White matter associations with spelling performance.

Multiple neurocognitive processes are involved in the highly complex task of producing written words. Yet, little is known about the neural pathways that support spelling in healthy adults. We assessed the associations between performance on a difficult spelling-to-dictation task and microstructural properties of language-related white matter pathways, in a sample of 73 native English-speaking neurotypical adults. Participants completed a diffusion magnetic resonance imaging scan and a cognitive assessment battery. Using constrained spherical deconvolution modeling and probabilistic tractography, we reconstructed dorsal and ventral white matter tracts of interest, bilaterally, in individual participants. Spelling associations were found in both dorsal and ventral stream pathways. In high-performing spellers, spelling scores significantly correlated with fractional anisotropy (FA) within the left inferior longitudinal fasciculus, a ventral stream pathway. In low-performing spellers, spelling scores significantly correlated with FA within the third branch of the right superior longitudinal fasciculus, a dorsal pathway. An automated analysis of spelling errors revealed that high- and low- performing spellers also differed in their error patterns, diverging primarily in terms of the orthographic distance between their errors and the correct spelling, compared to the phonological plausibility of their spelling responses. The results demonstrate the complexity of the neurocognitive architecture of spelling. The distinct white matter associations and error patterns detected in low- and high- performing spellers suggest that they rely on different cognitive processes, such that high-performing spellers rely more on lexical-orthographic representations, while low-performing spellers rely more on phoneme-to-grapheme conversion.

BLM helicase protein negatively regulates stress granule formation through unwinding RNA G-quadruplex structures.

Bloom's syndrome (BLM) protein is a known nuclear helicase that is able to unwind DNA secondary structures such as G-quadruplexes (G4s). However, its role in the regulation of cytoplasmic processes that involve RNA G-quadruplexes (rG4s) has not been previously studied. Here, we demonstrate that BLM is recruited to stress granules (SGs), which are cytoplasmic biomolecular condensates composed of RNAs and RNA-binding proteins. BLM is enriched in SGs upon different stress conditions and in an rG4-dependent manner. Also, we show that BLM unwinds rG4s and acts as a negative regulator of SG formation. Altogether, our data expand the cellular activity of BLM and shed light on the function that helicases play in the dynamics of biomolecular condensates.

Examining the synergistic effects of a cognitive control video game and a home-based, self-administered non-invasive brain stimulation on alleviating depression: the DiSCoVeR trial protocol.

Enhanced behavioral interventions are gaining increasing interest as innovative treatment strategies for major depressive disorder (MDD). In this study protocol, we propose to examine the synergistic effects of a self-administered home-treatment, encompassing transcranial direct current stimulation (tDCS) along with a video game based training of attentional control. The study is designed as a two-arm, double-blind, randomized and placebo-controlled multi-center trial (ClinicalTrials.gov: NCT04953208). At three study sites (Israel, Latvia, and Germany), 114 patients with a primary diagnosis of MDD undergo 6 weeks of intervention (30 × 30 min sessions). Patients assigned to the intervention group receive active tDCS (anode F3 and cathode F4; 2 mA intensity) and an action-like video game, while those assigned to the control group receive sham tDCS along with a control video game. An electrode-positioning algorithm is used to standardize tDCS electrode positioning. Participants perform their designated treatment at the clinical center (sessions 1-5) and continue treatment at home under remote supervision (sessions 6-30). The endpoints are feasibility (primary) and safety, treatment efficacy (secondary, i.e., change of Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week six from baseline, clinical response and remission, measures of social, occupational, and psychological functioning, quality of life, and cognitive control (tertiary). Demonstrating the feasibility, safety, and efficacy of this novel combined intervention could expand the range of available treatments for MDD to neuromodulation enhanced interventions providing cost-effective, easily accessible, and low-risk treatment options.ClinicalTrials.gov: NCT04953208.

JAK2V617F Is a Risk Factor for TIA/Stroke in Young Patients.

