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Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Tangential velocity (V t) of tornadoes is the major parameter that causes building damage. In-field tornado measurements are less reliable at less than 20 m above ground level (AGL). Laboratory tornado simulators suggest that swirl ratio (S) and radius (r o) are the major tornado parameters that influence the V t. However, due to scaling problems, the laboratory simulators also report the V t at greater than 20 m AGL. Well-refined computational fluid dynamics (CFD) models can evaluate the V t at less than 10 m AGL. However, the CFD models are limited to r o = 1.0 km, and the effect of r o on V t is not investigated. The aim of this study is to investigate the maximum V t for different r o close to ground. Simulation results show that increasing r o decreases the maximum V t with respect to V ro. Moreover, by increasing ro, the corresponding elevation of occurrence of maximum Vt (zmax) will increase. However, for all tornado radii, the zmax is between 20 m and 64 m AGL. In addition, results show that for all r o , the radial V t profile has two peaks at z < 10 m AGL due to strong shear force close to the ground and at higher elevation the profile transits to Rankine Combined Vortex Model (RCVM). • When the tornado or tornado chamber radius (r o) increases the touchdown swirl ratio increases. • o The increase in radius (r) reduces the ratio of the maximum tangential velocity to radial velocity. • Close to the ground, the radial profile of the tangential velocity has two peaks. • Close to the ground the radial velocity profile is not same as the Rankine Combined Vortex Model. [ABSTRACT FROM AUTHOR]

Pretreatment and hydrolysis of lignocellulosic biomass are affected by several uncertainties, which must be systematically considered for a robust process design. In this work, stochastic simulations for expected uncertainties in feedstock composition, kinetic parameter values, and operational parameter values for these two steps were performed. The results indicated that these uncertainties significantly impacted the concentration profiles, which could also affect the optimal batch time. Global sensitivity analysis was then used to identify the critical uncertain parameters. In the feedstock components, cellulose and xylan fractions for acid pretreatment and cellulose fraction for enzymatic hydrolysis were important. Temperature was the most sensitive operating parameter for both acid pretreatment and hydrolysis. The activation energies for different reactions were ranked in terms of their impact on process output. The selected parameters were used to develop stochastic process models using Ito process and mean reverting process for feed composition and kinetic parameter uncertainty. [ABSTRACT FROM AUTHOR]

We present a reservoir geophysics study, including rock physics modeling and seismic inversion, of a carbon dioxide sequestration site in Southwestern Wyoming, namely the Rock Springs Uplift, and build a petrophysical model for the potential injection reservoirs for carbon dioxide sequestration. Our objectives include the facies classification and the estimation of the spatial model of porosity and permeability for two sequestration targets of interest, the Madison Limestone and the Weber Sandstone. The available dataset includes a complete set of well logs at the location of the borehole available in the area, a set of 110 core samples, and a seismic survey acquired in the area around the well. The proposed study includes a formation evaluation analysis and facies classification at the well location, the calibration of a rock physics model to link petrophysical properties and elastic attributes using well log data and core samples, the elastic inversion of the pre-stack seismic data, and the estimation of the reservoir model of facies, porosity and permeability conditioned by seismic inverted elastic attributes and well log data. In particular, the rock physics relations are facies-dependent and include granular media equations for clean and shaley sandstone, and inclusion models for the dolomitized limestone. The permeability model has been computed by applying a facies-dependent porosity-permeability relation calibrated using core sample measurements. The study shows that both formations show good storage capabilities. The Madison Limestone includes a homogeneous layer of high-porosity high-permeability dolomite; the Weber Sandstone is characterized by a lower average porosity but the layer is thicker than the Madison Limestone. [ABSTRACT FROM AUTHOR]

