariates, the study found significant negative relationships between the consumption of salted fish-water, Mahyaveh and Suragh (traditional Iranian fish sauces), and BP. Conclusions: This study suggests that consuming traditional Iranian fish sauces, Mahyaveh and Suragh, is associated with lower BP levels. This study sheds light on potential benefits of traditional dietary choices for regulating blood pressure.

Background: Hypertension (HTN) is a significant global public health concern and can elevate the risk of cardiovascular and kidney diseases. Tamarind (Tamarindus indica, Fabaceae), a tropical fruit highly valued for its pulp, offers many health benefits, including a reduction in oxidative stress and inflammation. Nonetheless, emerging uncertainties surround Tamarind’s efficacy in certain health aspects. This study examined its potential negative impact on HTN within the Bandar Kong cohort. Materials and Methods: The current study included 2823 participants of the Bandar Kong cohort study, of whom 693 individuals (24.5%) had HTN, with 288 men (25.3%) and 405 women (24.0%) being affected. Binary logistic regression analysis was used to investigate the connections between variables and the likelihood of HTN in both men and women. Moreover, multivariable binary logistic regression analysis and multivariable linear regression were utilized to determine the correlation between Tamarind consumption and the risk of HTN. Results: After adjusting for covariates, the odds of HTN in males with moderate consumption of Tamarind were 0.55 higher than in males with low consumption of Tamarind. Tamarind consumption was significantly associated with the risk of HTN in both genders, with males and females who consumed moderate to high amounts having a higher risk. The findings revealed that high consumption of Tamarind was associated with higher diastolic blood pressure (BP) in females. Conclusion: The study suggests that moderate to high consumption of Tamarind may have a negative impact on HTN among both males and females. Although Tamarind is highly valued for its pulp and offers some health benefits, its potential negative impact on HTN should be taken into consideration.

The word “secretome” was first used to describe the proteins that cells secrete under different circumstances; however, recent studies have proven the existence of other molecules such as RNA and chemical compounds in the secretome. The study of secretome has significance for the diagnosis and treatment of disease as it provides insight into cellular functions, including immune responses, development, and homeostasis. By halting cell division, cellular senescence plays a role in both cancer defense and aging by secreting substances known as senescence-associated secretory phenotypes (SASP). A variety of techniques could be used to analyze the secretome: protein-based approaches like mass spectrometry and protein microarrays, nucleic acid-based methods like RNA sequencing, microarrays, and in silico prediction. Each method offers unique advantages and limitations in characterizing secreted molecules. Top-down and bottom-up strategies for thorough secretome analysis are became possible by mass spectrometry. Understanding cellular function, disease causes, and proper treatment targets is aided by these methodologies. Their approaches, benefits, and drawbacks will all be discussed in this review.

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BackgroundSwimmers commonly access performance metrics such as lap splits, distance, and pacing information between work bouts while they rest. Recently, a new category of tracking devices for swimming was introduced with the FORM Smart Swim Goggles (FORM Goggles). The goggles have a built-in see-through display and are capable of tracking and displaying distance, time splits, stroke, and pace metrics in real time using machine learning and augmented reality through a heads-up display. The purpose of this study was to assess the validity and reliability of the FORM Goggles compared with video analysis for stroke type, pool length count, pool length time, stroke rate, and stroke count in recreational swimmers and triathletes.MethodA total of 36 participants performed mixed swimming intervals in a 25-m pool across two identical 900-m swim sessions performed at comparable intensities with 1 week interval. The participants wore FORM Goggles during their swims, which detected the following five swim metrics: stroke type, pool length time, pool length count, stroke count, and stroke rate. Four video cameras were positioned on the pool edges to capture ground truth video footage, which was then manually labeled by three trained individuals. Mean (SD) differences between FORM Goggles and ground truth were calculated for the selected metrics for both sessions. The absolute mean difference and mean absolute percentage error were used to assess the differences of the FORM Goggles relative to ground truth. The test–retest reliability of the goggles was assessed using both relative and absolute reliability metrics.ResultsCompared with video analysis, the FORM Goggles identified the correct stroke type at a rate of 99.7% (N = 2,354 pool lengths, p

IRE1α cleaves several mRNAs upon accumulation of misfolded proteins. Here the authors show that active IRE1α cleaves DGAT2 mRNA encoding the rate-limiting enzyme in the synthesis of triacylglycerols, suggesting a role of IRE1α in reprogramming lipid metabolism in cancer cells.

