Remote assessment of the Penn computerised neurocognitive battery in individuals with 22q11.2 deletion syndrome.

BACKGROUND: Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in-person assessment can be unavailable or burdensome. The current study compares in-person and remote assessments of the Penn computerised neurocognitive battery (CNB). METHODS: Participants (mean age = 17.82, SD = 6.94 years; 48% female) completed the CNB either in-person at a laboratory (n = 222) or remotely (n = 162). RESULTS: Results show that accuracy of CNB performance was equivalent across the two testing locations, while slight differences in speed were detected in 3 of the 11 tasks. CONCLUSIONS: These findings suggest that the CNB can be used in remote settings to assess multiple neurocognitive domains.

Association among income loss, financial strain and depressive symptoms during COVID-19: evidence from two longitudinal studies.

BACKGROUND: The COVID-19 pandemic has major ramifications for global health and the economy, with growing concerns about economic recession and implications for mental health. Here we investigated the associations between COVID-19 pandemic-related income loss with financial strain and mental health trajectories over a 1-month course. METHODS: Two independent studies were conducted in the U.S and in Israel at the beginning of the outbreak (March-April 2020, T1; N = 4 171) and at a 1-month follow-up (T2; N = 1 559). Mixed-effects models were applied to assess associations among COVID-19-related income loss, financial strain, and pandemic-related worries about health, with anxiety and depression, controlling for multiple covariates including pre-COVID-19 income. FINDINGS: In both studies, income loss and financial strain were associated with greater depressive symptoms at T1, above and beyond T1 anxiety, worries about health, and pre-COVID-19 income. Worsening of income loss was associated with exacerbation of depression at T2 in both studies. Worsening of subjective financial strain was associated with exacerbation of depression at T2 in one study (US). INTERPRETATION: Income loss and financial strain were uniquely associated with depressive symptoms and the exacerbation of symptoms over time, above and beyond pandemic-related anxiety. Considering the painful dilemma of lockdown versus reopening, with the tradeoff between public health and economic wellbeing, our findings provide evidence that the economic impact of COVID-19 has negative implications for mental health. FUNDING: This study was supported by grants from the National Institute of Mental Health, the US-Israel Binational Science Foundation, Foundation Dora and Kirsh Foundation.

Common and dissociable regional cerebral blood flow differences associate with dimensions of psychopathology across categorical diagnoses.

The high comorbidity among neuropsychiatric disorders suggests a possible common neurobiological phenotype. Resting-state regional cerebral blood flow (CBF) can be measured noninvasively with magnetic resonance imaging (MRI) and abnormalities in regional CBF are present in many neuropsychiatric disorders. Regional CBF may also provide a useful biological marker across different types of psychopathology. To investigate CBF changes common across psychiatric disorders, we capitalized upon a sample of 1042 youths (ages 11-23 years) who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. CBF at rest was quantified on a voxelwise basis using arterial spin labeled perfusion MRI at 3T. A dimensional measure of psychopathology was constructed using a bifactor model of item-level data from a psychiatric screening interview, which delineated four factors (fear, anxious-misery, psychosis and behavioral symptoms) plus a general factor: overall psychopathology. Overall psychopathology was associated with elevated perfusion in several regions including the right dorsal anterior cingulate cortex (ACC) and left rostral ACC. Furthermore, several clusters were associated with specific dimensions of psychopathology. Psychosis symptoms were related to reduced perfusion in the left frontal operculum and insula, whereas fear symptoms were associated with less perfusion in the right occipital/fusiform gyrus and left subgenual ACC. Follow-up functional connectivity analyses using resting-state functional MRI collected in the same participants revealed that overall psychopathology was associated with decreased connectivity between the dorsal ACC and bilateral caudate. Together, the results of this study demonstrate common and dissociable CBF abnormalities across neuropsychiatric disorders in youth.

Emergent, remitted and persistent psychosis-spectrum symptoms in 22q11.2 deletion syndrome.

