The MeerKAT Fornax Survey

We present the science case and observations plan of the MeerKAT Fornax Survey, an HI and radio continuum survey of the Fornax galaxy cluster to be carried out with the SKA precursor MeerKAT. Fornax is the second most massive cluster within 20 Mpc and the largest nearby cluster in the southern hemisphere. Its low X-ray luminosity makes it representative of the environment where most galaxies live and where substantial galaxy evolution takes place. Fornax's ongoing growth makes it an excellent laboratory for studying the assembly of clusters, the physics of gas accretion and stripping in galaxies falling in the cluster, and the connection between these processes and the neutral medium in the cosmic web. We will observe a region of 12 deg2 reaching a projected distance of 1.5 Mpc from the cluster centre. This will cover a wide range of environment density out to the outskirts of the cluster, where gas-rich in-falling groups are found. We will: study the HI morphology of resolved galaxies down to a column density of a few times 1e+19 cm−2 at a resolution of 1 kpc; measure the slope of the HI mass function down to M(HI) 5e+5 M(sun); and attempt to detect HI in the cosmic web reaching a column density of 1e+18 cm−2 at a resolution of 10 kpc

Comparison of Complications of Laparoscopic Versus Laparoendoscopic Single Site Donor Nephrectomy Using the Modified Clavien Grading System

We compared postoperative complications of laparoendoscopic single site and standard laparoscopic living donor nephrectomy using a standardized complication reporting system.We retrospectively analyzed the records of consecutive patients who underwent a total of 663 laparoscopic living donor nephrectomies and 101 laparoendoscopic single site donor nephrectomies. All data were recorded retrospectively. The 30-day complication rate was compiled and graded using the modified Clavien complication scale. Multivariate binary logistic regression was used to determine independent predictors of complications.Baseline demographics were comparable between the groups. Compared to those with laparoscopic living donor nephrectomy patients who underwent laparoendoscopic single site donor nephrectomy had a shorter hospital stay and less estimated blood loss but longer operative time (p 0.05). There were 8 major complications (grade 3 to 5) in the laparoscopic living donor nephrectomy group but only 1 in the laparoendoscopic single site group. Multivariate binary logistic regression analysis revealed that estimated blood loss was a predictor of fewer complications at 30 days.With appropriate patient selection and operative experience laparoendoscopic single site donor nephrectomy may be a safe procedure associated with postoperative outcomes similar to those of laparoscopic living donor nephrectomy as well as low morbidity. Using a standardized complication system can aid in counseling potential donors in the future

Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development.

While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten pathogenic CNVs and 20 neurodevelopmental genes in Drosophila melanogaster. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including 21 lines with severe wing defects and six lines with lethality. In fact, we found that 10/31 homologs of CNV genes also showed complete or partial lethality at larval or pupal stages with ubiquitous knockdown. Comparisons between eye and wing-specific knockdown of 37/45 homologs showed both neuronal and non-neuronal defects, but with no correlation in the severity of defects. We further observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further supported by tissue-specific differences in expression patterns of human CNV genes, as well as connectivity of CNV genes to signaling pathway genes in brain, heart and kidney-specific networks. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions

Precision Chemoradiotherapy for HER2 Tumors Using Antibody Conjugates of an Auristatin Derivative with Reduced Cell Permeability

The most successful therapeutic strategies for locally advanced cancers continue to combine decades-old classical radiosensitizing chemotherapies with radiotherapy. Molecular targeted radiosensitizers offer the potential to improve the therapeutic ratio by increasing tumor-specific kill while minimizing drug delivery and toxicity to surrounding normal tissue. Auristatins are a potent class of anti-tubulins that sensitize cells to ionizing radiation damage and are chemically amenable to antibody conjugation. To achieve tumor-selective radiosensitization, we synthesized and tested anti-HER2 antibody-drug conjugates of two auristatin derivatives with ionizing radiation. Monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) were attached to the anti-HER2 antibodies trastuzumab and pertuzumab through a cleavable linker. While MMAE is cell permeable, MMAF has limited cell permeability as free drug resulting in diminished cytotoxicity and radiosensitization. However, when attached to trastuzumab or pertuzumab, MMAF was as efficacious as MMAE in blocking HER2-expressing tumor cells in G2-M. Moreover, MMAF anti-HER2 conjugates selectively killed and radiosensitized HER2-rich tumor cells. Importantly, when conjugated to targeting antibody, MMAF had the advantage of decreased bystander and off-target effects compared with MMAE. In murine xenograft models, MMAF anti-HER2 antibody conjugates had less drug accumulated in the normal tissue surrounding tumors compared with MMAE. Therapeutically, systemically injected MMAF anti-HER2 conjugates combined with focal ionizing radiation increased tumor control and improved survival of mice with HER2-rich tumor xenografts. In summary, our results demonstrate the potential of cell-impermeable radiosensitizing warheads to improve the therapeutic ratio of radiotherapy by leveraging antibody-drug conjugate technology

Cross-generational impact of a male murine pheromone 2-sec-butyl-4,5- dihydrothiazole in female mice

The current understanding of the activity of mammalian pheromones is that endocrine and behavioural effects are limited to the exposed individuals. Here, we demonstrate that the nasal exposure of female mice to a male murine pheromone stimulates expansion of mammary glands, leading to prolonged nursing of pups. Subsequent behavioural testing of the pups from pheromone-exposed dams exhibited enhanced learning. Sialic acid components in the milk are known to be involved in brain development. We hypothesized that the offspring might have received more of this key nutrient that promotes brain development. The mRNA for polysialyltransferase, which produces polysialylated neural cell adhesion molecules related to brain development,was increased in the brain of offspring of pheromone-exposed dams at post-natal day 10, while it was not different at embryonic stages, indicating possible differential brain development during early post-natal life