Molecular and physiologic changes in the SpaceX Inspiration4 civilian crew.

Human spaceflight has historically been managed by government agencies, such as the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first-ever all civilian crew to low Earth orbit, which included the youngest American astronaut (age 29), novel in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables, and immune profiling), ocular alignment measurements, and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match long-term spaceflight2, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiologic, and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts3, which can inform countermeasure development for both private and government-sponsored space missions.

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.

BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus.

OBJECTIVE: Neuropsychiatric events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. This study examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrolment predicted subsequent neuropsychiatric events. METHODS: Patients with a recent SLE diagnosis were assessed prospectively for up to 10 years for neuropsychiatric events using the American College of Rheumatology case definitions. Decision rules of graded stringency determined whether neuropsychiatric events were attributable to SLE. Associations between the first neuropsychiatric event and baseline autoantibodies (lupus anticoagulant (LA), anticardiolipin, anti-ß(2) glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression. RESULTS: Disease duration at enrolment was 5.4 ± 4.2 months, follow-up was 3.6 ± 2.6 years. Patients were 89.1% female with mean (±SD) age 35.2 ± 13.7 years. 495/1047 (47.3%) developed one or more neuropsychiatric event (total 917 events). Neuropsychiatric events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrolment 21.9% of patients had LA, 13.4% anticardiolipin, 15.1% anti-ß(2) glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. LA at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (HR 2.54, 95% CI 1.08 to 5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR 3.92, 95% CI 1.23 to 12.5, p=0.02). Other autoantibodies did not predict neuropsychiatric events. CONCLUSION: In a prospective study of 1047 recently diagnosed SLE patients, LA and anti-ribosomal P antibodies are associated with an increased future risk of intracranial thrombosis and lupus psychosis, respectively.

Australian clinical consensus guideline for the subacute rehabilitation of childhood stroke.

Childhood stroke results in long-term, multifaceted difficulties, affecting motor, cognitive, communication, and behavioral domains of function which impact on participation and quality of life. The Childhood Stroke Consensus Rehabilitation Guideline was developed to improve the care of children with stroke by providing health professionals with recommendations to assist in their rehabilitative treatment. Clinical questions were formulated to inform systematic database searches from 2001 to 2016, limited to English and pediatric studies. SIGN methodology and the National Health and Medical Research Council system were used to screen and classify the evidence. The Grade of Recommendation, Assessment, Development and Evaluation system was used to grade evidence as strong or weak. Where evidence was inadequate or absent, a modified Delphi consensus process was used to develop consensus-based recommendations. The guideline provides 56 recommendations (1 evidence-based recommendation and 55 consensus recommendations). These relate to the framework of rehabilitation service delivery as well as domain-specific rehabilitation treatment strategies for each domain of function. It is anticipated that this guideline will provide health professions with recommendations to improve the subacute care of children with stroke both in Australia and internationally.

Phase-sensitive neutron reflectometry measurements applied in the study of photovoltaic films.

Due to low charge carrier mobilities in polymer-based solar cells, device performance is dictated by the nanoscale morphology of the active layer components. However, their morphological details are notoriously difficult to distinguish due to the low electron contrast difference between the components. Phase-sensitive neutron reflectivity (PSNR) is uniquely suited to characterize these systems due to the large, natural scattering length density difference between two common device materials, poly(3-hexylthiophene) and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM). Using PSNR we find a high concentration of PCBM at the substrate and near but not at the air interface. Herein we discuss the method of applying PSNR to polymer-based solar cells, the results obtained, and an evaluation of its effectiveness.

Lepidoptera in cretaceous amber.

The discovery of the head capsule of a lepidopterous larva in Canadian amber of the Cretaceous period is the first fossil evidence of Lepidoptera before the Tertiary period.

Carbon-13 nuclear magnetic resonance study of osmoregulation in a blue-green alga.

The process of osmoregulation in a unicellular blue-green alga, Synechococcus sp., has been studied by natural-abundance carbon-13 nuclear magnetic resonance spectroscopy of intact cells and cell extracts. 2-O-alpha-D-Glucopyranosylglycerol was identified as the major organic osmoregulatory solute. This demonstrates the presence of a major osmoregulatory solute in a blue-green alga and is also an example of an osmoregulatory role for glucosylglycerol.