Individuals with 22q11.2 deletion syndrome (22q11DS) are at markedly elevated risk for schizophrenia-related disorders. Stability, emergence, remission and persistence of psychosis-spectrum symptoms were investigated longitudinally. Demographic, clinical and cognitive predictors of psychosis were assessed. Prospective follow-up over 2.8 years was undertaken in 75 individuals with 22q11DS aged 8-35 years. Mood, anxiety, attention-deficit hyperactivity disorders and psychosis-spectrum symptoms were assessed with the Kiddie-Schedule for Affective Disorders and Schizophrenia and Scale of Prodromal Symptoms (SOPS). Four domains of cognition were evaluated with the Penn Computerized Neurocognitive Battery (executive functioning, memory, complex cognition and social cognition). Psychotic disorder or clinically significant SOPS-positive ratings were consistently absent in 35%, emergent in 13%, remitted in 22% and persistent in 31% of participants. Negative symptoms and functional impairment were found to be predictive of the emergence of positive psychosis-spectrum symptoms and to reflect ongoing deficits after remission of positive symptoms. Dysphoric mood and anxiety were predictive of emergent and persistent-positive psychosis-spectrum symptoms. Lower baseline global cognition and greater global cognitive decline were predictive of psychosis-spectrum outcomes but no particular cognitive domain stood out as being significantly more discriminating than others. Our findings suggest that negative symptoms, functioning and dysphoric mood are important predictors of psychosis risk in this population.

Association between polygenic risk for schizophrenia, neurocognition and social cognition across development.

Breakthroughs in genomics have begun to unravel the genetic architecture of schizophrenia risk, providing methods for quantifying schizophrenia polygenic risk based on common genetic variants. Our objective in the current study was to understand the relationship between schizophrenia genetic risk variants and neurocognitive development in healthy individuals. We first used combined genomic and neurocognitive data from the Philadelphia Neurodevelopmental Cohort (4303 participants ages 8-21 years) to screen 26 neurocognitive phenotypes for their association with schizophrenia polygenic risk. Schizophrenia polygenic risk was estimated for each participant based on summary statistics from the most recent schizophrenia genome-wide association analysis (Psychiatric Genomics Consortium 2014). After correction for multiple comparisons, greater schizophrenia polygenic risk was significantly associated with reduced speed of emotion identification and verbal reasoning. These associations were significant by age 9 years and there was no evidence of interaction between schizophrenia polygenic risk and age on neurocognitive performance. We then looked at the association between schizophrenia polygenic risk and emotion identification speed in the Harvard/MGH Brain Genomics Superstruct Project sample (695 participants ages 18-35 years), where we replicated the association between schizophrenia polygenic risk and emotion identification speed. These analyses provide evidence for a replicable association between polygenic risk for schizophrenia and a specific aspect of social cognition. Our findings indicate that individual differences in genetic risk for schizophrenia are linked with the development of aspects of social cognition and potentially verbal reasoning, and that these associations emerge relatively early in development.

Photophysics of GFP-related chromophores imposed by a scaffold design.

In this paper, a rigid scaffold imposes the photophysics of chromophores with a benzylidene imidazolidinone core by mimicking the ß-barrel structure of the green fluorescent protein (GFP) and its analogs. The designed artificial frameworks maintain fluorescence responses and, therefore, conformational rigidity of typically non-emissive GFP-related chromophores. To replicate a small weight percent of the chromophore inside the natural GFP, two synthetic approaches were utilized: coordinative immobilization and non-coordinative inclusion. Despite low chromophore loading in the rigid matrix, both approaches resulted in formation of photoluminescent hybrid materials. Furthermore, the rigid scaffold dictates chromophore fluorescence by replicating its behavior in solution or the solid state. The presented results open an avenue for utilization of rigid scaffolds in the engineering of materials with tunable photoluminescence profiles for a variety of practical applications.

Characterizing social environment's association with neurocognition using census and crime data linked to the Philadelphia Neurodevelopmental Cohort.

BACKGROUND: The contribution of 'environment' has been investigated across diverse and multiple domains related to health. However, in the context of large-scale genomic studies the focus has been on obtaining individual-level endophenotypes with environment left for future decomposition. Geo-social research has indicated that environment-level variables can be reduced, and these composites can then be used with other variables as intuitive, precise representations of environment in research. METHOD: Using a large community sample (N = 9498) from the Philadelphia area, participant addresses were linked to 2010 census and crime data. These were then factor analyzed (exploratory factor analysis; EFA) to arrive at social and criminal dimensions of participants' environments. These were used to calculate environment-level scores, which were merged with individual-level variables. We estimated an exploratory multilevel structural equation model (MSEM) exploring associations among environment- and individual-level variables in diverse communities. RESULTS: The EFAs revealed that census data was best represented by two factors, one socioeconomic status and one household/language. Crime data was best represented by a single crime factor. The MSEM variables had good fit (e.g. comparative fit index = 0.98), and revealed that environment had the largest association with neurocognitive performance (ß = 0.41, p < 0.0005), followed by parent education (ß = 0.23, p < 0.0005). CONCLUSIONS: Environment-level variables can be combined to create factor scores or composites for use in larger statistical models. Our results are consistent with literature indicating that individual-level socio-demographic characteristics (e.g. race and gender) and aspects of familial social capital (e.g. parental education) have statistical relationships with neurocognitive performance.

