Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative

We conducted genomewide linkage analyses on 1,152 individuals from 250 families segregating for bipolar disorder and related affective illnesses. These pedigrees were ascertained at 10 sites in the United States, through a proband with bipolar I affective disorder and a sibling with bipolar I or schizoaffective disorder, bipolar type. Uniform methods of ascertainment and assessment were used at all sites. A 9-cM screen was performed by use of 391 markers, with an average heterozygosity of 0.76. Multipoint, nonparametric linkage analyses were conducted in affected relative pairs. Additionally, simulation analyses were performed to determine genomewide significance levels for this study. Three hierarchical models of affection were analyzed. Significant evidence for linkage (genomewide P<.05) was found on chromosome 17q, with a peak maximum LOD score of 3.63, at the marker D17S928, and on chromosome 6q, with a peak maximum LOD score of 3.61, near the marker D6S1021. These loci met both standard and simulation-based criteria for genomewide significance. Suggestive evidence of linkage was observed in three other regions (genomewide P<.10), on chromosomes 2p, 3q, and 8q. This study, which is based on the largest linkage sample for bipolar disorder analyzed to date, indicates that several genes contribute to bipolar disorder.     

The association between prion proteins and Aβ₁₋₄₂ oligomers in cytotoxicity and apoptosis

Microglia are cells from non-neuronal lineages that reside in the central nervous system. In zebrafish, early macrophages migrate from the yolk sac to the brain and retina at 26-30 hour post fertilization (hpf) and transform into microglia at 55-60 hpf. The migration of macrophages into the central nervous system requires signaling by macrophage colony stimulating factor-1 receptor (csf-1r), which is encoded by the gene fms. In this study, we show that the targeted knockdown of csf-1r with morpholino oligonucleotides delays migration of macrophages from the yolk sac to the retina, and this delay in macrophage migration results in microphthalmia, delay in cell cycle withdrawal among retinal progenitors and the absence of neuronal differentiation. When embryos were allowed to survive beyond the time when morpholino-dependent translation inhibition is lost, microglia re-occupy the retina and neuronal differentiation partially recovers. Our data demonstrate that microglia are required for normal retinal growth and neurogenesis. This study provides new insight into the neurogenic role of microglia during retinal development in zebrafish.     

Vegetation changes during a 36-year period in northern Chobe National Park, Botswana

Changes in vegetation cover in northern Chobe National Park (Botswana) were assessed using aerial photographs from 1962, 1985 and 1998, with subsequent ground proofing. In addition, cumulative browsing by elephants and the occurrence of fire scars were recorded on random vegetation sites within shrubland (n = 20) and mixed woodland (n = 20). Coverage of woodland vegetation decreased from 60% to 30% between 1962 and 1998, while shrubland vegetation increased from 5% to 33% during the same period. During the study period, woodland has gradually retreated away from the river front. While riparian forest covered a continuous area along the riverfront in 1962, only fragments were left in 1998. We found a significant decrease in browse use with increasing distance to the Chobe river for Combretum apiculatum, Combretum elaeagnoides, Combretum mossambicense and other woody plants combined (all P < 0.0001). The occurrence of fire (P < 0.0001) and basal area (P < 0.0001) were positively related to distance to the river. Elephant browsing occurred on >70% of available stems within 2 km from the river, while less than 20% of the trees had fire scars in the same zone. Beyond 7 km from the river, elephant browsing was reduced to >50% of available stems, while more than 50% of the trees had fire scars. The density of any of the shrubs was not related to distance to the river neither within shrubland (all P > 0.05) nor within mixed woodlands (all P > 0.05).     