Alterations in Blood-Brain Barrier Permeability in Patients with Systemic Lupus Erythematosus.

BACKGROUND AND PURPOSE: Neuropsychiatric systemic lupus erythematosus refers to central and peripheral nervous system involvement, which may occur secondary to antineuronal antibodies crossing the blood-brain barrier that preferentially target cells in the hippocampus leading to abnormal hypermetabolism and atrophy. Thus, we hypothesized that alterations in BBB permeability, detected on dynamic contrast-enhanced MR imaging, occur in the hippocampus in patients with systemic lupus erythematosus before development of neuropsychiatric systemic lupus erythematosus. MATERIALS AND METHODS: Six patients with systemic lupus erythematosus without neuropsychiatric systemic lupus erythematosus and 5 healthy controls underwent dynamic contrast-enhanced MR imaging with postprocessing into BBB permeability parameters (K trans and Ve) and CBF. Standardized methods selected ROI sampling of the abnormal brain regions detected on FDG-PET. The mean and SD of K trans, Ve, and CBF were calculated. Linear regression and nonparametric Spearman rank correlation analyses of K trans and Ve with CBF were performed. Dynamic contrast-enhanced curves and the area under the curve were generated for each brain region. Student t test comparisons were performed. RESULTS: Quantitative data revealed that patients with systemic lupus erythematosus have statistically increased K trans (P < .001) and Ve (P < .001) compared with controls. In patients with systemic lupus erythematosus, statistically significant positive correlations were seen between K trans (P < .001) and Ve (P < .001) with CBF. Furthermore, the mean area under the curve revealed statistically increased BBB permeability in the hippocampus (P = .02) compared with other brain regions in patients with systemic lupus erythematosus compared with controls. CONCLUSIONS: These initial findings are proof-of-concept to support the hypothesis that patients with systemic lupus erythematosus have increased BBB permeability, specifically in the hippocampus, compared with other brain regions. These findings may advance our understanding of the underlying pathophysiology affecting the brain in autoimmune diseases.

Dynamic Contrast-Enhanced MRI Reveals Unique Blood-Brain Barrier Permeability Characteristics in the Hippocampus in the Normal Brain.

We report a prospective dynamic contrast-enhanced MR imaging analysis of region-specific blood-brain barrier permeability in 5 healthy subjects. By means of standardized postprocessing and ROI sampling methods, the hippocampi revealed significantly elevated area under the dynamic contrast-enhanced curve and significantly increased blood-brain barrier permeability metrics (volume transfer constant and volume in the extravascular extracellular space) from model-based quantitation. These findings suggest unique blood-brain barrier permeability characteristics in the hippocampus, which are concordant with previous animal studies, potentially laying the groundwork for future studies assessing patient populations in which hippocampal pathology plays a role.

Examining the sensitivity of an injury surveillance program using population-based estimates.

This study uses population-based estimates to assess the sensitivity and representativeness of an injury surveillance system using a 1-year population-based approach. Data from the Ottawa Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) site (Children's Hospital of Eastern Ontario) were compared with those from six expansion sites. The overall sensitivity of CHIRPP was 43% of all treated injuries and 57% of injuries treated at emergency departments. CHIRPP was less likely to be representative for older children and more likely to capture children with more severe injuries. The limitations related to using CHIRPP for representing population-based injury remain fairly stable over time. A one-time population-based sample can provide useful information to add to routinely collected injury surveillance.

Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Results of the VIPS Study.

