Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

Neurospora COP9 Signalosome Integrity Plays Major Roles for Hyphal Growth, Conidial Development, and Circadian Function

The COP9 signalosome (CSN) is a highly conserved multifunctional complex that has two major biochemical roles: cleaving NEDD8 from cullin proteins and maintaining the stability of CRL components. We used mutation analysis to confirm that the JAMM domain of the CSN-5 subunit is responsible for NEDD8 cleavage from cullin proteins in Neurospora crassa. Point mutations of key residues in the metal-binding motif (EXnHXHX10D) of the CSN-5 JAMM domain disrupted CSN deneddylation activity without interfering with assembly of the CSN complex or interactions between CSN and cullin proteins. Surprisingly, CSN-5 with a mutated JAMM domain partially rescued the phenotypic defects observed in a csn-5 mutant. We found that, even without its deneddylation activity, the CSN can partially maintain the stability of the SCFFWD-1 complex and partially restore the degradation of the circadian clock protein FREQUENCY (FRQ) in vivo. Furthermore, we showed that CSN containing mutant CSN-5 efficiently prevents degradation of the substrate receptors of CRLs. Finally, we found that deletion of the CAND1 ortholog in N. crassa had little effect on the conidiation circadian rhythm. Our results suggest that CSN integrity plays major roles in hyphal growth, conidial development, and circadian function in N. crassa

Women’s, partners’ and healthcare providers’ views and experiences of assisted vaginal birth: a systematic mixed methods review

Background When certain complications arise during the second stage of labour, assisted vaginal delivery (AVD), a vaginal birth with forceps or vacuum extractor, can effectively improve outcomes by ending prolonged labour or by ensuring rapid birth in response to maternal or fetal compromise. In recent decades, the use of AVD has decreased in many settings in favour of caesarean section (CS). This review aimed to improve understanding of experiences, barriers and facilitators for AVD use. Methods Systematic searches of eight databases using predefined search terms to identify studies reporting views and experiences of maternity service users, their partners, health care providers, policymakers, and funders in relation to AVD. Relevant studies were assessed for methodological quality. Qualitative findings were synthesised using a meta-ethnographic approach. Confidence in review findings was assessed using GRADE CERQual. Findings from quantitative studies were synthesised narratively and assessed using an adaptation of CERQual. Qualitative and quantitative review findings were triangulated using a convergence coding matrix. Results Forty-two studies (published 1985–2019) were included: six qualitative, one mixed-method and 35 quantitative. Thirty-five were from high-income countries, and seven from LMIC settings. Confidence in the findings was moderate or low. Spontaneous vaginal birth was most likely to be associated with positive short and long-term outcomes, and emergency CS least likely. Views and experiences of AVD tended to fall somewhere between these two extremes. Where indicated, AVD can be an effective, acceptable alternative to caesarean section. There was agreement or partial agreement across qualitative studies and surveys that the experience of AVD is impacted by the unexpected nature of events and, particularly in high-income settings, unmet expectations. Positive relationships, good communication, involvement in decision-making, and (believing in) the reason for intervention were important mediators of birth experience. Professional attitudes and skills (development) were simultaneously barriers and facilitators of AVD in quantitative studies. Conclusions Information, positive interaction and communication with providers and respectful care are facilitators for acceptance of AVD. Barriers include lack of training and skills for decision-making and use of instruments

Parenting-by-gender interactions in child psychopathology: attempting to address inconsistencies with a Canadian national database