Cyanobacteria have demonstrated their therapeutic potential for many human diseases. In this work, cyanobacterial extracts were screened for lipid reducing activity in zebrafish larvae and in fatty-acid-overloaded human hepatocytes, as well as for glucose uptake in human hepatocytes and ucp1 mRNA induction in murine brown adipocytes. A total of 39 cyanobacteria strains were grown and their biomass fractionated, resulting in 117 chemical fractions. Reduction of neutral lipids in zebrafish larvae was observed for 12 fractions and in the human hepatocyte steatosis cell model for five fractions. The induction of ucp1 expression in murine brown adipocytes was observed in six fractions, resulting in a total of 23 bioactive non-toxic fractions. All extracts were analyzed by untargeted UPLC-Q-TOF-MS mass spectrometry followed by multivariate statistical analysis to prioritize bioactive strains. The metabolite profiling led to the identification of two markers with lipid reducing activity in zebrafish larvae. Putative compound identification using mass spectrometry databases identified them as phosphatidic acid and aromatic polyketides derivatives—two compound classes, which were previously associated with effects on metabolic disorders. In summary, we have identified cyanobacterial strains with promising lipid reducing activity, whose bioactive compounds needs to be identified in the future.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has currently caused a significant pandemic among worldwide populations. The high transmission and mortality rates of the disease necessitate studies for rapid designing and effective vaccine production. This study aims to predict and design a novel multi-epitope vaccine against the SARS-CoV-2 virus using bioinformatics approaches. Materials and Methods: Coronavirus envelope proteins, Open Reading Frame 7b (ORF7b), Open Reading Frame 8 (ORF8), Open Reading Frame 10 (ORF10), and Nonstructural protein 9 (Nsp9) were selected as targets for epitope mapping using Immune Epitope Data Bank (IEDB) and BepiPred 2.0 servers. Also, molecular docking studies were performed to determine the candidate vaccine’s affinity to Toll-Like Receptor (TLR3, TLR4) and Major Histocompatibility Complex (MHC I and MHC II) molecules. Thirteen epitopes were selected to construct the multi-epitope vaccine. Results: We found that the constructed peptide has valuable antigenicity, stability, and appropriate half-life. The Ramachandran and ERRAT plots approved the quality of the predicted model after the refinement process. Molecular docking investigations revealed that antibody-mode in the ClusPro 2.0 server showed the lowest binding energy for MHC I, MHC II, TLR3, and TLR4. Conclusion: The designed vaccine has a good antigenicity and stability and could be a proper vaccine candidate against the Coronavirus Disease 2019 (COVID-19) infectious disease though, in vitro and in vivo experiments are necessary to complete and confirm our results.

Abstract Walking while using a mobile phone has been shown to affect the walking dynamics of young adults. However, this has only been investigated using treadmill walking at a fixed walking speed. In this study, the dynamics of over ground walking were investigated using lower trunk acceleration measured over 12 consecutive trials, following differing walking speed and mobile phone use instructions. Higher walking speed significantly increased the proportion of acceleration along the vertical measurement axis, while decreasing the proportion of acceleration along the anteroposterior axis (p

Unilateral spatial neglect (USN) is a disorder characterized by the failure to report, respond to, or orient toward the contralateral side of space to a brain lesion. Current assessment methods often fail to discover milder forms, cannot differentiate between unilateral spatial neglect subtypes and lack ecological validity. There is also a need for treatment methods that target subtypes. Immersive virtual reality (VR) systems in combination with eye-tracking (ET) have the potential to overcome these shortcomings, by providing more naturalistic environments and tasks, with sensitive and detailed measures. This systematic review examines the state of the art of research on these technologies as applied in the assessment and treatment of USN. As we found no studies that combined immersive VR and ET, we reviewed these approaches individually. The review of VR included seven articles, the ET review twelve. The reviews revealed promising results. (1) All included studies found significant group-level differences for several USN measures. In addition, several studies found asymmetric behavior in VR and ET tasks for patients who did not show signs of USN in conventional tests. Particularly promising features were multitasking in complex VR environments and detailed eye-movement analysis. (2) No VR and only a few ET studies attempted to differentiate USN subtypes, although the technologies appeared appropriate. One ET study grouped USN participants using individual heatmaps, and another differentiated between subtypes on drawing tasks. Regarding (3) ecological validity, although no studies tested the prognostic validity of their assessment methods, VR and ET studies utilized naturalistic tasks and stimuli reflecting everyday situations. Technological characteristics, such as the field of view and refresh rate of the head-mounted displays, could be improved, though, to improve ecological validity. We found (4) no studies that utilized VR or ET technologies for USN treatment up until the search date of the 26th of February 2020. In conclusion, VR-ET-based systems show great potential for USN assessment. VR-ET holds great promise for treatment, for example, by monitoring behavior and adapting and tailoring to the individual person’s needs and abilities. Future research should consider developing methods for individual subtypes and differential diagnostics to inform individual treatment programs.