BACKGROUND AND PURPOSE: Childhood arteriopathies are rare but heterogenous, and difficult to diagnose and classify, especially by nonexperts. We quantified clinical and imaging characteristics associated with childhood arteriopathy subtypes to facilitate their diagnosis and classification in research and clinical settings. MATERIALS AND METHODS: The Vascular Effects of Infection in Pediatric Stroke (VIPS) study prospectively enrolled 355 children with arterial ischemic stroke (2010-2014). A central team of experts reviewed all data to diagnose childhood arteriopathy and classify subtypes, including arterial dissection and focal cerebral arteriopathy-inflammatory type, which includes transient cerebral arteriopathy, Moyamoya disease, and diffuse/multifocal vasculitis. Only children whose stroke etiology could be conclusively diagnosed were included in these analyses. We constructed logistic regression models to identify characteristics associated with each arteriopathy subtype. RESULTS: Among 127 children with definite arteriopathy, the arteriopathy subtype could not be classified in 18 (14%). Moyamoya disease (n = 34) occurred mostly in children younger than 8 years of age; focal cerebral arteriopathy-inflammatory type (n = 25), in children 8-15 years of age; and dissection (n = 26), at all ages. Vertigo at stroke presentation was common in dissection. Dissection affected the cervical arteries, while Moyamoya disease involved the supraclinoid internal carotid arteries. A banded appearance of the M1 segment of the middle cerebral artery was pathognomonic of focal cerebral arteriopathy-inflammatory type but was present in <25% of patients with focal cerebral arteriopathy-inflammatory type; a small lenticulostriate distribution infarct was a more common predictor of focal cerebral arteriopathy-inflammatory type, present in 76%. It remained difficult to distinguish focal cerebral arteriopathy-inflammatory type from intracranial dissection of the anterior circulation. We observed only secondary forms of diffuse/multifocal vasculitis, mostly due to meningitis. CONCLUSIONS: Childhood arteriopathy subtypes have some typical features that aid diagnosis. Better imaging methods, including vessel wall imaging, are needed for improved classification of focal cerebral arteriopathy of childhood.

Proline uptake by monolayers of human intestinal absorptive (Caco-2) cells in vitro.

Monolayers of the Caco-2 human intestinal cell line exhibit active and passive uptake systems for the imino acid L-proline. The active transport component is saturable and it is responsible for about two thirds of the observed flux over the nanomolar concentration range, at 37 degrees C and pH 7.4. In contrast to L-phenylalanine, specific L-proline uptake has a high degree of sodium dependency and the efficiency of the carrier system is significantly reduced when protein synthesis (cycloheximide), Na+/K(+)-ATPase (ouabain) or cellular metabolism (sodium azide) are inhibited. The expression of the L-proline carrier by Caco-2 cells was under some degree of nutritional control. Glucose deficiency, over the time scale of the experiment, had no effect. The temperature-dependence of the specific uptake process followed the Arrhenius model with an apparent activation energy of 93.5 kJ nmol-1. This pathway also displayed Michaelis-Menten concentration-dependence with a Ksdm of 5.28 mM and a maximal transport flux (Jsdmax) of 835 pmol min-1 (10(6) cells)-1. Although the passive component was unchanged, the pH of the donor phase exerted a profound effect on the active carrier component. Within the physiological pH range a local maximum efficiency was found at pH 7.4 but dramatic increases were noted as pH 5.0 was approached. In competition studies, with 100-fold excess of a second amino acid, strong inhibition of uptake was found with alpha-aminoisobutyric acid, L-alanine and L-serine whereas moderate inhibition was observed with glycine, D-proline and gamma-aminoisobutyric acid. Aromatic and branched amino acids showed weak (L-valine) or no interaction (L-phenylalanine, L-leucine) with the carrier system. These data indicate that the carrier system for the uptake of L-proline has many features in common with the A system for amino acid transport.

The transport of acidic amino acids and their analogues across monolayers of human intestinal absorptive (Caco-2) cells in vitro.