<p>Abstract</p> <p>Background</p> <p>Research has shown strong links between parenting and child psychopathology. The moderating role of child gender is of particular interest, due to gender differences in socialization history and in the prevalence of psychiatric disorders. Currently there is little agreement on how gender moderates the relationship between parenting and child psychopathology. This study attempts to address this lack of consensus by drawing upon two theories (self-salience vs. gender stereotyped misbehaviour) to determine how child gender moderates the role of parenting, if at all.</p> <p>Methods</p> <p>Using generalized estimating equations (GEE) associations between three parenting dimensions (hostile-ineffective parenting, parental consistency, and positive interaction) were examined in relationship to child externalizing (physical aggression, indirect aggression, and hyperactivity-inattention) and internalizing (emotional disorder-anxiety) dimensions of psychopathology. A sample 4 and 5 year olds from the National Longitudinal Survey of Children and Youth (NLSCY) were selected for analysis and followed over 6 years (N = 1214). Two models with main effects (Model 1) and main effects plus interactions (Model 2) were tested.</p> <p>Results</p> <p>No child gender-by-parenting interactions were observed for child physical aggression and indirect aggression. The association between hostile-ineffective parenting and child hyperactivity was stronger for girls, though this effect did not reach conventional levels of statistical significance (<it>p </it>= .059). The associations between parenting and child emotional disorder did vary as a function of gender, where influences of parental consistency and positive interaction were stronger for boys.</p> <p>Discussion</p> <p>Despite the presence of a few significant interaction effects, hypotheses were not supported for either theory (i.e. self-salience or gender stereotyped misbehaviour). We believe that the inconsistencies in the literature regarding child gender-by-parenting interactions is due to the reliance on gender as an indicator of a different variable which is intended to explain the interactions. This may be problematic because there is likely within-gender and between-sample variability in such constructs. Future research should consider measuring and modelling variables that are assumed to explain such interactions when conducting gender-by-parenting research.</p

Noise and Robustness in Phyllotaxis

A striking feature of vascular plants is the regular arrangement of lateral organs on the stem, known as phyllotaxis. The most common phyllotactic patterns can be described using spirals, numbers from the Fibonacci sequence and the golden angle. This rich mathematical structure, along with the experimental reproduction of phyllotactic spirals in physical systems, has led to a view of phyllotaxis focusing on regularity. However all organisms are affected by natural stochastic variability, raising questions about the effect of this variability on phyllotaxis and the achievement of such regular patterns. Here we address these questions theoretically using a dynamical system of interacting sources of inhibitory field. Previous work has shown that phyllotaxis can emerge deterministically from the self-organization of such sources and that inhibition is primarily mediated by the depletion of the plant hormone auxin through polarized transport. We incorporated stochasticity in the model and found three main classes of defects in spiral phyllotaxis – the reversal of the handedness of spirals, the concomitant initiation of organs and the occurrence of distichous angles – and we investigated whether a secondary inhibitory field filters out defects. Our results are consistent with available experimental data and yield a prediction of the main source of stochasticity during organogenesis. Our model can be related to cellular parameters and thus provides a framework for the analysis of phyllotactic mutants at both cellular and tissular levels. We propose that secondary fields associated with organogenesis, such as other biochemical signals or mechanical forces, are important for the robustness of phyllotaxis. More generally, our work sheds light on how a target pattern can be achieved within a noisy background

Hippocampal Atrophy as a Quantitative Trait in a Genome-Wide Association Study Identifying Novel Susceptibility Genes for Alzheimer's Disease

With the exception of APOE ε4 allele, the common genetic risk factors for sporadic Alzheimer's Disease (AD) are unknown., which can be considered potential “new” candidate loci to explore in the etiology of sporadic AD. These candidates included EFNA5, CAND1, MAGI2, ARSB, and PRUNE2, genes involved in the regulation of protein degradation, apoptosis, neuronal loss and neurodevelopment. Thus, we identified common genetic variants associated with the increased risk of developing AD in the ADNI cohort, and present publicly available genome-wide data. Supportive evidence based on case-control studies and biological plausibility by gene annotation is provided. Currently no available sample with both imaging and genetic data is available for replication.Using hippocampal atrophy as a quantitative phenotype in a genome-wide scan, we have identified candidate risk genes for sporadic Alzheimer's disease that merit further investigation