The objective of this study was to assess the risk of arterial thrombosis in patients who harbor the JAK2V617F allele burden ≥1% detected during workup for myeloproliferative neoplasms (MPNs). We conducted a large cross-sectional analysis consisted of 5,220 patients who were tested for JAK2V617F and 1,047,258 people matched in age from health care insurance provider, taking into account age, sex, hypertension, diabetes, atrial fibrillation. Compared with noncarriers, mutation carriers were older, less likely to be current or past smokers and had lower body mass index. There was no significant difference between the groups regarding myocardial infarction and peripheral vascular disease. However, JAK2V617F ≥1% at age 34 to 54 years was associated with eightfold more likely to have transient ischemic attack (TIA)/stroke history unrelated to hypertension, diabetes, or atrial fibrillation. Association of JAK2V617F with TIA/stroke was also observed in the older age group, albeit a weaker association and not statistically significant. Prevalence of TIA/stroke was higher in patients with JAK2V617F negative, with odds ratio of 3.93 when compared with the general population after confounder adjustments. Further research is warranted to verify the relation between allele burden of JAK2V617F mutation and TIA/stroke and the role of JAK2V617F per se as a risk factor for arterial thrombosis in the absence of overt MPN. Also, consideration should be paid to the screened group with JAK2V617F negative due to the high incidence of TIA/stroke among them in comparison to the general population.

T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy.

Metastasis is the main cause of cancer-related mortality. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechanostructural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse model harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8+ T cells expressing LOX. Consistently, adoptive transfer of CD8+ T cells, but not CD4+ T cells or B cells, from PTX-treated mice to naïve immunodeprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer. SIGNIFICANCE: Chemotherapy induces prometastatic pulmonary ECM remodeling by upregulating LOX in T cells, which can be targeted with LOX inhibitors to suppress metastasis.See related commentary by Kolonin and Woodward, p. 197.

Lung mechanics modifications facilitating metastasis are mediated in part by breast cancer-derived extracellular vesicles.

Tumor microenvironment-mechanics greatly affect tumor-cell characteristics such as invasion and proliferation. We and others have previously shown that after chemotherapy, tumor cells shed more extracellular vesicles (EVs), leading to tumor growth and even spread, via angiogenesis and the mobilization of specific bone-marrow-derived cells contributing to metastasis. However, physical, mechanobiological and mechanostructural changes at premetastatic sites that may support tumor cell seeding, have yet to be determined. Here, we collected tumor-derived extracellular vesicles (tEV) from breast carcinoma cells exposed to paclitaxel chemotherapy, and tested their effects on tissue mechanics (eg, elasticity and stiffness) of likely metastatic organs in cancer-free mice, using shear rheometry. Cancer-free mice were injected with saline or with tEVs from untreated cells and lung tissue demonstrated widely variable, viscoelastic mechanics, being more elastic than viscous. Contrastingly, tEVs from chemotherapy-exposed cells induced more uniform, viscoelastic lung mechanics, with lower stiffness and viscosity; interestingly, livers were significantly stiffer than both controls. We observe statistically significant differences in softening of lung samples from all three groups under increasing strain-amplitudes and in their stiffening under increasing strain-frequencies; the groups reach similar values at high strain amplitudes and frequencies, indicating local changes in tissue microstructure. Evaluation of genes associated with the extracellular matrix and fibronectin protein-expression revealed potential compositional changes underlying the altered mechanics. Thus, we propose that tEVs, even without cancer cells, contribute to metastasis by changing microstructures at distant organs. This is done partially by altering the composition and mechanostructure of tissues to support tumor cell invasion and seeding.

Sodium pyruvate pre-treatment prevents cell death due to localised, damaging mechanical strains in the context of pressure ulcers.