Connectome-wide network analysis of youth with Psychosis-Spectrum symptoms.

Adults with psychotic disorders have dysconnectivity in critical brain networks, including the default mode (DM) and the cingulo-opercular (CO) networks. However, it is unknown whether such deficits are present in youth with less severe symptoms. We conducted a multivariate connectome-wide association study examining dysconnectivity with resting state functional magnetic resonance imaging in a population-based cohort of 188 youths aged 8-22 years with psychosis-spectrum (PS) symptoms and 204 typically developing (TD) comparators. We found evidence for multi-focal dysconnectivity in PS youths, implicating the bilateral anterior cingulate, frontal pole, medial temporal lobe, opercular cortex and right orbitofrontal cortex. Follow-up seed-based and network-level analyses demonstrated that these results were driven by hyper-connectivity among DM regions and diminished connectivity among CO regions, as well as diminished coupling between frontal and DM regions. Collectively, these results provide novel evidence for functional dysconnectivity in PS youths, which show marked correspondence to abnormalities reported in adults with established psychotic disorders.

Solid-organ transplantation in older adults: current status and future research.

An increasing number of patients older than 65 years are referred for and have access to organ transplantation, and an increasing number of older adults are donating organs. Although short-term outcomes are similar in older versus younger transplant recipients, older donor or recipient age is associated with inferior long-term outcomes. However, age is often a proxy for other factors that might predict poor outcomes more strongly and better identify patients at risk for adverse events. Approaches to transplantation in older adults vary across programs, but despite recent gains in access and the increased use of marginal organs, older patients remain less likely than other groups to receive a transplant, and those who do are highly selected. Moreover, few studies have addressed geriatric issues in transplant patient selection or management, or the implications on health span and disability when patients age to late life with a transplanted organ. This paper summarizes a recent trans-disciplinary workshop held by ASP, in collaboration with NHLBI, NIA, NIAID, NIDDK and AGS, to address issues related to kidney, liver, lung, or heart transplantation in older adults and to propose a research agenda in these areas.

Contribution of endogenously expressed Trp1 to a Ca2+-selective, store-operated Ca2+ entry pathway.

Heterologous expression of the transient receptor potential-1 gene product (Trp1) encodes for a Ca2+ entry pathway, though it is unclear whether endogenous Trp1 contributes to a selective store-operated Ca2+ entry current. We examined the role of Trp1 in regulating both store-operated Ca2+ entry and a store-operated Ca2+ entry current, I(SOC), in A549 and endothelial cells. Twenty different 'chimeric' 2'-O-(2-methoxy)ethylphosphothioate antisense oligonucleotides were transfected separately using cationic lipids and screened for their ability to inhibit Trp1 mRNA. Two hypersensitive regions were identified, one at the 5' end of the coding region and the second in the 3' untranslated region beginning six nucleotides downstream of the stop codon. Antisense oligonucleotides stably decreased Trp1 at concentrations ranging from 10 to 300 nM, for up to 72 h. Thapsigargin increased global cytosolic Ca2+ and activated a I(SOC), which was small (-35 pA @ -80 mV), reversed near +40 mV, inhibited by 50 microM La3+, and exhibited anomalous mole fraction dependence. Inhibition of Trp1 reduced the global cytosolic Ca(2+) response to thapsigargin by 25% and similarly reduced I(SOC) by 50%. These data collectively support a role for endogenously expressed Trp1 in regulating a Ca2+-selective current activated upon Ca2+ store depletion.

Quantitative electroencephalography (QEEG) and neuropsychological syndrome analysis.

The ideographic, syndrome analysis and the nomothetic, standardized test battery approaches to neuropsychological assessment are compared and contrasted within the context of advances in noninvasive technology readily available for use within the examiner's office. By demonstrating the relative strengths and benefits of syndrome analysis, it is suggested that this approach provides a thorough and efficient method of neuropsychological assessment. Subsequently, the utility of an a priori hypothesis testing process approach as a critical technique in syndrome analysis will be supported. It will be proposed that QEEG procedures provide a useful method for further substantiating conclusions generated from a syndrome analysis approach to neuropsychological assessment. Two cases are described demonstrating the utility and flexibility of the QEEG as a confirmatory test of localization following syndrome analysis. In summary, the contributions that neuropsychologists make to the understanding of brain-behavior relationships may be strengthened by combining neuropsychological and neurophysiological assessment methods.

Store-operated calcium entry and increased endothelial cell permeability.