Several studies have been carried out to investigate the magnitude of forces induced by tornado-like winds on buildings from experimental as well as computational side. The number of experimental studies evaluating the wind loads due to tornado-like vortices are comparatively greater in number than studies based on computational fluid dynamics (CFD). Furthermore, the limited number of CFD studies were often not validated by comparing with experimental measurements. In this work, an attempt is made to validate a CFD model by comparing the pressures induced by tornado-like vortices on a building model with experimental measurements from the tornado simulator at Texas Tech University (TTU). Results of the comparison indicate that the pressure coefficients obtained from the CFD model agree well with TTU experimental datasets. Besides, the effect of building size as well as the effect of flow structure of vortex on pressure coefficients on the building induced by tornado-like vortex is also investigated. It is observed that the pressures on the building can differ by up to 100% when different sizes of building is considered and the vortex with a single celled structure creates the most unfavorable loading conditions on the building model. • A state of the art review on pressures induced by tornado-like vortex on building from existing literature is presented. • Tornado-induced pressures on building computed from CFD model are validated by comparing with TTU experimental datasets. • Influence of size of the building model on the pressures induced by tornado-like vortex is presented. • The influence of different flow structures of vortex on induced pressures on the building is presented. [ABSTRACT FROM AUTHOR]

Abstract: This paper examines the effect of mixer size on the density of the propellant and it also explores the role of the propellant density with regards to burning rate and burn rate pressure index. Propellant samples were prepared in the four different size (15, 70, 200 and 1000g) mixers with identical input of ingredients to examine the effect of mixer size on density and burning rate of the composite solid propellant. It was noticed that density and burning rate of the propellant changes significantly with change in the mixer size from 15g to 1000g. This is because for the smaller mixers the surface area to volume ratio is large and the actual percentage of aluminum and ammonium perchlorate (especially coarse) that goes into the propellant reduces. High burning rate with decrease in mixer size is also accompanied with increase in burn rate pressure index. The composition analysis was also carried out and it is noticed that the actual percentage of the ingredients is different from the intended percentage of the ingredients and percentage change is more when the mixer size decreases. [Copyright &y& Elsevier]

Abstract: Evaluation of acute ataxia in a child poses a dilemma for the clinician in determining the extent and timing of initial screening tests. This article reviews the evidence concerning the diagnostic yield of commonly ordered tests in evaluating the child with acute ataxia. The literature revealed the following frequencies of laboratory screening abnormalities in children with acute ataxia: CT (∼2.5%), MRI (∼5%), lumbar puncture (43%), EEG (42%), and toxicology (49%). In most studies, abnormalities detected by these screening tests were nondiagnostic. There are insufficient data to assess yields of testing for autoimmune disorders or inborn errors of metabolism. A toxicology screen should be considered in all children presenting with acute ataxia. Neuroimaging should be considered in all children with new onset ataxia. Cerebrospinal fluid analysis has limited diagnostic specificity unless clinically indicated. Studies to examine neurophysiology testing did have sufficient evidence to support their use. There is insufficient evidence to establish a role for autoantibody testing or for routine screening for inborn error of metabolism in children presenting with acute ataxia. Finally, in a child presenting with ataxia and opsoclonus myoclonus, urine catecholamine testing for occult neuroblastoma is recommended. Nuclear scan may be considered, however, there is insufficient evidence for additional body imaging. [Copyright &y& Elsevier]

Abstract: This paper reports the discovery of activated charcoal as an effective burn rate enhancer of aluminized composite solid propellant. Experiments were carried out using a strand burner at pressures ranging from 10 to 70bar with varying fractions of activated charcoal. The results show that with the addition of activated charcoal in an aluminized composite propellant higher burn rates (in excess of 25mm/s at 70bar) were obtained. This paper also explores the possibility of further enhancing the burn rates of aluminized composite propellant by using iron oxide along with activated charcoal. Burn rates recorded with iron oxide and activated charcoal both present in the propellant were in excess of 50mm/s at 70bar. It was noticed that these high burn rates were accompanied by a higher (0.65) pressure index of combustion. A series of experiments were designed to understand the burn rate enhancement with activated charcoal in aluminized composite propellant. TGA and DSC tests were carried out on AP pellets with and without activated charcoal to detect any condensed phase activity of activated charcoal. These tests did not show any significant difference between the AP pellets with and without activated charcoal. The AP pellets with and without activated charcoal were also burnt in a strand burner to understand if any gas phase reaction was being catalyzed by activated charcoal. AC does not enhance any gas phase activity while addition of AC in AP increased the LPDL of AP and reduced the burn rate. Lastly, sandwich propellant with activated charcoal at the interface was prepared to determine if interface reactions were being affected with the addition of activated charcoal. It has been observed that with the addition of activated charcoal at the AP–binder interface the burn rates are higher than those recorded without activated charcoal at the AP–binder interface. [Copyright &y& Elsevier]