We demonstrate sodium pyruvate (NaPy) pre-treatment as a successful approach for pressure ulcer (PU) prevention by averting their aetiological origin-cell-level damage and death by large, sustained mechanical loads. We evaluated the NaPy pre-treatment effect on permeability changes in the cell's plasma membrane (PM) following application of in vitro damaging-level strains. Fibroblasts or myoblasts, respectively, models for superficial or deep-tissue damage were grown in 0 or 1 mM NaPy, emulating typical physiological or cell culture conditions. Cells were pre-treated for 4 hours with 0 to 5 mM NaPy prior to 3-hour sustained, damaging-level loads (12% strain). PM permeability was quantified by the cell uptake of small (4 kDa), fluorescent dextran compared with unstrained control using fluorescence-activated cell sorting (FACS). Pre-treatment with 1 mM, and especially 5 mM, NaPy significantly reduces damage to PM integrity. Long-term NaPy pre-exposure can improve protective treatment, affecting fibroblasts and myoblasts differently. Pre-treating with NaPy, a natural cell metabolite, allows cells under damaging-level mechanical loads to maintain their PM integrity, that is, to avoid loss of homeostasis and inevitable, eventual cell death, by preventing initial, microscale stages of PU formation. This pre-treatment may be applied prior to planned periods of immobility, for example, planned surgery or transport, to prolong safe time in a position by preventing initial cell damage that can cascade and lead to PU formation.

Future Needs for Science-Driven Geospatial and Temporal Extravehicular Activity Planning and Execution.

Future human missions to Mars are expected to emphasize scientific exploration. While recent Mars rover missions have addressed a wide range of science objectives, human extravehicular activities (EVAs), including the Apollo missions, have had limited experience with science operations. Current EVAs are carefully choreographed and guided continuously from Earth with negligible delay in communications between crew and flight controllers. Future crews on Mars will be expected to achieve their science objectives while operating and coordinating with a science team back on Earth under communication latency and bandwidth restrictions. The BASALT (Biologic Analog Science Associated with Lava Terrains) research program conducted Mars analog science on Earth to understand the concept of operations and capabilities needed to support these new kinds of EVAs. A suite of software tools (Minerva) was used for planning and executing all BASALT EVAs, supporting text communication across communication latency, and managing the collection of operational and scientific EVA data. This paper describes the support capabilities provided by Minerva to cope with various geospatial and temporal constraints to support the planning and execution phases of the EVAs performed during the BASALT research program. The results of this work provide insights on software needs for future science-driven planetary EVAs.

Standard errors and confidence intervals for correlations corrected for indirect range restriction: A simulation study comparing analytic and bootstrap methods.

A frequent topic of psychological research is the estimation of the correlation between two variables from a sample that underwent a selection process based on a third variable. Due to indirect range restriction, the sample correlation is a biased estimator of the population correlation, and a correction formula is used. In the past, bootstrap standard error and confidence intervals for the corrected correlations were examined with normal data. The present study proposes a large-sample estimate (an analytic method) for the standard error, and a corresponding confidence interval for the corrected correlation. Monte Carlo simulation studies involving both normal and non-normal data were conducted to examine the empirical performance of the bootstrap and analytic methods. Results indicated that with both normal and non-normal data, the bootstrap standard error and confidence interval were generally accurate across simulation conditions (restricted sample size, selection ratio, and population correlations) and outperformed estimates of the analytic method. However, with certain combinations of distribution type and model conditions, the analytic method has an advantage, offering reasonable estimates of the standard error and confidence interval without resorting to the bootstrap procedure's computer-intensive approach. We provide SAS code for the simulation studies.

Can doubt attenuate access to internal states? Implications for obsessive-compulsive disorder.

BACKGROUND AND OBJECTIVES: We have previously reported that obsessive-compulsive individuals perform more poorly on tasks that require accurate perception of internal states. As these individuals are also characterized by elevated levels of doubt regarding internal states, the causal relationship between doubt and accurate perception remained unclear. The presented study examines whether undermining participants' confidence in their ability to accurately produce a specific internal state would affect their performance on a task that requires accurate perception of this state. METHODS: Participants were trained to produce specific levels of forearm muscle tension and then required to produce various tension levels in four experimental phases. The first three alternated in terms of whether the participants viewed a biofeedback monitor while the fourth offered participants several times the choice to view the monitor. Prior to the task, half of the participants received instructions that undermined their confidence in their ability to accurately assess their own muscle tension. We measured participants' accuracy in producing the required muscle tension levels and the number of times they requested to view the monitor in the final phase. RESULTS: Undermined confidence participants were less accurate in producing the required muscle tension levels in the absence of biofeedback, and were also more likely to request the monitor in the final phase. CONCLUSIONS: Doubt can affect performance on tasks that require perceiving and experiencing internal states. This finding supports the possibility that access to internal states in OCD is attenuated due to elevated levels of doubt regarding these states.