The X-AG system, a sodium-dependent, acidic amino-acid transport system has been implicated in the transport of L-aspartate and L-glutamate across monolayers of human Caco-2 cells, an in vitro model of intestinal absorption. This system, which shares many properties with the L-glutamate carrier present in the human jejunum, is highly saturable (> 95% at 50 microM), vectorial (apical-to-basolateral >> basolateral-to-apical) and sodium-, pH- and temperature-dependent. L-Aspartate was also transported against a 10-fold reverse concentration gradient. These data are consistent with a major (saturable) carrier-mediated pathway superimposed onto a minor non-saturable (diffusional) pathway. The carrier has an absolute sodium-dependence and the Michaelis constants for the sodium-dependent transport component (Km) for L-aspartate and L-glutamate were 56 +/- 3 microM and 65 +/- 6 microM, respectively. Cross-inhibition studies showed that strong interaction with the carrier was limited to close analogues of the natural substrates. Potent inhibitors included L-aspartate, D-aspartate (Ki, 70 microM), L-glutamate (Ki 180 microM) and threo-beta-hydroxy-DL-aspartate (Ki, 55 microM), while partial inhibitors included alpha-methyl-DL-aspartate, D-glutamate, L-asparagine, L-proline and L-alanine. Replacement of the side-chain -COO- group (aspartate) with -SO-3 (L-cysteate, Ki, 65 microM) or -(H)P(O)O- (DL-3-(hydroxyphosphoryl)alanine, Ki, 60 microM) maintained strong interaction with the carrier while -As(O)(OH)O- (DL-3-arsonoalanine, Ki, 1100 microM) and -P(O)(OH)O- (DL-3-phosphonoalanine, Ki, 3270 microM) were much more weakly bound, with the larger, but probably less ionised, arsono analogue being more tightly bound than the phosphono compound. The corresponding analogues of glutamate (homologous extension of the methylene chain) showed negligible interaction. We conclude that Caco-2 monolayers are a relevant experimental model for the study of the transport of acidic amino acids and their analogues in man.

Allelic dimorphism in a surface antigen gene of the malaria parasite Plasmodium falciparum.

Merozoites of the malaria parasite Plasmodium falciparum carry surface proteins processed from a precursor termed p190 or p195. Polymorphism has been reported in this protein. Since the protein is a candidate for a malaria vaccine, it is important to understand the nature of this polymorphism. We have determined the complete nucleotide sequence of the p190 gene from the MAD20 strain (a Papua New Guinea isolate). Comparisons of the gene with that from other strains of P. falciparum allowed us to study the genetic basis of the antigen's polymorphism. The gene consists of sequences distributed in variable blocks, which are separated by conserved or semi-conserved sequences. Variable sequences occur both in regions that code for tripeptide repeats and in regions with no apparent repeats. Interestingly, according to the present data, variable sequences are not widely polymorphic but fall into two distinct types. We argue that the p190 protein is encoded by dimorphic alleles capable of limited genetic exchange and present evidence at the nucleotide level documenting intragenic recombination in Plasmodium.

Cloning of the DNA repair genes mtcA, mtcB, uvsC, uvsD, uvsE and the leuB gene from Deinococcus radiodurans.

A gene library from Deinococcus radiodurans has been constructed in the cosmid pJBFH. A 51.5-kb hybrid cosmid, pUE40, that transduced Escherichia coli HB101 from leucine dependence to independence was selected, and a 6.9-kb fragment which carried the leuB gene from D. radiodurans was subcloned into the EcoRI site of pAT153. The DNA repair genes mtcA, mtcB, uvsC, uvsD and uvsE, which code for two D. radiodurans UV endonucleases were identified by transforming appropriate repair-deficient mutants of D. radiodurans to repair proficiency with DNA derived from the gene library. Hybrid cosmid pUE50 (37.9 kb) containing an insert carrying both the mtcA and mtcB genes was selected and 5.6- and 2.7-kb DNA fragments carrying mtcA and mtcB, respectively, i.e., the genes that code for UV endonuclease alpha, were subcloned into the EcoRI site of pAT153. The three genes uvsC, uvsD and uvsE, that code for UV endonuclease beta, were all present in the 46.0-kb hybrid cosmid pUE60. The uvsE gene in a 12.2-kb fragment was subcloned into the HindIII site of pAT153 and the size of the insert reduced to 6.1 kb by deletion of a 6.7-kb fragment from the hybrid plasmid pUE62. None of the uvs genes introduced into the UV-sensitive E. coli CSR603 (uvrA-) was able to complement its repair defect. The mtcA, uvsC, uvsD and uvsE genes were found in the 52.5-kb hybrid cosmid pUE70. It is concluded that the DNA repair genes mtcA, mtcB, uvsC, uvsD and uvsE are located within an 83.0-kb fragment of the D. radiodurans genome.

Childhood chemotherapy and later drug abuse and growth curve: a follow-up study of 30 adolescents.