• Integrated model was developed for acid pretreatment and enzymatic hydrolysis. • Actual profit from integrated model was mainly affected by cost of enzyme. • Sensitivity analysis under exogenous uncertainties performed for integrated model. • At low cost of enzyme hot utility flow rate and batch time are important. Acid pretreatment (AP) is one of the most widely used processing step in the biochemical route of ethanol production from sugarcane bagasse. During AP, changes in structural features of bagasse, such as crystallinity and surface area, influence enzymatic hydrolysis (EH). Therefore, an integrated optimization study is performed by combining these two processes. Hot utility flow rate and acid concentration of AP are decision variables and the combined severity factor (CSF) of AP affects the EH yields. Three optimization studies, namely, yield maximization, profit maximization of AP, and profit maximization of AP and EH together, are considered, and the actual profit for combined AP and EH for the optimal operating condition recommended by each study are compared. The results showed that combined profit maximization improved in the actual profit as compared to yield maximization study by as much as 18–130 % across various combinations of solid loading and batch times. The benefit was due to implementation of less severe conditions in AP, reflected in 7–13 % reduction in CSF. However, it was also observed that the benefit of combined profit maximization over profit maximization of AP was a function of enzyme cost. The benefit was marginal for low enzyme cost of 0.85 $/kg, but increased up to 13.6 % for the enzyme cost of 3 $/kg. Sensitivity analysis was performed to identify batch time and enzyme cost as key exogenous parameters. [ABSTRACT FROM AUTHOR]

Abstract Breast cancer remains one of the leading causes of cancer related deaths in women worldwide. Bharangin is a diterpenoid quinonemethide that has demonstrated therapeutic potential against leukemia, lymphoma, and multiple myeloma cells. Whether this diterpenoid exhibit activities against breast cancer cells and the underlying mechanism is largely unknown. Herein, we provide evidence that bharangin suppresses the proliferation of MCF-7, MDA-MB-231, MDA-MB-453, MDA-MB-468 and T-47D breast cancer cells. As examined by AO/PI staining, DAPI staining, sub-G1 analysis, phosphatidylserine externalization, caspase activation, DNA laddering, and poly-ADP ribose polymerase cleavage, the diterpenoid induced apoptosis in breast cancer cells. The growth inhibitory effect of bharangin on breast cancer cells was further confirmed from colony-formation assay. Furthermore, the cancer cell migration was also suppressed by the diterpenoid. Mechanistically, bharangin was found to modulate multiple cancer related cell signalling pathways in breast cancer cells. Bharangin suppressed the expression of cell survival and invasive proteins, and induced Bax and mitochondrial depolarization in breast cancer cells. The diterpenoid also suppressed the activation of pro-inflammatory transcription factor, nuclear factor (NF)-κB induced by okadaic acid. Finally, the diterpenoid induced the expression of tumor suppressor lncRNAs (MEG-3, GAS-5), while down-regulating oncogenic H19 expression. Overall, these results suggest that bharangin exhibits anti-carcinogenic, anti-proliferative and anti-inflammatory activities against breast cancer cells. The modulation of lncRNA expression and inhibition of NF-κB activation by bharangin may contribute to its anti-carcinogenic activities. Graphical abstract Unlabelled Image Highlights • Bharangin is a diterpenoid quinonemethide derived from Pigmacopremna herbacea. • Bharangin induces apoptosis and suppresses proliferation of breast cancer cells. • Bharangin suppresses NF-κB activation in breast cancer cells. • Bharangin suppresses NF-κB regulated tumorigenic proteins in breast cancer cells. • Bharangin modulates lncRNAs expression in breast cancer cells. [ABSTRACT FROM AUTHOR]

Progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) is a severe and rare progressive neurodegenerative disease (OMIM 617913). This condition has been described in individuals with pathogenic variants affecting tubulin-specific chaperone protein D (TBCD), which is responsible for proper folding and assembly of tubulin subunits. Here we describe two unrelated infants from Central America presenting with worsening neuromuscular weakness, respiratory failure, polyneuropathy, and neuroimaging findings of severe cerebral volume loss with thin corpus callosum. These individuals harbored the same homozygous variant of uncertain significance in the TBCD gene on whole exome sequencing (WES). Predicted protein modeling of this variant confirmed disruption of the protein helix at the surface of TBCD. The goal of this report is to emphasize the importance of rapid WES, careful interpretation of uncertain variants, prognostication, and family counseling especially when faced with a neurodegenerative clinical course. [ABSTRACT FROM AUTHOR]

