A novel heterozygous SOX2 mutation causing congenital bilateral anophthalmia,hypogonadotropic hypogonadism and growth hormone deficiency

Heterozygous de novo mutations in SOX2 have been reported in approximately 10–20% of patients with unilateral or bilateral anophthalmia or microphthalmia. An additional phenotype of hypopituitarism, with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, has been reported in patients carrying SOX2 alterations. We report a novel heterozygous mutation in the SOX2 gene in a male affected with congenital bilateral anophthalmia, hypogonadotrophic hypogonadism and growth hormone deficiency. The mutation we describe is a cytosine deletion in position 905 (c905delC) which causes frameshift and an aberrant C-terminal domain. Our report highlights the fact that subjects affected with eye anomalies and harboring SOX2 mutations are at high risk for gonadotropin deficiency, which has important implications for their clinical management.     

Training-Dependent Associative Learning Induced Neocortical Structural Plasticity: A Trace Eyeblink Conditioning Analysis

Studies utilizing general learning and memory tasks have suggested the importance of neocortical structural plasticity for memory consolidation. However, these learning tasks typically result in learning of multiple different tasks over several days of training, making it difficult to determine the synaptic time course mediating each learning event. The current study used trace-eyeblink conditioning to determine the time course for neocortical spine modification during learning. With eyeblink conditioning, subjects are presented with a neutral, conditioned stimulus (CS) paired with a salient, unconditioned stimulus (US) to elicit an unconditioned response (UR). With multiple CS-US pairings, subjects learn to associate the CS with the US and exhibit a conditioned response (CR) when presented with the CS. Trace conditioning is when there is a stimulus free interval between the CS and the US. Utilizing trace-eyeblink conditioning with whisker stimulation as the CS (whisker-trace-eyeblink: WTEB), previous findings have shown that primary somatosensory (barrel) cortex is required for both acquisition and retention of the trace-association. Additionally, prior findings demonstrated that WTEB acquisition results in an expansion of the cytochrome oxidase whisker representation and synaptic modification in layer IV of barrel cortex. To further explore these findings and determine the time course for neocortical learning-induced spine modification, the present study utilized WTEB conditioning to examine Golgi-Cox stained neurons in layer IV of barrel cortex. Findings from this study demonstrated a training-dependent spine proliferation in layer IV of barrel cortex during trace associative learning. Furthermore, findings from this study showing that filopodia-like spines exhibited a similar pattern to the overall spine density further suggests that reorganization of synaptic contacts set the foundation for learning-induced neocortical modifications through the different neocortical layers.     

Antibody VH and VL recombination using phage and ribosome display technologies reveals distinct structural routes to affinity improvements with VH-VL interface residues providing important structural diversity

In vitro selection technologies are an important means of affinity maturing antibodies to generate the optimal therapeutic profile for a particular disease target. Here, we describe the isolation of a parent antibody, KENB061 using phage display and solution phase selections with soluble biotinylated human IL-1R1. KENB061 was affinity matured using phage display and targeted mutagenesis of VH and VL CDR3 using NNS randomization. Affinity matured VHCDR3 and VLCDR3 library blocks were recombined and selected using phage and ribosome display protocol. A direct comparison of the phage and ribosome display antibodies generated was made to determine their functional characteristics.     

Pattern of chromosome involvement in childhood hyperdiploid pre-B-cell acute lymhoblastic leukemia cases from India

BACKGROUND:

Hyperdiploid pre-B-cell acute lymhoblastic leukemia (pre-B-ALL) is a common form of childhood leukemia with very good prognosis with present day chemotherapy. However, the chromosomal composition of the hyperdiploidy has not been extensively studied and possible mechanism for this pathology remains so far conjectural.

OBJECTIVE:

To analyze the pattern of chromosome involvement in a cohort of childhood hyperdiploid pre-B-ALL from India and from this pattern to develop an understanding on the causation of such pathology. Whether such patients also carry translocations and FLT3 mutations in addition to their hyperdiploid karyotype.

MATERIALS AND METHODS:

One hundred and twenty-six childhood pre-B-ALL patients were studied. Bone marrow aspirate of these patients were evacuated for morphology, FAB classification, immunophenotyping and both conventional and molecular cytogenetics.

