A new target for Alzheimer’s disease: A small molecule SERCA activator is neuroprotective in vitro and improves memory and cognition in APP/PS1 mice

Amongst the cellular cacophony of altered signals in Alzheimer’s disease (AD), disrupted Ca²⁺ homeostasis and consequential endoplasmic reticulum (ER) stress signals have been recognized as key determinants of neuron fate. This altered Ca²⁺ state is accompanied by a failing sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump, which has been recognized as a causal feature of the underlying disease state. Repair of the Ca²⁺ dyshomeostasis represents a putative drug target via alleviation of ER stress and rescue of injured neurons, effectively modifying the AD state. Herein, we report a small molecule SERCA activator that rescues brain cells and raises ER Ca²⁺ in vitro, and shows efficacy in the APP/PS1 double transgenic mouse model of Alzheimer’s disease. These results support SERCA activation as a therapeutic target for AD.     

Small molecule SUMOylation activators are novel neuroprotective agents

Neuronal loss characterizes many of the most intractable nervous system diseases that deprive our ageing population of their quality of life. Neuroprotective pharmacological modalities are urgently needed to address this burgeoning population. Small ubiquitin-like modifier (SUMO) conjugation has been established as an endogenous neuroprotective response, and we have discovered several classes of small molecules that enhance SUMO conjugation. Herein we describe the hit to lead campaign that enabled the discovery of 3 diverse classes of drug-like SUMOylation activators. Optimized compounds were ultimately validated in cell-based models of neuronal loss and provide a foundation for establishing systemically active SUMO activators to treat degenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and stroke.     

Cell Size and Growth Rate Are Modulated by TORC2-Dependent Signals

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Continued Tumor Reduction of Metastatic Pheochromocytoma/Paraganglioma Harboring Succinate Dehydrogenase Subunit B Mutations with Cyclical Chemotherapy

Patients harboring germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene present with pheochromocytomas and paragangliomas (PPGL) that are more likely malignant and clinically aggressive. The combination chemotherapy cyclophosphamide, vincristine, and dacarbazine (CVD) was retrospectively evaluated in patients with SDHB-associated metastatic PPGL.Query Twelve metastatic PPGL patients harboring SDHB mutations/polymorphisms with undetectable SDHB immunostaining were treated with CVD. CVD therapy consisted of 750 mg/m² cyclophosphamide with 1.4 mg/m² vincristine on day 1 and 600 mg/m² dacarbazine on days 1 and 2, every 21–28 days. Treatment outcome was determined by RECIST criteria as well as determination of response duration and progression-free and overall survivals. A median of 20.5 cycles (range 4–41) was administered. All patients had tumor reduction (12–100% by RECIST). Complete response was seen in two patients, while partial response was observed in 8. The median number of cycles to response was 5.5. Median duration of response was 478 days, with progression-free and overall survivals of 930 and 1190 days, respectively. Serial [¹⁸F]-fluorodeoxyglucose positron emission tomography and computed tomography imaging demonstrated continued incremental reduction in maximal standardized uptake values (SUV_max) values in 26/30 lesions. During treatment administration, the median SUV decreased from?> 25 to?< 6, indicating the efficacy of chemotherapy over a prolonged period of time. Prolonged therapy results in continued incremental tumor reduction, and is consistent with persistent drug sensitivity. CVD chemotherapy is recommended to be considered part of the initial management in patients with metastatic SDHB-related PPGL.     

Rural Livelihood Variation and its Effects on Child Growth in Timor-Leste

Economic development introduces opportunities for subsistence households to diversify income sources. Timor-Leste is undergoing this transition; however, little is known about the patterns of household strategies and the effects of rural development on child wellbeing. We derive strategies from 190 households in two rural Timor-Leste communities and examine the links between resource strategies and child growth using linear mixed modeling. Children’s z-height, z-weight, and z-BMI are well below international standards. We find agriculture remains predominantly subsistence-based, with some reliance on cash flow from government pensions and salaries. Households with stable income sources are better able to accumulate wealth, and children living in salaried households have better z-height. However, child growth is best predicted by individual-level factors rather than household ecology. Substantial variation in household strategy and little association of strategy with growth indicates there is no ‘best’ strategy in this transitioning environment.     