We hypothesized that myosin light chain kinase (MLCK) links calcium release to activation of store-operated calcium entry, which is important for control of the endothelial cell barrier. Acute inhibition of MLCK caused calcium release from inositol trisphosphate-sensitive calcium stores and prevented subsequent activation of store-operated calcium entry by thapsigargin, suggesting that MLCK serves as an important mechanism linking store depletion to activation of membrane calcium channels. Moreover, in voltage-clamped single rat pulmonary artery endothelial cells, thapsigargin activated an inward calcium current that was abolished by MLCK inhibition. F-actin disruption activated a calcium current, and F-actin stabilization eliminated the thapsigargin-induced current. Thapsigargin increased endothelial cell permeability in the presence, but not in the absence, of extracellular calcium, indicating the importance of calcium entry in decreasing barrier function. Although MLCK inhibition prevented thapsigargin from stimulating calcium entry, it did not prevent thapsigargin from increasing permeability. Rather, inhibition of MLCK activity increased permeability that was especially prominent in low extracellular calcium. In conclusion, MLCK links store depletion to activation of a store-operated calcium entry channel. However, inhibition of calcium entry by MLCK is not sufficient to prevent thapsigargin from increasing endothelial cell permeability.

Receptor-dependent activation of store-operated calcium entry increases endothelial cell permeability.

The present study evaluated the necessity of store-operated Ca(2+) entry in mediating thrombin-induced 20-kDa myosin light chain (MLC(20)) phosphorylation and increased permeability in bovine pulmonary artery endothelial cells (BPAECs). Thrombin (7 U/ml) and thapsigargin (1 microM) activated Ca(2+) entry through a common pathway in confluent BPAECs. Similar increases in MLC(20) phosphorylation were observed 5 min after thrombin and thapsigargin challenge, although thrombin produced a sustained increase in MLC(20) phosphorylation that was not observed in response to thapsigargin. Neither agonist increased MLC(20) phosphorylation when Ca(2+) influx was inhibited. Thrombin and thapsigargin induced inter-endothelial cell gap formation and increased FITC-dextran (molecular radii 23 A) transfer across confluent BPAEC monolayers. Activation of store-operated Ca(2+) entry was required for thapsigargin and thrombin receptor-activating peptide to increase permeability, demonstrating that activation of store-operated Ca(2+) entry is coupled with MLC(20) phosphorylation and is associated with intercellular gap formation and increased barrier transport of macromolecules. Unlike thrombin receptor-activating peptide, thrombin increased permeability without activation of store-operated Ca(2+) entry, suggesting that it partly disrupts the endothelial barrier through a proteolytic mechanism independent of Ca(2+) signaling.

Cyclic nucleotide-gated channels mediate membrane depolarization following activation of store-operated calcium entry in endothelial cells.

Calcium agonists induce membrane depolarization in endothelial cells through an unknown mechanism. Present studies tested the hypothesis that pulmonary artery endothelial cells express a cyclic nucleotide-gated (CNG) cation channel activated by store-operated calcium entry to produce membrane depolarization. In the whole-cell configuration, voltage-clamped cells revealed a large non-inactivating, outwardly rectifying cationic current in the absence of extra- or intracellular Ca(2+) that was reduced upon replenishment of Ca(2+). The inward current was non-selective for K(+), Na(+), Cs(+), and Rb(+) and was not inhibited by high tetraethylammonium concentrations. cAMP and cGMP stimulated the current and changed the cation permeability to favor Na(+). Moreover, 8-bromo-cAMP stimulated the current in voltage-clamped cells in the perforated patch mode. The cationic current was inhibited by the CNG channel blocker LY83,583, and reverse transcriptase-polymerase chain reaction cloning identified expression of a CNG channel resembling that seen in olfactory neurons. Activation of store-operated calcium entry using thapsigargin increased a current through the CNG channel. Stimulation of the current paralleled pulmonary artery endothelial cell membrane depolarization, and both the current and membrane depolarization were abolished using LY83,583. Taken together, these data demonstrate activation of store-operated calcium entry stimulates a CNG channel producing membrane depolarization. Such membrane depolarization may contribute to slow feedback inhibition of store-operated calcium entry.

PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization.