The authors studies the correlation of methylphenidate medication in childhood with later drug abuse and growth in height. Thirty adolescents with histories of minimal brain dysfunction who had been treated for at least six months with chemotherapy were compared with 30 adolescents who had not been so treated. The findings do not indicate that methylphenidate prescribed in childhood contributed to later drug abuse or seriously interfered with growth in height.

Structure of the human VIPR2 gene for vasoactive intestinal peptide receptor type 2.

The VPAC(2) (vasoactive intestinal peptide (VIP)(2)) receptor is a seven-transmembrane spanning G protein-coupled receptor which responds similarly to VIP and pituitary adenylate cyclase activating polypeptide (PACAP) in stimulating cAMP production. Recently, we reported the localisation of the human VPAC(2) receptor gene (VIPR2) to chromosome 7q36.3 (Mackay, M. et al. (1996) Genomics 37, 345-353). Here, we describe the characterisation of the VIPR2 gene structure and promoter region. The VIPR2 gene is encoded by 13 exons, the initiator codon of the 438 amino acid open reading frame is located in exon 1 and the termination signal and a poly-adenylation signal sequence are located in exon 13. The 5' untranslated region extends 187 bp upstream of the initiator codon and is extremely GC-rich (80%). The poly-adenylation signal is located 2416 bp downstream of the stop codon. Intron sizes range from 68 bp (intron 11) to 45 kb (intron 4) and the human gene spans 117 kb.

Benign acute childhood myositis: laboratory and clinical features.

BACKGROUND: Benign acute myositis of childhood is a disorder of midchildhood, typically affecting boys. Symptoms include calf pain and difficulty walking after a viral illness. There is an epidemiologic association with influenza. OBJECTIVES: To describe the clinical and laboratory features of benign acute myositis. RESULTS: Thirty-eight children (32 boys, 6 girls) were seen with 41 episodes of myositis between 1978 and 1997. Two were siblings and three had recurrent episodes. Mean age at onset of symptoms was 8.1 years. Children remained ambulant during 33 of 41 episodes. Two characteristic gaits were noted: toe-walking in 13, with a wide-based stiff-legged gait in another 7. Muscle tenderness was isolated to the gastrocnemius-soleus muscles in 82% of episodes. Recovery occurred within 1 week. Creatine kinase levels were elevated during all episodes. Viral studies were positive in 10 of 24 episodes, 5 because of influenza B. CONCLUSION: Benign acute myositis is a syndrome of midchildhood that can be differentiated from more serious causes of walking difficulty by the presence of calf tenderness, normal power, intact tendon reflexes, and elevated creatine kinase. The gait patterns noted may minimize power generation of the calf muscles by splinting the ankles. Onset in childhood may reflect an age-related response to viral infection, and occurrence primarily in boys may reflect a genetic predisposition or an as-yet unknown metabolic defect.

Reliability of cancer registration data in Scotland, 1997.

The aim of this study was to assess the reliability of cancer registration data in Scotland following a major re-organisation of the Scottish Cancer Registry. From a random sample of 3500 primary cancers (excluding non-melanoma skin cancers and death certificate only (DCO) registrations) diagnosed between April and September 1997, 3175 (90.7%) had medical records available for scrutiny. Data were re-abstracted by a team of trained medical coders and compared with information registered originally. Reliability was generally high for demographic, diagnostic, and fact of treatment details, but less reliable for grade of differentiation, staging variables and dates of treatment. Some discrepancies probably arose because of differing availability of information at the time of registration compared with the time of re-abstraction. Although data quality is high overall, further improvements might be achieved through continued training, structured recording of information by clinicians in medical records, and continued exploitation of the data.

A signal detection procedure eliminates priming biases in dichotic listening.

Dichotic digit names were presented to normal right-handed adults in two experiments, the first of which used a standard free report procedure and the second of which used a signal detection procedure. Prior to each test, a priming bias was generated by having subjects monitor either the left or right ear for 30 selective listening trials. The expected priming effect was found in Experiment 1: ear asymmetry and order of report were altered according to the ear previously monitored. In contrast, no priming effect was observed with the signal detection procedure used in Experiment 2. There was a right-ear advantage in sensitivity irrespective of the ear previously monitored. The findings suggest that priming biases act by altering the order in which multiple stimuli are processed and reported.