Abstract
Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene ...variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5′UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5′UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5′UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.
In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset ...lymphoproliferation and autoimmunity.
This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants.
We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3.
Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate.
: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
Transmission of Zika virus (ZIKV) in the Americas was first confirmed in May 2015 in northeast Brazil. Brazil has had the highest number of reported ZIKV cases worldwide (more than 200,000 by 24 ...December 2016) and the most cases associated with microcephaly and other birth defects (2,366 confirmed by 31 December 2016). Since the initial detection of ZIKV in Brazil, more than 45 countries in the Americas have reported local ZIKV transmission, with 24 of these reporting severe ZIKV-associated disease. However, the origin and epidemic history of ZIKV in Brazil and the Americas remain poorly understood, despite the value of this information for interpreting observed trends in reported microcephaly. Here we address this issue by generating 54 complete or partial ZIKV genomes, mostly from Brazil, and reporting data generated by a mobile genomics laboratory that travelled across northeast Brazil in 2016. One sequence represents the earliest confirmed ZIKV infection in Brazil. Analyses of viral genomes with ecological and epidemiological data yield an estimate that ZIKV was present in northeast Brazil by February 2014 and is likely to have disseminated from there, nationally and internationally, before the first detection of ZIKV in the Americas. Estimated dates for the international spread of ZIKV from Brazil indicate the duration of pre-detection cryptic transmission in recipient regions. The role of northeast Brazil in the establishment of ZIKV in the Americas is further supported by geographic analysis of ZIKV transmission potential and by estimates of the basic reproduction number of the virus.
BACKGROUND
The aim of this study was to investigate the frequency of gonadal tumors among patients with Turner syndrome (TS) carrying Y-derivative sequences in their chromosomal constitution.
METHODS
...Six out of 260 patients with TS were selected based on mosaicism of the entire Y chromosome; 10 were included because Y-derivative sequences have been detected by PCR with specific oligonucleotides (sex-determining region on the Y, testis specific-protein, Y and DYZ3) and further confirmed by FISH. The 16 patients were subjected to bilateral gonadectomy at ages varying from 8.7 to 18.2 years. Both histopathological investigation with hematoxylin and eosin (H&E) and immunohistochemical analysis with anti-octamer-binding transcription factor 4 (OCT4) antibody were performed.
RESULTS
Gonadal neoplasia was not detected in any of the 32 gonads evaluated by H however, four gonads (12%) from three patients (19%) had positive OCT4 staining in 50–80% of nuclei, suggesting the existence of germ cell tumors (gonadoblastoma or in situ carcinoma).
CONCLUSIONS
Evaluation of the real risk of development of gonadal tumors in TS patients with Y-derivative sequences in their chromosomal constitution may require a specific histopathological study, such as immunohistochemistry with OCT4.
We report a comprehensive discussion of quantum interference effects due to the finite structure of neutral excitons in quantum rings and their first experimental corroboration observed in the ...optical recombinations. The signatures of built-in electric fields and temperature on quantum interference are demonstrated by theoretical models that describe the modulation of the interference pattern and confirmed by complementary experimental procedures.
Aiming to predict the strength of bonded joints by techniques such as cohesive zone models (CZM), it is highly relevant to estimate the adhesive strength and fracture toughness (G
C
). Here, the ...tensile and shear fracture toughness (G
IC
and G
IIC
, respectively) and the corresponding mixed-mode behaviour acquire special relevancy. However, it is known that these parameters are highly dependent on the adhesive thickness (t
A
). The present work experimentally addresses the t
A
effect on the mixed-mode behaviour of bonded joints, namely on the tensile and shear fracture energies (G
I
and G
II
, respectively), using the Single-Leg Bending (SLB) test. Different data reduction schemes were applied. With this purpose, the respective resistance curves (R-curves) were calculated, which enabled plotting the respective fracture envelope for a sample t
A
by the knowledge of the pure-mode G
IC
and G
IIC
. Overall, it was possible to obtain a good agreement between methods for the mixed-mode G
I
and G
II
calculation and to estimate the most suitable fracture envelope of the adhesive for a given t
A
. The compliance-based beam method (CBBM) was found to be particularly suited to perform data reduction, since it accounts for the adhesives' ductility and it is not affected by crack length (a) measuring errors.
Introduction
Current neuroimaging research has revealed several brain alterations in idiopathic REM sleep behaviour disorder (iRBD) that mirror and precede those reported in PD. However, none have ...specifically addressed the presence of changes across the reward system, and their role in the emergence of impulse control disorders (ICDs). We aimed to compare the volumetric and functional connectivity characteristics of the reward system in relation to the psychobehavioral profile of patients with iRBD versus healthy controls and PD patients.
Methods
Twenty patients with polysomnography confirmed iRBD along with 17 PD patients and 14 healthy controls (HC) underwent structural and functional resting-state brain MRI analysis. Participants completed the questionnaire for impulsive-compulsive disorders in PD (QUIP), the short UPPS-P impulsive behaviour scale, as well as neuropsychological testing of cognitive function.
Results
A higher percentage of iRBD patients reported hypersexuality, compared to HC and PD (
p
= 0.008). Whole-brain and striatal voxel-based morphometry analyses showed no significant clusters of reduced grey matter volume between groups. However, iRBD compared to HC demonstrated functional hypoconnectivity between the limbic striatum and temporo-occipital regions. Furthermore, the presence of ICDs correlated with hypoconnectivity between the limbic striatum and clusters located in cuneus, lingual and fusiform gyrus.
Conclusion
Altered functional connectivity between the limbic striatum and posterior cortical regions was associated with increased hypersexuality in iRBD. It is possible that this change may ultimately predispose individuals to the emergence of ICDs when they receive dopaminergic medications, after transitioning to PD.
Males have higher weight and length at birth than females.
To verify the influence of the Y chromosome and the action of intrauterine androgens on weight and length at birth of children with ...Disorders of Sex Development (DSD).
A cross-sectional and retrospective study. Patients with Turner syndrome (TS), complete (XX and XY), mixed (45,X/46,XY) and partial (XY) gonadal dysgenesis (GD), complete (CAIS) and partial (PAIS) androgen insensitivity syndromes and XX and XY congenital adrenal hyperplasia (CAH) were included. Weight and length at birth were evaluated.
Weight and length at birth were lower in TS and mixed GD when compared to XY and XX DSD cases. In turn, patients with increased androgen action (117 cases) had higher weight and length at birth when compared to those with absent (108 cases) and decreased (68 cases) production/action. In birthweight, there was a negative influence of the 45,X/46,XY karyotype and a positive influence of increased androgen and gestational age. In birth length, there was a negative influence of the 45,X and 45,X/46,XY karyotypes and also a positive influence of increased androgen and gestational age.
The sex dimorphism of weight and length at birth could possibly be influenced by intrauterine androgenic action.
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