ATP binding cassette (ABC) transporters at the blood–brain barrier function as ATP‐driven xenobiotic efflux pumps and limit delivery of small molecule drugs to the brain. Here I review recent ...progress in understanding the regulation of the expression and transport activity of these transporters and comment on how this new information might aid in improving drug delivery to the brain.
Summary
Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious ...pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.
This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for ...the 3 variants of PPA--nonfluent/agrammatic, semantic, and logopenic--were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as "imaging-supported" if the expected pattern of atrophy is found and "with definite pathology" if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.
Objective
Charcot‐Marie‐Tooth disease (CMT) affects 1 in 2,500 people and is caused by mutations in more than 30 genes. Identifying the genetic cause of CMT is often necessary for family planning, ...natural history studies, and for entry into clinical trials. However genetic testing can be both expensive and confusing to patients and physicians.
Methods
We analyzed data from 1,024 of our patients to determine the percentage and features of each CMT subtype within this clinic population. We identified distinguishing clinical and physiological features of the subtypes that could be used to direct genetic testing for patients with CMT.
Results
Of 1,024 patients evaluated, 787 received CMT diagnoses. A total of 527 patients with CMT (67%) received a genetic subtype, while 260 did not have a mutation identified. The most common CMT subtypes were CMT1A, CMT1X, hereditary neuropathy with liability to pressure palsies (HNPP), CMT1B, and CMT2A. All other subtypes accounted for less than 1% each. Eleven patients had >1 genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities.
Interpretation
Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we propose a strategy of focused genetic testing for CMT, illustrated in a series of flow diagrams created as testing guides. ANN NEUROL 2011;69:22–33.
ABSTRACTHeishman, AD, Daub, BD, Miller, RM, Freitas, EDS, Frantz, BA, and Bemben, MG. Countermovement jump reliability performed with and without an arm swing in NCAA Division 1 intercollegiate ...basketball players. J Strength Cond Res 34(2)546–558, 2020—The countermovement jump (CMJ) is routinely used in athlete performance to quantify adaptions to training, as well as monitor neuromuscular readiness and fatigue. However, controversy remains in whether to incorporate an arm swing during the CMJ (CMJ AS) or keep the hands placed on the hips (CMJ NAS). Incorporating the arms provides a higher degree of sport-specificity that may yield improved reliability, especially in skilled jumpers. By contrast, the hands-on-hips approach isolates lower extremity force production and eliminates potential arm-swing variation. Therefore, the purpose of this study was to establish the reliability of CMJ typical (CMJ-TYP), CMJ concentric alternative (CMJ-Conc-ALT), and CMJ eccentric alternative (CMJ-Ecc-ALT) variables obtained during the CMJ AS and CMJ NAS. Twenty-two (men = 14, women = 8) NCAA Division 1 collegiate basketball players performed 3 CMJ AS and 3 CMJ NAS on a force plate, in a randomized order. To assess the test-retest reliability, participants returned 1 week later to perform 3 additional CMJ AS and 3 CMJ NAS. Intraclass correlation coefficient (ICC) and coefficient of variation (CV) were used to assess intersession and intrasession reliability for the various CMJ variables. A majority of CMJ-TYP and several CMJ-Conc-ALT and CMJ-Ecc-ALT variables exhibited adequate intersession and intrasession reliability (ICC > 0.700 and CV <10%) during both the CMJ AS and the CMJ NAS. Countermovement jump AS may provide more pertinent information about long-term changes in sport-specific performance, whereas the CMJ NAS may be more beneficial for detecting acute changes in neuromuscular fatigue and athlete readiness.
Objective
Dysbiosis of the infant gut microbiota may have long‐term health consequences. This study aimed to determine the impact of maternal intrapartum antibiotic prophylaxis (IAP) on infant gut ...microbiota, and to explore whether breastfeeding modifies these effects.
Design
Prospective pregnancy cohort of Canadian infants born in 2010–2012: the Canadian Healthy Infant Longitudinal Development (CHILD) Study.
Setting
General community.
Sample
Representative sub‐sample of 198 healthy term infants from the CHILD Study.
Methods
Maternal IAP exposures and birth method were documented from hospital records and breastfeeding was reported by mothers. Infant gut microbiota was characterised by Illumina 16S rRNA sequencing of faecal samples at 3 and 12 months.
Main outcome measures
Infant gut microbiota profiles.
Results
In this cohort, 21% of mothers received IAP for Group B Streptococcus prophylaxis or pre‐labour rupture of membranes; another 23% received IAP for elective or emergency caesarean section (CS). Infant gut microbiota community structures at 3 months differed significantly with all IAP exposures, and differences persisted to 12 months for infants delivered by emergency CS. Taxon‐specific composition also differed, with the genera Bacteroides and Parabacteroides under‐represented, and Enterococcus and Clostridium over‐represented at 3 months following maternal IAP. Microbiota differences were especially evident following IAP with emergency CS, with some changes (increased Clostridiales and decreased Bacteroidaceae) persisting to 12 months, particularly among non‐breastfed infants.