RESULTS:

Of 126 patients with pre-B-ALL (age 2-15 years), 90 patients with abnormal karyotype showed 50 with hyperdiploid karyotype (50/90 i.e. 55.5%). Chromosomes 9, 10, 14, 17, 18, 20 and 21 were more often involved in hyperdiploidy. Chromosome 21 duplication was present in 92% of the cases. Chromosomes 5, 15, 16, 17 and Y were less often involved (18-20%) in hyperdiploidy. About 44% of patients with hyperdiploidy had additional karyotypic abnormality of which TEL-AML1 was predominant (24%). Chromosome loss was rare and accounted for 20% of the cases only. We did not find any FLT3 mutation in our patients.

CONCLUSION:

In this study, the pattern of chromosome involvement in hyperdiploid karyotype of ALL patients is same as other studies except some chromosomes like 1, 6, 11, 12, 19 and 22 have some more frequent involvement than other studies. This study also showed the occurrence of TEL/AML1 fusion is more (19.8%) than other reports from India.     

In situ nitrogen fixation associated with seagrasses in the Gulf of Elat (Red Sea)

In situ nitrogen fixation associated with the seagrass Halophila stipulacea, at the northern Gulf of Elat (Red Sea), is eight to ten times higher than that of nearby plant-free areas. A daily cycle of nitrogen fixation is evident, with rates during the day being seven times greater than during the night. Removal of seagrass leaves only from a patch within a seagrass bed gradually decreases nitrogen fixation activity, reaching the rates of plant-free areas after ten hours. A method devised for the in situ measurement of nitrogen fixation rates using belljars is described in detail. Nitrogen fixation rates in situ are higher than in the laboratory and lack the lag period typical to laboratory measurements. In laboratory experiments using intact plant samples, glucose enhances nitrogen fixation rates both in light and dark. Photosystem II inhibitor (3-3,4-dichloro-phenyl-1,1-dimethylurea) doubles nitrogen fixation rates in light. Both field and laboratory results indicate that light is essential for nitrogen fixation activity in the H. stipulacea bed possibly through its effect on cyanobacterial population that occupy the aerobic niches of the phyllosphere and on photosynthetic Rhodospirillacean bacteria that inhabit the anaerobic ones. Nitrogen fixation rates evident in H. stipulacea beds in situ account for a considerable portion of the biomass production by the seagrasses. The dependence of high nitrogenase activity by the diazotrophs on the presence of the seagrasses indicates the great importance of the seagrass community to the nitrogen cycle in its highly oligotrophic surroundings of the Gulf of Elat.     

Mesenchymal stem cells protect neurons against hypoxic-ischemic injury via inhibiting parthanatos,necroptosis, and apoptosis,but not autophagy

Cellular therapy with mesenchymal stem cells (MSCs) protects cortical neurons against hypoxic-ischemic injury of stroke. Although sorts of efforts have been made to confirm the neuroprotective effect of MSCs on neurons against hypoxic-ischemic injury, the mechanism is until now far away from clear. Here in this study, oxygen-glucose deprivation (OGD)-injured neuron model was applied to mimic the neuronal hypoxic-ischemic injury in vitro. Co-culturing with MSCs in a transwell co-culture system, the OGD injured neurons were rescued by 75.0 %. Further data demonstrated that co-culturing with MSCs protected the cortical neurons from the OGD-induced parthanatos by alleviating apoptosis-inducing factor (AIF) nuclear translocation; attenuated the neuronal necroptosis by down-regulating the expression of the two essential kinases in necroptosis, receptor interacting protein kinase1 (RIP1) and 3 (RIP3); rescued the neurons from apoptosis by deactivating caspase-3; whilst performed no significant influence on OGD-induced neuronal autophagy, according to its failed regulation on Beclin1. In conclusion, MSCs potentially protect the cortical neurons from OGD-injury in vitro, through rescuing neurons from the cell death of parthanatos, necroptosis, and apoptosis, but not autophagy, which could provide some evidence to the mechanism explanation on stem cell treatment for ischemic stroke.     

Projecting the SARS-CoV-2 transition from pandemicity to endemicity: Epidemiological and immunological considerations

In this review, we discuss the epidemiological dynamics of different viral infections to project how the transition from a pandemic to endemic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) might take shape. Drawing from theories of disease invasion and transmission dynamics, waning immunity in the face of viral evolution and antigenic drift, and empirical data from influenza, dengue, and seasonal coronaviruses, we discuss the putative periodicity, severity, and age dynamics of SARS-CoV-2 as it becomes endemic. We review recent studies on SARS-CoV-2 epidemiology, immunology, and evolution that are particularly useful in projecting the transition to endemicity and highlight gaps that warrant further research.