Background & objectives: Nuclear Factor kappa B (NF-κB), a master switch transcription factor, plays a critical role in the progression and development of hyperglycemia-induced microangiopathy. Hyperglycemia activates NF-κB, and subsequently increases pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β leading to development of inflammation. Some new studies have revealed the involvement of microRNA-146a (miR-146a) in the pathogenesis of diabetic complications through an NF-κB-dependent negative feedback loop manner. Despite numerous reports indicating changes of plasma miR-146a during hyperglycemia, the origin of this change remains unclear. This study was designed to evaluate the role of NF-κB on the miR-146a gene expression level in human umbilical vein endothelial cells (HUVECs) during a hyperglycemic condition. Methods: HUVECs were cultured in normal glucose (5 mmol/L), and hyperglycemic (25 mmol/L) endothelial cell growth medium in the six well plates for 24 h. JSH-23 (30 μmol/L), as an inhibitor of NF-κB translocation to the nucleus, was added to the culture medium, 30 min before induction of hyperglycemia. Quantitative Real Time PCR was performed to measure the expression levels of miR-146a and mRNA NF-κB. NF-κB activity was measured by Elisa. Results: Hyperglycemia markedly increased the NF-κB activity and mRNA level in HUVECs. The expression of miR-146a significantly increased in hyperglycemic group compared to the normoglycemic group. On the other hand, JSH-23 prevented from miR-146a increment in hyperglycemic group and also it increased the mRNA expression level of NF-κB in this group. Conclusion: This result shows that NF-κB increases the gene expression of miRNA-146a in the early phase of hyperglycemia in HUVECs.

Abstract Background The prevalence of cognitive disorders in hemodialysis patients is twice as high as the general population, while these disorders often are undiagnosed. Timely prevention and treatment can improve their personal and social functions. Aim of study was determined the effect of Valerian on cognitive disorders and electroencephalography (EGG) in hemodialysis patients. Methods This crossover, double-blind clinical trial was conducted on 39 hemodialysis patients. The patients were randomly divided into two groups. Group A (n = 19) took Valerian capsules and Group B (n = 20) received placebo capsules 60 min before bedtime for one month. The type of treatment was replaced between the two groups after a one-month wash-out. The Mini Mental State Examination (MMSE) questionnaire was completed and EGG was performed before and after intervention in both periods. Results The cognitive scores of the Group valerian were increased significantly in the first (p = 0.003) and the second (p = 0.005) periods. In addition, the mean increase in the cognitive scores in the Group valerian was significant in the first (p = 0.028) and the second periods (p = 0.030). However, the changes in EGG showed no significant difference before and after intervention in two groups. Conclusion The findings of this study indicated that valerian could be effective and significantly improve patients’ cognitive status; however, no significant changes were observed in the electroencephalography of the hemodialysis patients. Trial registration IRCT201606076318N7–2016-06-17.