Demonstrating the validity of three general scores of PET in predicting higher education achievement in Israel / Demostrando la validez de tres puntuaciones generales del PET para predecir el rendimiento en la educación superior en Israel

BACKGROUND: The Psychometric Entrance Test (PET), used for admission to higher education in Israel together with the Matriculation (Bagrut), had in the past one general (total) score in which the weights for its domains: Verbal, Quantitative and English, were 2:2:1, respectively. In 2011, two additional total scores were introduced, with different weights for the Verbal and the Quantitative domains. This study compares the predictive validity of the three general scores of PET, and demonstrates validity in terms of utility. METHOD: Sample: 100,863 freshmen students of all Israeli universities over the classes of 2005-2009. Regression weights and correlations of the predictors with FYGPA were computed. Simulations based on these results supplied the utility estimates. RESULTS: On average, PET is slightly more predictive than the Bagrut; using them both yields a better tool than either of them alone. Assigning differential weights to the components in the respective schools further improves the validity. CONCLUSION: The introduction of the new general scores of PET is validated by gathering and analyzing evidence based on relations of test scores to other variables. The utility of using the test can be demonstrated in ways different from correlations

ANTECEDENTES: el Psychometric Entrance Test (PET), utilizado para la admisión a la educación superior en Israel junto con la Matriculation (Bagrut), tuvo en el pasado una puntuación general en la que los pesos para sus dominios: Verbal, Cuantitativo e Inglés eran 2:2:1, respectivamente. En 2011 se introdujeron dos puntuaciones totales adicionales, con pesos diferentes para los dominios Verbal y Cuantitativo. Este estudio compara la validez predictiva de las tres puntuaciones generales del PET y demuestra la validez en términos de utilidad. MÉTODO: muestra: 100.863 estudiantes de primer año de todas las universidades israelíes en los cursos de 2005 a 2009. Se calcularon los coeficientes de regresión y las correlaciones de los predictores con FYGPA. Las simulaciones basadas en estos resultados aportaron la utilidad de las estimaciones. RESULTADOS: en promedio, PET es ligeramente más predictivo que el «Bagrut». Asignar pesos diferentes a los componentes en las escuelas respectivas mejora más la validez. CONCLUSIONES: la introducción de las nuevas puntuaciones generales del PET es validada mediante la obtención y análisis de evidencia basada en las relaciones de las puntuaciones del test con otras variables. Puede demostrarse la utilidad del uso del test en formas diferentes de las correlacio

Demonstrating the validity of three general scores of PET in predicting higher education achievement in Israel.

BACKGROUND: The Psychometric Entrance Test (PET), used for admission to higher education in Israel together with the Matriculation (Bagrut), had in the past one general (total) score in which the weights for its domains: Verbal, Quantitative and English, were 2:2:1, respectively. In 2011, two additional total scores were introduced, with different weights for the Verbal and the Quantitative domains. This study compares the predictive validity of the three general scores of PET, and demonstrates validity in terms of utility. SAMPLE: 100,863 freshmen students of all Israeli universities over the classes of 2005-2009. Regression weights and correlations of the predictors with FYGPA were computed. Simulations based on these results supplied the utility estimates. RESULTS: On average, PET is slightly more predictive than the Bagrut; using them both yields a better tool than either of them alone. Assigning differential weights to the components in the respective schools further improves the validity. CONCLUSION: The introduction of the new general scores of PET is validated by gathering and analyzing evidence based on relations of test scores to other variables. The utility of using the test can be demonstrated in ways different from correlations.

New tools in HCV diagnosis, in light of the enhanced awareness and the new drugs for treatment: SMARTube and stimmunology.

