To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilises forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.membrane trafficking | COPII-mediated secretion | ER exit site H ereditary spastic paraplegias (HSPs) are a diverse group of disorders characterized by spastic weakness in the lower extremities, which results from degeneration of upper motoneuron axons in the corticospinal tract (1, 2). Based on the presence or absence of other neurological abnormalities, HSPs are classified as complicated or pure, respectively. In addition to lower-limb spasticity, complicated forms of HSP may be associated with ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction, and/or epilepsy. HSPs are typically progressive, but age of onset is highly variable. The heterogeneity in clinical presentation is accompanied by genetic heterogeneity. To date, more than 40 different genetic loci, which include nearly all modes of inheritance, have been linked to HSPs (1-5). However, in nearly half of these cases, the identities of the causative genes remain unknown. The identification of additional HSP genes and, more importantly, the functional characterization of their encoded products, will both contribute to our understanding of the pathomechanisms underlying HSPs and reveal the general requirements for lifelong axonal maintenance.More than half the HSP cases in North America and Northern Europe can be attributed to defects in organelle dynamics (6). In particular, mutations that impact the architecture of the endoplasmic reticulum (ER) are common in patients with HSP. The ER is comprised of a network of membrane tubules and sheetlike cisternae that extend throughout the cytoplasm and encase the nucleus (7-9). Several factors contribute to this architecture, including (i) membrane-bending proteins of the REEP and reticulon families; (ii) regulators of the microtubule cytoskeleton, which governs the spatial patterning of the ER network; and (iii) components of the ear...

These results advocate the role of paternal lymphocyte immunotherapy for the maintenance of pregnancy in women with RSA.

Of several subtypes of breast cancer, triple negative breast cancer (TNBC) is a highly aggressive tumor that lacks expression of hormone receptors for estrogen, progesterone and human epidermal growth factor receptor 2 and shows a worst prognosis. The small noncoding RNAs (miRNAs) considered as master regulator of gene expression play a key role in cancer initiation, progression and drug resistance and have emerged as attractive molecular biomarkers for diagnosis, prognosis and treatment targets in cancer. We have done expression profiling of selected miRNAs in paired serum and tissue samples of TNBC patients and corresponding cell lines and compared with that of other subtypes, in order to identify novel serum miRNA biomarkers for early detection and progression of TNBC. A total of 85 paired tumor tissues and sera with an equal number of adjacent normal tissue margins and normal sera from age matched healthy women including tissue and sera samples from 15 benign fibroadenomas were employed for the study. We report for the first time an extremely high prevalence (73.9%) of TNBC in premenopausal women below 35 years of age and a significant altered expression of a panel of three specific oncogenic miRNAs- miR-21, miR-221, miR-210, and three tumor suppressor miRNAs- miR-195, miR-145 and Let-7a in both tissues and corresponding sera of TNBC patients when compared with triple positive breast cancer (TPBC) patients. While miR-21, miR-221 and miR-210 showed significant over-expression, miR-195 and miR-145 were downregulated and well correlated with various clinicopathological and demographic risk factors, tumor grade, clinical stage and hormone receptor status. Interestingly, despite being a known tumor suppressor, Let-7a showed a significant overexpression in TNBCs. It is suggested that this panel of six miRNA signature may serve as a minimally invasive biomarker for an early detection of TNBC patients.

Objectives:The aim of this study was to evaluate the clinical and radiographic success of zinc oxide (ZnO)-ozonated oil, modified 3Mix antibiotic paste, and vitapex in the treatment of primary molars requiring pulpectomy.Methods:Sixty-four primary molars of forty-three healthy children aged between 4 and 8 years with primary molars requiring root canal procedure were treated with ZnO-ozonated oil, modified 3Mix-MP antibiotic paste, and vitapex. Clinical follow up was done at 1, 6,12 months and 18 months while radiographical follow-up was done at 6,12 and 18 months, respectively.Results:The results showed that the clinical success rates of ZnO-ozonated oil, modified 3Mix-MP paste and vitapex were 95.5%,89.5% and 100% respectively and radiographical success rates were 94.4%,80.95% and 100% respectively after 18 months period of observation.Conclusion:The overall success rates of ZnO-ozonated oil, vitapex and modified 3Mix antibiotic paste were comparable.

On the basis of the overall success rates of all the three medicaments, following order of performance can be inferred clinical success and radiographical success:- ZnO-OO = Vitapex > modified 3MIX-MP paste.

No abstract

Dens invaginatus occurs as a result of the invagination of the enamel organ. These cases may present difficulties with respect to its diagnosis and treatment because of canal morphology. It frequently leads to caries, pulpal, and periodontal involvement with necrosis and loss of attachment. The knowledge of classification and anatomical variations of teeth with dens invaginatus are of great importance for correct treatment. This article presents two case reports of two different types of dens invaginatus along with profound review of the literature regarding etiology, epidemiology, and histology. It discusses clinical appearance and diagnosis, and it provides guidelines for decision-making and treatment of invaginated teeth.