Introduction Cardiovascular and metabolic diseases are a growing concern for individuals with spinal cord injury (SCI). Physical inactivity contributes to cardiometabolic morbidity and mortality in the SCI population. However, previous studies have shown mixed results regarding the effects of exercise on cardiometabolic risk factors in individuals with SCI. This discrepancy could be influenced by insufficient exercise stimuli. Recent guidelines recommend 30 min of moderate-to-vigorous intensity aerobic exercise, three times per week, for improvement in cardiometabolic health in individuals with SCI. However, to date, no studies have implemented an exercise intervention matching the new recommendations to examine the effects on cardiometabolic risk factors. Therefore, the primary objective of this study is to determine the effects of 12 weeks of wheelchair user-modified upper-body rowing exercise on both traditional (constituents of the metabolic syndrome) and novel (eg, vascular structure and function) cardiometabolic risk factors in manual wheelchair users with SCI.Methods and analysis A randomised controlled trial will compare 12 weeks of upper-body rowing exercise, 30 min three times per week, with a control group continuing their normal lifestyle. Outcome measurements will be performed immediately before (baseline), after 6 weeks (halfway), 12 weeks of training (post) and 6 months after the termination of the intervention period (follow-up). Outcomes will include inflammatory (eg, C reactive protein) and metabolic biomarkers determined from venous blood (with serum fasting insulin as primary outcome), body composition, arterial blood pressure, cardiorespiratory fitness level, brachial artery vascular structure and function and autonomic nervous system function.Ethics and dissemination This trial is reported to the Danish Data Protection Agency (J.nr. 2019-899/10-0406) and approved by the Committees on Health Research Ethics in The North Denmark Region on 12 December 2019 (J.nr. N-20190053). The principal investigator will collect written informed consent from all participants prior to inclusion. Irrespective of study outcomes, the results will be submitted to peer-reviewed scientific journals for publication.Trial registration number NCT04390087.

IRE1/XBP-1 activation has a major role in Triple negative breast cancer (TNBC). Here, the authors show that inhibition of IRE1’s RNase activity attenuates autocrine and paracrine signaling of pro-tumorigenic cytokines and synergizes with paclitaxel to confer potent anti-tumor effects in TNBC.

Background and aim: Aphasia as a common consequence of stroke, is an acquired neurologic communication disorder that can affect symbol language processing. Different types of intervention approaches have been introduced. Multimodal Communication Program (MCP) is a new augmentative alternative communication approach in chronic aphasia. The aim of this study was to investigate the effect of MCP on communication skills of patients with chronic aphasia. Methods: This prospective, single subject, A-B-A design study was done during 2016 in Semnan, Iran. Participants were two patients with severe aphasia with a single left-hemisphere stroke. Three phases, including baseline, intervention and follow-up were administered. The patients received nine-hour intervention, over 10 working days. Results: Three different scores were calculated for each patient: verbal efforts, the frequency of each modality and the accuracy of switching between modalities and the reaction time. The frequency of verbal modality increased for both patients. They could switch between modalities more successfully than before the intervention. The results for the reaction time, however were challenging. The onset reaction time decreased for patient 1, and increased during switching between modalities, and patient 2 showed the opposite. Conclusion: The MCP can improve the communication skills in patients with chronic post stroke aphasia. However, some factors, such as reduction of the patients’ reaction time is probably related to the amount of allocated resources during intervention. Trial registration: The trial was registered at IRCT center with ID: IRCT2016032325194N3. Funding: The study was financed by Semnan University of Medical Sciences (Grant no.: A-10-333-3).

The sensitivity of oculometrics to the changes in mental load has already been investigated in several studies. However, the reliability of oculometrics remains unexplored, particularly under concurrent mental demands. To address this, we recruited 20 young and 18 elderly healthy adults to perform a functional computer task with three levels of mental load (i.e., low, medium, and high) on two days interspaced by at least seven days. We tracked the participants' eye movements and pupil size during the task and computed the characterizing features of saccades, fixations, blinks, pupillary responses as well as nonlinear dynamics of pupillary responses and gaze trajectories. In addition, we recorded the trace of the computer mouse for performance measurement and acquired subjective ratings of the perceived task load. Among the investigated oculometrics, saccadic peak velocity (SPV) and its rate of changes across saccade amplitude (SVA) were influenced by the level of the task load in both the young and elderly adults, and the effects remained consistent across days. Reliability assessments revealed good to excellent test-retest reliability and acceptable absolute reliability in SPV, SVA, and the duration of fixations and saccades. The perceived load and task performance were monotonically altered with the task load levels. These findings may provide practical implications on mental load quantification in occupational fields.