Hip joint articular soft tissues of non-dinosaurian Dinosauromorpha and early Dinosauria: evolutionary and biomechanical implications for Saurischia

Dinosauromorphs evolved a wide diversity of hind limb skeletal morphologies, suggesting highly divergent articular soft tissue anatomies. However, poor preservation of articular soft tissues in fossils has hampered any follow-on functional inferences. We reconstruct the hip joint soft tissue anatomy of non-dinosaurian dinosauromorphs and early dinosaurs using osteological correlates derived from extant sauropsids and infer trends in character transitions along the theropod and sauropodomorph lineagues. Femora and pelves of 107 dinosauromorphs and outgroup taxa were digitized using 3D imaging techniques. Key transitions were estimated using maximum likelihood ancestral state reconstruction. The hips of dinosauromorphs possessed wide a disparity of soft tissue morphologies beyond the types and combinations exhibited by extant archosaurs. Early evolution of the dinosauriform hip joint was characterized by the retention of a prominent femoral hyaline cartilage cone in post-neonatal individuals, with the cartilage cone independently reduced within theropods and sauropodomorphs. The femur of Dinosauriformes possessed a fibrocartilage sleeve on the metaphysis, which surrounded a hyaline core. The acetabulum of Dinosauriformes possessed distinct labrum and antitrochanter structures. In sauropodomorphs, hip congruence was maintained by thick hyaline cartilage on the femoral head, whereas theropods relied on acetabular tissues such as ligaments and articular pads. In particular, the craniolaterally ossified hip capsule of non- Avetheropoda neotheropods permitted mostly parasagittal femoral movements. These data indicate that the dinosauromorph hip underwent mosaic evolution within the saurischian lineage and that sauropodomorphs and theropods underwent both convergence and divergence in articular soft tissues, correlated with transitions in body size, locomotor posture, and joint loading

First shark from the late Devonian (Frasnian) gogo formation, Western Australia sheds new light on the development of tessellated calcified cartilage

Background: Living gnathostomes (jawed vertebrates) comprise two divisions, Chondrichthyes (cartilaginous fishes, including euchondrichthyans with prismatic calcified cartilage, and extinct stem chondrichthyans) and Osteichthyes (bony fishes including tetrapods). Most of the early chondrichthyan (‘shark’) record is based upon isolated teeth, spines, and scales, with the oldest articulated sharks that exhibit major diagnostic characters of the group—prismatic calcified cartilage and pelvic claspers in males—being from the latest Devonian, c. 360 Mya. This paucity of information about early chondrichthyan anatomy is mainly due to their lack of endoskeletal bone and consequent low preservation potential. Methodology/Principal Findings: Here we present new data from the first well-preserved chondrichthyan fossil from the early Late Devonian (ca. 380–384 Mya) Gogo Formation Lägerstatte of Western Australia. The specimen is the first Devonian shark body fossil to be acid-prepared, revealing the endoskeletal elements as three-dimensional undistorted units: Meckel’s cartilages, nasal, ceratohyal, basibranchial and possible epibranchial cartilages, plus left and right scapulocoracoids, as well as teeth and scales. This unique specimen is assigned to Gogoselachus lynnbeazleyae n. gen. n. sp.Conclusions/Significance: The Meckel’s cartilages show a jaw articulation surface dominated by an expansive cotylus, and a small mandibular knob, an unusual condition for chondrichthyans. The scapulocoracoid of the new specimen shows evidence of two pectoral fin basal articulation facets, differing from the standard condition for early gnathostomes which have either one or three articulations. The tooth structure is intermediate between the ‘primitive’ ctenacanthiform and symmoriiform condition, and more derived forms with a euselachian-type base. Of special interest is the highly distinctive type of calcified cartilage forming the endoskeleton, comprising multiple layers of nonprismatic subpolygonal tesserae separated by a cellular matrix, interpreted as a transitional step toward the tessellated prismatic calcified cartilage that is recognized as the main diagnostic character of the chondrichthyans