Background: Hereditary spastic paraplegia (HSP) encompasses several rare genetic disorders characterized by progressive lower extremity spasticity and weakness caused by corticospinal tract degeneration. Published literature on genetically confirmed pediatric HSP cases is limited.Methods: We conducted a retrospective review of childhood-onset HSP cases followed in the neuromuscular clinics at Children's and Emory Healthcare in Atlanta. Clinical presentation, family history, examination, electrodiagnostic data, neuroimaging, genetic test results, comorbidities, and treatment were recorded.Results: Sixteen patients with HSP (eight males, eight females) with a mean age 19 years ± 15.7 years were included. Ten patients (66%) presented with gait difficulty. Seven (44%) were ambulatory at the last clinic follow-up visit with an average disease duration of 7.4 years. Genetically confirmed etiologies included SPAST (3 patients), MARS (2), KIF1A (2), KIF5A (1), SACS (1), SPG7 (1), REEP1 (1), PNPT1 (1), MT-ATP6 (1), and ATL1 (1). Symptom onset to genetic confirmation on an average was 8.2 years. Sensory motor axonal polyneuropathy was found in seven patients, and two exhibited cerebellar atrophy on magnetic resonance imaging (MRI) of the brain. Neurological comorbidities included developmental delay (n = 9), autism (n = 5), epilepsy (n = 3), and attention-deficit/hyperactivity disorder (n = 2).Conclusions: In our study, a significant proportion (70%) of subjects with childhood-onset HSP had comorbid neurocognitive deficits, polyneuropathy with or without neuroimaging abnormalities, and rare genetic etiology. Genetic diagnosis was established either through inherited genetic neuropathy panel or whole-exome sequencing, which supports the utility of whole-exome sequencing in aiding in HSP diagnosis. [ABSTRACT FROM AUTHOR]

The current article provides a detailed account of the current understanding of molecular and clinico-pathological aspects of Human papilloma virus (HPV) driven head and neck squamous cell carcinoma (HNSCC). The literature review included most of the landmark trials and clinical studies related to the HPV driven HNSCC. HPV positive HNSCC differ distinctly from HPV negative tobacco-related HNSCC, especially in oropharyngeal region. Therefore, the American joint committee on cancer's latest manual for classification and staging of cancer suggests a separate staging system for HPV positive oropharyngeal cancers. Despite the younger patients being affected and the high propensity for cervical metastasis, the HPV positive oropharyngeal cancers respond much better to the treatment. The association with wild type TP53 and low EGFR expression confers the favorable prognosis in HPV driven HNSCC. Since the association is not universal, we suggest checking for p53 and EGFR expression status before considering de-intensification of therapy. In addition, the presence of matted lymph nodes and five or more nodes could mean relatively poorer prognosis, and are not suitable for de-intensification of therapy. The same is also true probably with higher T stage and co-existing tobacco use. The methods for the detection of p16, HPV DNA, HPV E6/E7 mRNA, anti-E6/E7 antibodies, in tissue, in serum and in saliva of patients, along with their clinical implications are also discussed. This article provides latest developments on the HPV driven HNSCC. 'Diagnosis of transcriptionally active HPV infection,' 'Modalities for surveillance,' 'Implication of de-escalation of therapy' are some of the critical issues that could serve the medical, the research as well as the patient communities. Unlabelled Image [ABSTRACT FROM AUTHOR]