Abstract Background Low back pain and neck-shoulder pain are the most reported types of work-related musculoskeletal disorders, and performing heavy lifting at work and working with trunk rotation increase the risk of developing work-related musculoskeletal disorders. Surface electromyography (sEMG) provides information about the electrical activity of muscles. Thus it has the potential to retrieve indirect information about the physical exposure of specific muscles of workers during their actual work. This study aimed to investigate the inter-day reliability of absolute and normalized amplitude of sEMG measurements obtained during repeated standardized reference lifts. Methods The inter-day reliability of sEMG of the erector spinae longissimus and trapezius descendens muscles was tested during standardized box lifts. The lifts were performed with loads of 3, 15 and 30 kg from floor to table and from table to table in three conditions, i.e., forearm length (short reaching distance), ¾ arm length (long reaching distance) and forearm length with trunk rotation. Absolute and normalized root mean square (absRMS and normRMS) values were extracted. In line with the guidelines for reporting reliability and agreement studies, we reported relative and absolute reliability estimated by intra class correlation (ICC3,K), standard error of measurement (SEM) and minimal detectable change in percent (MDC). Results The ICC3,K was higher for absRMS compared with normRMS while SEM and maximal voluntary contraction (MVC) were similar. A total of 50 out of 56, i.e., 89%, and 41 out of 56, i.e., 73%, of the lifting situations were in the range from moderate to almost perfect for absRMS and normRMS, respectively. The SEM and MDC shoved more variation in the lifting situations performed from floor to table and in the trapezius descendens muscle than in the erector spinae longissimus muscle. Conclusion This reliability study showed that maximum absRMS and normRMS were found to have a fair to substantial relative inter-day reliability for most lifts but were more reliable when lifting from table to table than from floor to table for both trapezius descendens and erector spinae muscles. The relative inter-day reliability was higher for absolute compared with normalized sEMG amplitudes while the absolute reliability was similar.

The increasingly widespread use of engineered nanoparticles in medical, industrial, and food applications has raised concerns regarding their potential toxicity to humans and the environment. Silicon dioxide nanoparticles (SiO2 NPs), which have relatively low direct toxicity, have been increasingly applied in both consumer products and biomedical applications, leading to significantly higher exposure for humans and the environment. We carried out a toxicity assessment of SiO2 NPs using the common water flea D. magna by focusing on physiological and behavioral indicators such as heart rate, swimming performance, and growth. Exposure to SiO2 NPs did not produce acute or chronic toxicity at limited concentrations (2 NP accumulation in D. magna, which was confirmed by ICP-MS. Although exposure to SiO2 NPs seemed to affect cardiac and swimming performance, such end-point experiments may be insufficient to fully understand the toxicity of these nanoparticles. However, the physiological and behavioral changes shown here suggest potential adverse effects on the aquatic environment by substances previously considered nontoxic.

Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject’s lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar–capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF.

Objective(s): Umbelliprenin is a prenyloxy-coumarin with pharmacologically polyvalent activity. Several studies have shown its anti-inflammatory, anti-tumor, antioxidant, and antigenotoxic activity, and other functions. However, the exact mechanism of action of this compound on the immune response has not yet been shown. Here, we investigated umbelliprenin effects on the predominance of Th1 and Th2 responses in normal C57/BL6 mice. Materials and Methods: Umbelliprenin (2.5 mg/200 µl IP) were administered to six C57/BL6 mice every other day for 8 days. Paraffin and PBS-injected mice were enrolled as solvent and control groups, respectively (n=6 mice/group). IL-10, IFN-γ, and IL-4 levels were determined in sera and also in splenocytes culture supernatants in the presence of Con A (3 µg/ml) after 72 hr. H&E staining of paraffin embedded blocks was performed for lung and liver tissues of mice. Results: Umbelliprenin could significantly increase the secretion of IFN-γ and IL-4 in sera and IL-10 in splenocytes cultures. Comparison of IFN-γ /IL-4 in the sera and splenocytes culture supernatants showed lower ratios in umbelliprenin treated mice than in solvent and untreated groups. Conclusion: The in vivo study showed that umbelliprenin could induce anti-inflammatory responses via the predominance of Th2 cells and some regulatory responses in C57/BL6 mice.