Seasonal dynamics of agonistic behavior and hormones in an ex situ all‐male colony of large flying foxes

Large flying foxes (Pteropus vampyrus) are a socially complex species. In situ colonies typically comprise thousands of individuals in small harems of one male to many females. In ex situ environments, all‐male colonies are becoming more common due to a surplus of males in the population. There is limited information describing the hormonal and behavioral patterns of all‐male colonies during the breeding season. We assessed seasonal changes in hormones and behavior in an all‐male colony of 12 large flying foxes at Disney's Animal Kingdom^®. We validated hormone assays using morning urine and fecal samples to assess seasonal changes in excreted immunoreactive testosterone and glucocorticoid metabolites. We collected behavior data using an all‐occurrence method, recording agonistic behaviors related to territorial defense (hooking, biting, wing flexing, vocalizing, and wrestling), and sexual behavior (mounting and frontal grabbing). Results indicated that (i) we could reliably measure testosterone and glucocorticoid metabolites concentrations from fecal and urine samples collected from individual bats; (ii) there were distinct relationships between changes in levels of agonism and hormone concentrations throughout the year; and (iii) three agonistic behaviors (chasing, wrestling, and open‐mouth threat) peaked prior to the increase in testosterone and glucocorticoid hormones measured during the breeding season. These three behaviors could potentially be used as early indicators to signal the onset of the breeding season and allow time to implement ex situ management changes to reduce the incidence of agonism between individuals.     

Environmental DNA detection of rare and invasive fish species in two Great Lakes tributaries

The extraction and characterization of DNA from aquatic environmental samples offers an alternative, noninvasive approach for the detection of rare species. Environmental DNA, coupled with PCR and next‐generation sequencing (“metabarcoding”), has proven to be very sensitive for the detection of rare aquatic species. Our study used a custom‐designed group‐specific primer set and next‐generation sequencing for the detection of three species at risk (Eastern Sand Darter, Ammocrypta pellucida; Northern Madtom, Noturus stigmosus; and Silver Shiner, Notropis photogenis), one invasive species (Round Goby, Neogobius melanostomus) and an additional 78 native species from two large Great Lakes tributary rivers in southern Ontario, Canada: the Grand River and the Sydenham River. Of 82 fish species detected in both rivers using capture‐based and eDNA methods, our eDNA method detected 86.2% and 72.0% of the fish species in the Grand River and the Sydenham River, respectively, which included our four target species. Our analyses also identified significant positive and negative species co‐occurrence patterns between our target species and other identified species. Our results demonstrate that eDNA metabarcoding that targets the fish community as well as individual species of interest provides a better understanding of factors affecting the target species spatial distribution in an ecosystem than possible with only target species data. Additionally, eDNA is easily implemented as an initial survey tool, or alongside capture‐based methods, for improved mapping of species distribution patterns.     

Factors associated with a low prevalence of exclusive breastfeeding during hospital stay in urban and semi-rural areas of southern Vietnam

Background

There is a paucity of data regarding risk factors associated with suboptimal breastfeeding practices in urbanized areas of low-middle income countries (LMICs).

Methods

Through a large prospective birth cohort, which enrolled 6706 infants in Vietnam between 2009 and 2013, we investigated the practice of exclusive breastfeeding during hospital stay in urban and semi-rural populations and aimed to identify factors associated with suboptimal breastfeeding practices. Univariate and multivariable logistic regression were performed to determine factors associated with not exclusive breastfeeding during hospital stay.

Results

Of 6076 mothers, 33% (2187) breastfed their infant exclusively before hospital discharge; 9% (364/4248) in urban and 74% (1823/2458) in semi-rural areas. Exclusive breastfeeding up to 4 months was recorded in 15% (959/6210) of participants; this declined to <?1% (56/6093) at 6 months. Delivery by Caesarean section (Odds Ratio [OR] 0.07; 95% Confidence Interval [CI] 0.04, 0.11 and OR 0.05; 95% CI 0.03, 0.08) and neonatal complications (OR 0.2; 95% CI 0.07, 0.47 and OR 0.25; 95% CI 0.14, 0.46) were common and highly significant risk factors associated with a lack of exclusive breastfeeding during hospital stay in urban and semi-rural settings, respectively.

Conclusions

To our knowledge, this is the first large-scale investigation aimed at identifying factors associated with exclusive breastfeeding during hospital stay in Vietnam. Breastfeeding promotion strategies should prioritize common risk factors in hospital, such as Caesarean section and neonatal complications, and other location specific factors associated with socioeconomics.

     

The β3‐integrin endothelial adhesome regulates microtubule‐dependent cell migration

Integrin β3 is seen as a key anti‐angiogenic target for cancer treatment due to its expression on neovasculature, but the role it plays in the process is complex; whether it is pro‐ or anti‐angiogenic depends on the context in which it is expressed. To understand precisely β3's role in regulating integrin adhesion complexes in endothelial cells, we characterised, by mass spectrometry, the β3‐dependent adhesome. We show that depletion of β3‐integrin in this cell type leads to changes in microtubule behaviour that control cell migration. β3‐integrin regulates microtubule stability in endothelial cells through Rcc2/Anxa2‐driven control of active Rac1 localisation. Our findings reveal that angiogenic processes, both in vitro and in vivo, are more sensitive to microtubule targeting agents when β3‐integrin levels are reduced.