Spatial regulation of MCAK promotes cell polarization and focal adhesion turnover to drive robust cell migration

The asymmetric distribution of microtubule (MT) dynamics in migrating cells is important for cell polarization, yet the underlying regulatory mechanisms remain underexplored. Here, we addressed this question by studying the role of the MT depolymerase, MCAK (mitotic centromere-associated kinesin), in the highly persistent migration of RPE-1 cells. MCAK knockdown leads to slowed migration and poor directional movement. Fixed and live cell imaging revealed that MCAK knockdown results in excessive membrane ruffling as well as defects in cell polarization and the maintenance of a major protrusive front. Additionally, loss of MCAK increases the lifetime of focal adhesions by decreasing their disassembly rate. These functions correlate with a spatial distribution of MCAK activity, wherein activity is higher in the trailing edge of cells compared with the leading edge. Overexpression of Rac1 has a dominant effect over MCAK activity, placing it downstream of or in a parallel pathway to MCAK function in migration. Together, our data support a model in which the polarized distribution of MCAK activity and subsequent differential regulation of MT dynamics contribute to cell polarity, centrosome positioning, and focal adhesion dynamics, which all help facilitate robust directional migration.     

Role of endothelins in congestive heart failure

Despite major advances in conventional medical therapy, patients with heart failure continue to experience significant morbidity and mortality. Endothelin-1 (ET-1) is a potent vasocontrictor and mitogenic peptide that is activated in heart failure. There is increasing experimental and clinical evidence in support of an important role of ET-1 in the pathophysiology of heart failure. Manipulation of the activity of ET-1, especially using endothelin receptor blockers, has allowed for the further elucidation of the role of this neurohormonal system and development of novel therapeutic strategies in heart failure. Published clinical studies of these agents to date have involved relatively small numbers of patients with severe heart failure, followed for a relatively short period of time, and have mainly examined surrogate endpoints. Large-scale trials that address to hard clinical outcomes are ongoing and their results forthcoming. A key question that remains concerns whether selective ETA or dual ETA-ETB receptor blockade will be more effective.     

Synthesis, biological activity, and absolute stereochemical assignment of NPS 1392: a potent and stereoselective NMDA receptor antagonist.

The synthesis, biological activity, and single crystal X-ray structure of NPS 1392, (R)-(-)-3,3-bis(3-fluorophenyl)-2-methylpropan-1-amine (3a), a potent, stereoselective antagonist of the NMDA receptor, are described. The NMDA receptor selectively bound the levo isomer (3a) over its enantiomer (3b), which prompted a rigorous absolute configuration assignment. NPS 1392 has the R configuration based on the single-crystal X-ray diffraction analysis of the hydroiodide salt of NPS 1392. This compound is a potential neuroprotective agent for use in the treatment of ischemic stroke.     

Short term clinical outcomes of accelerated hypofractionated radiotherapy in inoperable non-small cell lung cancer patients

BackgroundThis study aimed to evaluate short term clinical outcomes of accelerated hypofractionated radiotherapy (AHR T) regarding locoregional response (LRR), symptoms relief and acute toxicities in non-small cell lung cancer (NSCLC) patients. The radical treatment for inoperable NSCLC is intolerable for some patients. An alternative RT regime should be considered for them.Materials and methodsInoperable NSCLC patients who could not tolerate radical treatment were treated with AHRT (45 Gy in 15 fractions over three weeks) by using the 3-dimensional conformal (RT) technique. The LRR was assessed by chest computed tomography (CT) performed before and 6 weeks after RT. Relief of symptoms such as cough, dyspnoea and chest pain was evaluated during RT and 6 and 12 weeks after RT, compared with the status before RT. Treatment-related acute toxicities such as dysphagia and radiation dermatitis were observed during and 6 and 12 weeks after RT.ResultsTotal 65 patients (seven patients of stage II and fifty-eight patients of stage III) were included. Partial response was seen in 70.8% of patients, and stable disease was seen in 29.2% while there was neither complete response nor progressive disease after RT. Statistically significant associations were found between tumour response vs. pre-treatment tumour size and tumour response vs. performance status of the patients. Satisfactory symptom relief was found after RT, but severe acute dysphagia and radiation dermatitis (more than grade 3) were not observed.ConclusionSatisfactory LRR, symptom relief and acute toxicities were achieved by this regime. Long term studies are recommended to evaluate late toxicities and survival outcome further.Trial registration noTCTR20200110001