Degenerate polymerase chain reaction against conserved kinase catalytic subdomains identified 15 tyrosine and serine-threonine kinases expressed in surgically removed prostatic carcinoma tissues, including six receptor kinases (PDGFBR, IGF1-R, VEGFR2, MET, RYK, and EPH-A1), six non-receptor kinases (ABL, JAK1, JAK2, TYK2, PLK-1, and EMK), and three novel kinases. Several of these kinases are oncogenic, and may function in the development of prostate cancer. One of the novel kinases is a new member of the sterile 20 (STE20) family of serine-threonine kinases which we have called prostate-derived STE20-like kinase (PSK) and characterized functionally. PSK encodes an open reading frame of 3705 nucleotides and contains an N-terminal kinase domain. Immunoprecipitated PSK phosphorylates myelin basic protein and transfected PSK stimulates MKK4 and MKK7 and activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway. Microinjection of PSK into cells results in localization of PSK to a vesicular compartment and causes a marked reduction in actin stress fibers. In contrast, C-terminally truncated PSK (1-349) did not localize to this compartment or induce a decrease in stress fibers demonstrating a requirement for the C terminus. Kinase-defective PSK (K57A) was unable to reduce stress fibers. PSK is the first member of the STE20 family lacking a Cdc42/Rac binding domain that has been shown to regulate both the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and the actin cytoskeleton.

Segmental regulation of pulmonary vascular permeability by store-operated Ca2+ entry.

An intact endothelial cell barrier maintains normal gas exchange in the lung, and inflammatory conditions result in barrier disruption that produces life-threatening hypoxemia. Activation of store-operated Ca2+ (SOC) entry increases the capillary filtration coefficient (Kf,c) in the isolated rat lung; however, activation of SOC entry does not promote permeability in cultured rat pulmonary microvascular endothelial cells. Therefore, current studies tested whether activation of SOC entry increases macro- and/or microvascular permeability in the intact rat lung circulation. Activation of SOC entry by the administration of thapsigargin induced perivascular edema in pre- and postcapillary vessels, with apparent sparing of the microcirculation as evaluated by light microscopy. Scanning and transmission electron microscopy revealed that the leak was due to gaps in vessels >/= 100 micrometer, consistent with the idea that activation of SOC entry influences macrovascular but not microvascular endothelial cell shape. In contrast, ischemia and reperfusion induced microvascular endothelial cell disruption independent of Ca2+ entry, which similarly increased Kf,c. These data suggest that 1) activation of SOC entry is sufficient to promote macrovascular barrier disruption and 2) unique mechanisms regulate pulmonary micro- and macrovascular endothelial barrier functions.

Time- and dose-dependent development of potassium bromate-induced tumors in male Fischer 344 rats.

Potassium bromate (KBrO3) is a rodent carcinogen and a nephro- and neurotoxicant in humans. KBrO3 is used in cosmetics and food products and is a by-product of water disinfection by ozonization. KBrO3 is carcinogenic in the rat kidney, thyroid, and mesothelium and is a renal carcinogen in the male mouse. The present study was designed to investigate the relationship of time and dose to bromate-induced tumors in male Fischer 344 (F344) rats and to provide some insight into the development of these tumors. KBrO3 was dissolved in drinking water at nominal concentrations of 0, 0.02, 0.1, 0.2, and 0.4 g/L and administered to male F344 rats as the sole water source for 12, 26, 52, 78, or 100 wk. Renal cell tumors were present after 52 wk of treatment only in the high-dose group. Mesotheliomas developed after 52 wk of treatment on the tunica vaginalis. Mesotheliomas were present at sites other than the testicle after 78 wk of treatment, indicating that their origin was the testicular tunic. Thyroid follicular tumors were present as early as 26 wk in 1 rat each from the 0.1- and 0.2-g/L groups. The present study can be used as a basis for the determination of dose-time relationships of tumor development for a better understanding of KBrO3-induced cancer.

Carcinogenicity of potassium bromate administered in the drinking water to male B6C3F1 mice and F344/N rats.

Ozone has been proposed for water disinfection because it is more efficient than chlorine for killing microbes and results in much lower levels of carcinogenic trihalomethanes than does chlorination. Ozone leads to formation of hypobromous acid in surface waters with high bromine content and forms brominated organic by-products and bromate. The carcinogenicity and chronic toxicity of potassium bromate (KBrO3) was studied in male B6C3F1 mice and F344/N rats to confirm and extend the results of previous work. Mice were treated with 0, 0.08, 0.4, or 0.8 g/L KBrO3 in the drinking water for up to 100 wk, and rats were provided with 0, 0.02, 0.1, 0.2, or 0.4 g/L KBrO3. Animals were euthanatized, necropsied, and subjected to a complete macroscopic examination. Selected tissues and gross lesions were processed by routine methods for light microscopic examination. The present study showed that KBrO3 is carcinogenic in the rat kidney, thyroid, and mesothelium and is a renal carcinogen in the male mouse, KBrO3 was carcinogenic in rodents at water concentrations as low as 0.02 g/L (20 ppm; 1.5 mg/kg/day). These data can be used to estimate the human health risk that would be associated with changing from chlorination to ozonation for disinfection of drinking water.