Background: Interleukin (IL)-23 has an important role in tumor immune regulation. Objective: To investigate the possible association of interleukin-23 receptor (IL23R) gene variants rs1884444, rs10889677 and rs11209026 with development of acute lymphoblastic leukemia (ALL). Methods: The IL23R variants were studied in 164 ALL patients and compared to 175 healthy controls by polymerase chain reaction-restriction fragment length polymorphism. The relationship between these variants and clinical and laboratory features of the patients and response to therapy were evaluated. Results: No significant differences in genotype and allele frequencies existed between patients and controls. The rs1884444TG genotype was significantly lower in patients who relapsed (24.2%) compared to those without relapse (55.9%, p=0.006). Fewer patients who relapsed had evidence of the G allele (P=0.034). The TG genotype was associated with a longer complete remission at1804±116 days compared to other genotypes (100×103μL (68.4% and 52.4%, respectively). Conclusion: Our findings showed a lack of association of the studied polymorphisms with the risk of ALL. The influence of the rs1884444 polymorphism on relapse rate and association of rs10889677 AA genotype with favorable prognostic factors suggest the influence of the studied polymorphisms on ALL response to therapy and prognosis.

Background: Arachnoid cysts are cerebrospinal fluid (CSF) fluid-filled sacs that are located between the brain and spinal cord. Spinal column arachnoid cysts are rare and mostly asymptomatic, being mostly located in intradural regions. We reported a patient who presented with neurological deficits and mid-thoracic extradural arachnoid cyst treated with en-bloc resection. Case Presentation: Patient was a 34-year-old female who presented with progressive back pain, lower extremity weakness and paresthesia in her lower limbs. Magnetic resonance imaging (MRI) study revealed an extradural hyperintense signal lesion in T2-weighted, extending from T7 to T9, which did not enhance on T1-weighted post-contrast MRI. Patient underwent T6-T10 laminectomy and en-bloc resection of the lesion which was compatible with arachnoid cyst after histopathological examination. Patient did not experience worsening of neurological symptoms and lesion recurrence in clinical and imaging evaluation during 2-year follow-up. Conclusion: Clinical and neuroimaging evaluation of every patient with progressive neurological deficits should be carried out in detail. This report suggests that rare spinal lesion, as extradural spinal arachnoid cyst in this case, may cause neurologic deficits and en-bloc resection of the lesion is feasible and may prevent local recurrence.

Abstract Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses.

A biofeedback system may objectively identify fatigue and provide an individualized timing plan for micro-breaks. We developed and implemented a biofeedback system based on oculometrics using continuous recordings of eye movements and pupil dilations to moderate fatigue development in its early stages. Twenty healthy young participants (10 males and 10 females) performed a cyclic computer task for 31-35 min over two sessions: 1) self-triggered micro-breaks (manual sessions), and 2) biofeedback-triggered micro-breaks (automatic sessions). The sessions were held with one-week inter-session interval and in a counterbalanced order across participants. Each session involved 180 cycles of the computer task and after each 20 cycles (a segment), the task paused for 5-s to acquire perceived fatigue using Karolinska Sleepiness Scale (KSS). Following the pause, a 25-s micro-break involving seated exercises was carried out whether it was triggered by the biofeedback system following the detection of fatigue (KSS≥5) in the automatic sessions or by the participants in the manual sessions. National Aeronautics and Space Administration Task Load Index (NASA-TLX) was administered after sessions. The functioning core of the biofeedback system was based on a Decision Tree Ensemble model for fatigue classification, which was developed using an oculometrics dataset previously collected during the same computer task. The biofeedback system identified fatigue with a mean accuracy of approx. 70%. Perceived workload obtained from NASA-TLX was significantly lower in the automatic sessions compared with the manual sessions, p = 0.01 Cohen's dz = 0.89. The results give support to the effectiveness of integrating oculometrics-based biofeedback in timing plan of micro-breaks to impede fatigue development during computer work.