Caffeine (1,3,7-trimethylxanthine) is a naturally occurring, habitually consumed food constituent throughout the world. Prospective cohort studies revealed that caffeine consumption reduces the relative risk of various cancers. Avoiding immune destruction is one of the emerging hallmarks of cancer. One of the immunosuppressive pathways that contribute in avoiding immune destruction by cancer cells is adenosine-A2A receptor pathway. Based on prospective epidemiological and mechanistic preclinical studies of caffeine and its predominant antagonistic effect on A2A receptor, we aimed to investigate the effect of caffeine on T cell infiltration into the tumor and expression of PD-1 receptor on T lymphocytes during tumor initiation and progression in a carcinogen-induced tumor model. Our results demonstrate that caffeine treatment significantly lowered tumor incidence and tumor growth rate. We found that the total T-lymphocyte infiltration and CD8+ T lymphocyte infiltration was significantly increased in caffeine-treated groups. On the other hand, the infiltration of CD4+CD25+ regulatory T lymphocyte was significantly decreased in caffeine-treated groups. In addition, the PD-1 expression on CD8+ T lymphocytes and CD4+CD25+ regulatory T lymphocytes was significantly reduced in caffeine-treated groups. We further investigated whether the observed anti-tumor effect of caffeine is mediated through the release of cytokines. We found that TNF-α and IFN-γ levels were significantly higher in caffeine-treated groups. The findings of the present study unraveled the immune-related mechanisms behind the caffeinated coffee consumption and lower tumor incidence in humans. In conclusion, the blockade of adenosine pathway by caffeine may constitute an effective means to enhance anti-tumor immune response. Image 1 [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is an aggressive malignancy of gastrointestinal tract. Due to uncontrolled growth, GBC cells rapidly synthesize biomolecules including lipids. The lipids are integral component of cell membrane with a wide range of cellular functions. In this study, we measured the clinicopathological features in 40 cases of histologically confirmed GBC and 16 cases of chronic cholecystitis (CC). The female to male ratio in the GBC and CC groups were 3.44:1 and 2.2:1, respectively. The GBC patients exhibited well to poorly differentiated tumor. In the CC group, all patients showed cholecystitis with no evidence of dysplasia or malignancy. The majority of GBC and CC patients reported pain. Using 1H NMR spectroscopy, we observed 4-folds increase in the level of choline containing phospholipids (CCPLs) in the gallbladder of GBC patients as compared to CC patients. Other lipid metabolites such as cholesterol ester, C18-cholesterol and saturated fatty acids were insignificantly changed between GBC and CC patients. Moreover, the level of CCPLs in the GBC patients with BMI <25 kg/m2 was significantly higher as compared to CC patients. Further, a significant increase in the CCPLs level was observed in GBC female patients in comparison to CC patients. From the computational analyses, we observed that the genes involved in the biosynthesis of phosphatidylcholine (PtdCho) indirectly interact with the RELA, which encodes the NF-κB p65 subunit. The genes involved in the PtdCho biosynthesis were also correlated with the overall and disease-free survival of cholangiocarcinoma patients. The study opens new window for exploring the diagnostic and therapeutic potential of CCPLs in GBC patients. • Gallbladder cancer (GBC) is an aggressive malignancy of gastrointestinal tract. • GBC patients exhibit significantly high level of choline containing phospholipids. • The genes from phosphatidylcholine biosynthesis indirectly interact with RELA. • The genes from phosphatidylcholine biosynthesis associate with the survival of patients. [ABSTRACT FROM AUTHOR]

: BackgroundThe clinical use of positive inotropic therapy at home in patients awaiting cardiac transplantation has not been reported since United Network for Organ Sharing (UNOS) regulations were changed to allow home infusions in Status 1B patients.: MethodsWe observed 21 consecutive patients with UNOS 1B status during positive inotropic therapy at home. We used hemodynamic monitoring at the initiation of therapy to optimize dosing. We selected for home therapy patients with stable clinical status and improved functional capacity during inotropic treatment. Implantable cardioverter defibrillators were placed in all but 1 patient before discharge.: ResultsInitial positive inotropic therapy included dobutamine in 12 patients (mean dose, 4.5 mcg/kg/min; range, 2.5–7.5 mcg/kg/min), milrinone in 8 patients (mean dose, 0.44 mcg/kg/min; range, 0.375–0.55 mcg/kg/min), and dopamine at a dose of 3 mcg/kg/min in 1 patient. Patients had improved functional capacity (New York Heart Association Class 3.7 ± 0.1 to 2.4 ± 0.2, p < 0.01), improved renal function (serum creatinine, 1.5 ± 0.1 to 1.3 ± 0.1, p < 0.01), improved resting hemodynamics, and decreased number of hospitalizations during positive inotropic infusion therapy when compared with pre-treatment baseline. Implantable cardioverter defibrillator discharges were infrequent (0.19 per 100 patient days of follow-up). Actuarial survival to transplantation at 6 and 12 months was 84%.: ConclusionsContinuous positive inotropic therapy at home was safe and was associated with decreased health care costs in selected patients awaiting cardiac transplantation. [Copyright &y& Elsevier]