Conclusions
Intrapartum antibiotics in caesarean and vaginal delivery are associated with infant gut microbiota dysbiosis, and breastfeeding modifies some of these effects. Further research is warranted to explore the health consequences of these associations.
Tweetable
Maternal #antibiotics during childbirth alter the infant gut #microbiome.
Tweetable
Maternal #antibiotics during childbirth alter the infant gut #microbiome.
Summary Background The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and ...safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment. Methods In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18–55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00548405. Findings 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 95% CI 0·39–0·65; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 95% CI 0·38–0·87; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 66% of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia. Interpretation For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity. Funding Genzyme (Sanofi) and Bayer Schering Pharma.
Carbonaceous asteroids, such as (101955) Bennu, preserve material from the early Solar System, including volatile compounds and organic molecules. We report spacecraft imaging and spectral data ...collected during and after retrieval of a sample from Bennu’s surface. The sampling event mobilized rocks and dust into a debris plume, excavating a 9-meter-long elliptical crater. This exposed material is darker, spectrally redder, and more abundant in fine particulates than the original surface. The bulk density of the displaced subsurface material was 500 to 700 kilograms per cubic meter, which is about half that of the whole asteroid. Particulates that landed on instrument optics spectrally resemble aqueously altered carbonaceous meteorites. The spacecraft stored 250 ± 101 grams of material, which will be delivered to Earth in 2023.
Grabbing a sample of asteroid Bennu
The near-Earth carbonaceous asteroid Bennu was the target of the OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, Security-Regolith Explorer) sample return mission. After rendezvousing with the asteroid, the spacecraft spent 2 years studying its surface and selecting a suitable site. Lauretta
et al
. describe the sample collection process and its effects on Bennu. The asteroid provided almost no resistance to contact, and the gas released by the spacecraft blew a crater several meters wide, exposing redder rocks and dust. So much material was gathered that the collection chamber overflowed. Approximately 250 grams was successfully stowed, well above the mission goal of 60 grams. The samples are expected to arrive on Earth in September 2023. —KTS
Samples of the near-Earth asteroid Bennu were collected by the OSIRIS-REx mission and should arrive on Earth in 2023.
Kdm6a/Utx, a gene on the X chromosome, encodes a histone H3K27me3 demethylase that has an orthologue on the Y chromosome (Uty) (Zheng et al. 2018). We previously identified inactivating mutations of ...Kdm6a in approximately 50% of mouse acute promyelocytic leukemia samples; however, somatic mutations of KDM6A are more rare in human AML samples, ranging in frequency from 2-15% in different series of patients, where their role in pathogenesis is not yet clear. In this study, we show that female Kdm6aflox/flox mice (with allele inactivation initiated by Vav1-Cre in hematopoietic stem and progenitor cells (HSPCs) have a sex-specific phenotype that emerges with aging, with features resembling a myelodysplastic syndrome (MDS). Female Kdm6a-knockout (KO) mice have an age-dependent expansion of their HSPCs with aberrant self-renewal, but they did not differentiate normally into downstream progeny. These mice became mildly anemic and thrombocytopenic, but did not develop overt leukemia, or die from these cytopenias. ChIP-seq and ATAC-seq studies showed only minor changes in H3K27me3, H3K27ac, H3K4me, H3K4me3 and chromatin accessibility between Kdm6a-WT and Kdm6a-KO mice. Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
HiPERCAM is a portable, quintuple-beam optical imager that saw first light on the 10.4-m Gran Telescopio Canarias (GTC) in 2018. The instrument uses re-imaging optics and four dichroic ...beamsplitters to record $u_{\rm s}\, g_{\rm s}\, r_{\rm s}\, i_{\rm s}\, z_{\rm s}$ (320–1060 nm) images simultaneously on its five CCD cameras, each of 3.1-arcmin (diagonal) field of view. The detectors in HiPERCAM are frame-transfer devices cooled thermo-electrically to 183 K, thereby allowing both long-exposure, deep imaging of faint targets, as well as high-speed (over 1000 windowed frames per second) imaging of rapidly varying targets. A comparison-star pick-off system in the telescope focal plane increases the effective field of view to 6.7 arcmin for differential photometry. Combining HiPERCAM with the world’s largest optical telescope enables the detection of astronomical sources to gs ∼ 23 in 1 s and gs ∼ 28 in 1 h. In this paper, we describe the scientific motivation behind HiPERCAM, present its design, report on its measured performance, and outline some planned enhancements.
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