With improved HCV therapy, challenges regarding HCV diagnosis, such as seronegative window period, false positive readings, and differentiation between recent, chronic, and resolved infections, are of increasing importance. To address these challenges an innovative device--SMARTube HIV & HCV--was used. Blood samples were tested for anti-HCV antibodies before and after incubation in the SMARTube, which promotes the in vitro stimulation of in vivo HCV primed lymphocytes, thus enhancing levels of anti-HCV antibodies. Comparing antibody levels, in concordant samples before and after SMARTube, yielded the Stimulation Index (SI). Among 5888 fresh blood samples, from various populations and regions worldwide, 641 were seropositive using plasma, while SMARTube processing (yielding enriched plasma, termed SMARTplasma) enabled diagnosis of 10 additional carriers in high-risk cohorts, that is, earlier detection. Using SMARTplasma eliminated all false positive results, using the current assays. In addition we show that SI calculation may serve as an important tool for differentiating between those who recently seroconverted, carriers of long-term infection, and those who have cleared the virus. SMARTube and the SI could lead to better, more informative diagnosis of HCV infections and play an important role in changing the way we treat both the infected individuals and the epidemic as a whole.

The challenges of hepatitis C diagnosis and the potential role of Stimmunology™ to address them.

The diagnosis of HCV infection is hindered by the long seronegative window period, the high rate of false-positives and the need to differentiate between current and cleared infection. Stimmunology™ is a technology by which antibody production can be stimulated, even in a whole blood sample, in vitro. Such stimulation leads to an increase in HCV antibody levels in the blood sample, enabling the detection of HCV infection prior to seroconversion. This increase in the levels of the HCV antibodies, which can be achieved within days of infection, practically resolves the window period problem. The detection of the infection, even at its seronegative stage, translates to increased diagnostic sensitivity and the concomitant dilution of 'noise' in the sample leads to a >96% reduction in the false-positive rate. The stimulation step acts upon HCV-primed lymphocytes in the blood sample; therefore, only in the presence of infection would the increased antibody levels be detected, thus differentiating between current and cleared infection. Clinical diagnostic data have been collected to provide insight as to how the diagnosis of HCV infection may be improved using this technology.

Detecting seronegative-early HIV infections among adult versus student Kenyan blood donors, by using Stimmunology.

BACKGROUND: Undetectable HIV infection in blood banks poses a serious threat to public health. Thus, donations from high school students are preferred over adult samples in Kenyan blood banks, due to lower HIV infection prevalence within this population, as detected by conventional serology testing. However, the number of recently infected individuals remains difficult to identify, as HIV-induced immunological window periods can span months. This study focuses on the potential contribution of a novel mode of diagnostic testing in revealing early, seronegative HIV carriers. METHODS AND FINDINGS: Stimmunology, an in vitro lymphocyte stimulation technique, was used to detect early HIV infection among random samples of adult and adolescent blood donors. The Stimmunology protocol unveiled a significant number of early, pre-seroconversion HIV carriers both among adult and teenage Kenyan populations, undetected by typical serological diagnostic kits. Both populations demonstrated a significant increase in HIV-specific antibody formation following activation using the Stimmunology assay. The younger population exhibited a higher proportion of early HIV infection (0.45) than the adult (0.27) population. CONCLUSIONS: While blood samples of young donors are preferred over adult donations, these data demonstrate a worrisome ratio of early, seronegative HIV carriers within this population. This simple, cost-effective, and reliable HIV-boosting antibody assay can be used in a resource-poor setting to increase blood supply safety and quality. Incorporation of Stimmunology into basic blood bank testing and into diagnostic protocols can also decrease undesirable disease transmission.

HIV type 1 infection among Ethiopian immigrants to Israel: enhanced in vitro antibody stimulation for estimating the length of the window period.