An important event in the unfolded protein response (UPR) is activation of the endoplasmic reticulum (ER) kinase PERK. The PERK signalling branch initially mediates a prosurvival response, which progresses to a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92 transcript and mature miRNAs belonging to the miR-17-92 cluster are decreased during UPR. We found that miR-17-92 promoter reporter activity was reduced during UPR in a PERK-dependent manner. Furthermore, we show that activity of the miR-17-92 promoter is repressed by ectopic expression of ATF4 and NRF2. Promoter deletion analysis mapped the region responding to UPR-mediated repression to a site in the proximal region of the miR-17-92 promoter. Hypericin-mediated photo-oxidative ER damage reduced the expression of miRNAs belonging to the miR-17-92 cluster in wild-type but not in PERK-deficient cells. Importantly, ER stress-induced apoptosis was inhibited upon miR-17-92 overexpression in SH-SY5Y and H9c2 cells. Our results reveal a novel function for ATF4 and NRF2, where repression of the miR-17-92 cluster plays an important role in ER stress-mediated apoptosis. Mechanistic details are provided for the potentiation of cell death via sustained PERK signalling mediated repression of the miR-17-92 cluster.

Gene therapy consists of the introduction of genetic material into cells for a therapeutic purpose. The understanding of the basics of the molecular and cellular mechanisms in disease treatments has resulted in the development of high-tech gene transfer materials with improved therapeutic efficacy. Based on the results of more than 2000 clinical trials to date, gene therapy is going to be included in standard treatment approaches in some specific diseases. Also, gene therapy has been highly improved in central and peripheral nervous system diseases. This review tried to focus on techniques and approaches in brain tumors and nervous system’s gene therapy strategies and will discuss about associated problems and potential future in management of inherited or acquired neurological disorders.

Background: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system and cytokines may play a role in the development of MS lesions. Objective: To determine levels of different cytokines in patients with relapsing-remitting MS (RR-MS) compared to healthy controls. Methods: Profiles of pro-inflammatory, Th1-, Th2-, and Th17-related cytokines were compared by quantitative multiplexed ELISA-based chemiluminescent assay in 44 RR-MS and 44 healthy age- and sex-matched individuals from the same ethnicity. Results: Among pro-inflammatory cytokines, the levels of IL-6 (p=0.003), IL-8 (p=0.05) and TNF-α (p=0.002) were higher in patients than controls, though IL-4 and IL-10 as well as ΣTh2 cytokines were lower in patients (p=0.05, p=0.02 and p=0.05, respectively). After gender classification, the higher levels of IL-4 in male patients remained significant and IL-13 also showed significantly higher levels in male patients compared to male controls (p=0.003 and p=0.05, respectively). A significant negative correlation was detected between EDSS and IL-10 or ΣTh2 levels (p=0.005). In addition, IL-1α (r=0.4, p=0.05) and IFN-γ (r=0.35, p=0.05) were also directly correlated with EDSS in female patients. Conclusions: Patients with RR‑MS who are in the relapse clinical phase exhibit higher levels of pro-inflammatory cytokines and reduction in protective Th2-related cytokines.

OBJECTIVES: This study aimed to investigate the association between forward bending of the trunk and low-back pain intensity (LBPi) among blue-collar workers in Denmark as well as whether the level of social support modifies the association. METHODS: In total, 457 workers were included in the study. The forward bending of ≥30° was computed from accelerometer recordings for several consecutive days during work, categorized into long (highest tertile) and short–moderate (remaining tertiles) duration. LBPi was measured on a 0–10 scale and categorized into low (≤5) and high (>5) pain. Self-reported social support was categorized into low, moderate, and high levels. Multi-adjusted logistic regressions estimated the association between forward bending and LBPi and the effect modification by social support. RESULTS: Forward bending and LBPi were not significantly associated but modified by social support. Workers with low social support and long duration of forward bending had higher likelihood of high LBPi [odds ratio (OR) 2.97, 95% confidence interval (95% CI) 1.11–7.95] compared to workers with high social support and long duration of forward bending. Among workers with low social support, workers with long duration of forward bending had higher likelihood of high LBPi (OR 3.28, 95% CI 0.99–10.90) compared to workers with short–moderate duration of forward bending. Among workers with high social support, workers with long duration of forward bending had reduced likelihood of high LBPi (OR 0.39, 95% CI 0.16–0.95) compared to workers with short–moderate duration of forward bending. CONCLUSIONS: Social support modifies the association between objectively measured forward bending and LBPi among blue-collar workers.

Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with a very poor survival rate. Temozolomide (TMZ) is the common chemotherapeutic agent used for GBM treatment. We recently demonstrated that simvastatin (Simva) increases TMZ-induced apoptosis via the inhibition of autophagic flux in GBM cells. Considering the role of the unfolded protein response (UPR) pathway in the regulation of autophagy, we investigated the involvement of UPR in Simva–TMZ-induced cell death by utilizing highly selective IRE1 RNase activity inhibitor MKC8866, PERK inhibitor GSK-2606414 (PERKi), and eIF2α inhibitor salubrinal. Simva–TMZ treatment decreased the viability of GBM cells and significantly increased apoptotic cell death when compared to TMZ or Simva alone. Simva–TMZ induced both UPR, as determined by an increase in GRP78, XBP splicing, eukaryote initiation factor 2α (eIF2α) phosphorylation, and inhibited autophagic flux (accumulation of LC3β-II and inhibition of p62 degradation). IRE1 RNase inhibition did not affect Simva–TMZ-induced cell death, but it significantly induced p62 degradation and increased the microtubule-associated proteins light chain 3 (LC3)β-II/LC3β-I ratio in U87 cells, while salubrinal did not affect the Simva–TMZ induced cytotoxicity of GBM cells. In contrast, protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibition significantly increased Simva–TMZ-induced cell death in U87 cells. Interestingly, whereas PERK inhibition induced p62 accumulation in both GBM cell lines, it differentially affected the LC3β-II/LC3β-I ratio in U87 (decrease) and U251 (increase) cells. Simvastatin sensitizes GBM cells to TMZ-induced cell death via a mechanism that involves autophagy and UPR pathways. More specifically, our results imply that the IRE1 and PERK signaling arms of the UPR regulate Simva–TMZ-mediated autophagy flux inhibition in U251 and U87 GBM cells.

Stroke impairments often present as cognitive and motor deficits, leading to a decline in quality of life. Recovery strategy and mechanisms, such as neuroplasticity, are important factors, as these can help improve the effectiveness of rehabilitation. The present study investigated chiropractic spinal manipulation (SM) and its effects on resting-state functional connectivity in 24 subacute to chronic stroke patients monitored by electroencephalography (EEG). Functional connectivity of both linear and non-linear coupling was estimated by coherence and phase lag index (PLI), respectively. Non-parametric cluster-based permutation tests were used to assess the statistical significance of the changes in functional connectivity following SM. Results showed a significant increase in functional connectivity from the PLI metric in the alpha band within the default mode network (DMN). The functional connectivity between the posterior cingulate cortex and parahippocampal regions increased following SM, t (23) = 10.45, p = 0.005. No significant changes occurred following the sham control procedure. These findings suggest that SM may alter functional connectivity in the brain of stroke patients and highlights the potential of EEG for monitoring neuroplastic changes following SM. Furthermore, the altered connectivity was observed between areas which may be affected by factors such as decreased pain perception, episodic memory, navigation, and space representation in the brain. However, these factors were not directly monitored in this study. Therefore, further research is needed to elucidate the underlying mechanisms and clinical significance of the observed changes.

Inositol-requiring enzyme 1α (IRE1α) is a transmembrane dual kinase/ribonuclease protein involved in propagation of the unfolded protein response (UPR). Inositol-requiring enzyme 1α is currently being explored as a potential drug target due to the growing evidence of its role in variety of disease conditions. Upon activation, IRE1 cleaves X-box binding protein 1 (XBP1) mRNA through its RNase domain. Small molecules targeting the kinase site are known to either increase or decrease RNase activity, but the allosteric relationship between the kinase and RNase domains of IRE1α is poorly understood. Subsets of IRE1 kinase inhibitors (known as “KIRA” compounds) bind to the ATP-binding site and allosterically impede the RNase activity. The KIRA compounds are able to regulate the RNase activity by stabilizing the monomeric form of IRE1α. In the present work, computational analysis, protein−protein and protein−ligand docking studies, and molecular dynamics simulations were applied to different IRE1 dimer systems to provide structural insights into the perturbation of IRE1 dimers by small molecules kinase inhibitors that regulate the RNase activity. By analyzing structural deviations, energetic components, and the number of hydrogen bonds in the interface region, we propose that the KIRA inhibitors act at an early stage of IRE1 activation by interfering with IRE1 face-to-face dimer formation thus disabling the activation of the RNase domain. This work sheds light on the mechanism of action of KIRA compounds and may assist in development of further compounds in, for example, cancer therapeutics. The work also provides information on the sequence of events and protein−protein interactions initiating the unfolded protein response.