The window period between infection and seroconversion varies based on viral genetics, dose and route of transmission, host genetics, and environmental factors. The in vitro Stimmunology blood pretreatment assay was utilized to promote the synthesis of HIV-specific antibodies in efforts to define the window period between infection and seroconversion. Ethiopians seeking immigration to Israel while in refugee camps provided a unique cohort to perform a comparative analysis of the window period between HIV-1 infection and diagnosis utilizing conventional Ab-ELISA and our laboratory established an in vitro Stimmunolog assay. This population was considered unique due to its exposure to an environment with a high seroprevalence rate for a defined period of time. Unlinked blood samples were tested and validated before and after Stimmunology. Diagnostic screening was conducted in Israel. A total of 285 and 537 random samples were tested from the 1992 and 1998 immigrant population, respectively. Analysis of HIV prevalence, incidence, and window period length among the immigrants was measured by comparing results obtained on samples prior to and following analysis by Stimmunology as compared with standard ELISA-based assay. This novel assay that promotes the in vitro stimulation of antibody synthesis led to the diagnosis of 2.7% and 0.36% of the 1992 and 1998 immigrant groups, respectively, as HIV infected individuals during the window period. Using mathematical modeling, the length of the window period in the surveyed population was estimated to range from 2 to 5 months. Stimmunology-aided detection of early seronegative HIV-infected individuals provided a reliable and consistent mode of identifying infection in seronegative HIV-1-infected individuals. Applying mathematical modeling to the data obtained enabled us to define the window period length, which was found to extend beyond previous estimates. These results suggest a need for the reevaluation of the techniques that are employed to assess the true incidence and prevalence of HIV-1 infection, especially in populations within sub-Saharan Africa.

Endoplasmic reticulum glucosidase II is inhibited by its end products.

The calnexin/calreticulin cycle is a quality control system responsible for promoting the folding of newly synthesized glycoproteins entering the endoplasmic reticulum (ER). The association of calnexin and calreticulin with the glycoproteins is regulated by ER glucosidase II, which hydrolyzes Glc 2Man X GlcNAc 2 glycans to Glc 1Man X GlcNAc 2 and further to Glc 0Man X GlcNAc 2 ( X represents any number between 5 and 9). To gain new insights into the reaction mechanism of glucosidase II, we developed a kinetic model that describes the interactions between glucosidase II, calnexin/calreticulin, and the glycans. Our model accurately reconstructed the hydrolysis of glycans with nine mannose residues and glycans with seven mannose residues, as measured by Totani et al. [Totani, K., Ihara, Y., Matsuo, I., and Ito, Y. (2006) J. Biol. Chem. 281, 31502-31508]. Intriguingly, our model predicted that glucosidase II was inhibited by its nonglucosylated end products, where the inhibitory effect of Glc 0Man 7GlcNAc 2 was much stronger than that of Glc 0Man 9GlcNAc 2. These predictions were confirmed experimentally. Moreover, our model suggested that glycans with a different number of mannose residues can be equivalent substrates of glucosidase II, in contrast to what had been previously thought. We discuss the possibility that nonglucosylated glycans, existing in the ER, might regulate the entry of newly synthesized glycoproteins into the calnexin/calreticulin cycle. Our model also shows that glucosidase II does not interact with monoglucosylated glycans while they are bound to calnexin or calreticulin.

Pilot-controlled trial of D-cycloserine for the treatment of post-traumatic stress disorder.

Dysfunction of glutamatergic neurotransmission may be relevant to the pathogenesis of post-traumatic stress disorder (PTSD). Preclinical and clinical evidence suggests that PTSD symptoms could be alleviated following enhancement of neurotransmission mediated at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Eleven patients with chronic PTSD participated in a double-blind, placebo-controlled, cross-over trial with 50 mg/d D-cycloserine which acts as a partial agonist at the glycine regulatory site on the NMDA receptor. D-cycloserine treatment resulted in significant improvements in numbing, avoidance, and anxiety symptoms; however, similar effects were also observed during placebo treatment. In addition, D-cycloserine treatment resulted in a significant (p=0.03), reduction in the perseverative error scores as measured by the Wisconsin Card Sorting Test. This pilot study is the first to assess the efficacy of a NMDA receptor modulator for PTSD treatment and its results warrant further, larger-scale investigation.