Is Bursting More Effective than Spiking in Evoking Pituitary Hormone Secretion? A Spatiotemporal Simulation Study of Calcium and Granule Dynamics

This is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this record.Endocrine cells of the pituitary gland secrete a number of hormones, and the amount of hormone released by a cell is controlled in large part by the cell's electrical activity and subsequent Ca2+ influx. Typical electrical behaviors of pituitary cells include continuous spiking and so-called pseudo-plateau bursting. It has been shown that the amplitude of Ca2+ fluctuations is greater in bursting cells, leading to the hypothesis that bursting cells release more hormone than spiking cells. In this work, we apply computer simulations to test this hypothesis. We use experimental recordings of electrical activity as input to mathematical models of Ca2+ channel activity, buffered Ca2+ diffusion, and Ca2+-driven exocytosis. To compare the efficacy of spiking and bursting on the same cell, we pharmacologically block the large conductance potassium (BK) current from a bursting cell, or add a BK current to a spiking cell via dynamic clamp. We find that bursting is generally at least as effective as spiking at evoking hormone release, and is often considerably more effective, even when normalizing to Ca2+ influx. Our hybrid experimental/modeling approach confirms that adding a BK-type K+ current, which is typically associated with decreased cell activity and reduced secretion, can actually produce an increase in hormone secretion, as suggested earlier.JT and RB were partially supported by grant DMS1220063 from the National Science Foundation

Scalable Hierarchical Instruction Cache for Ultralow-Power Processors Clusters

High performance and energy efficiency are critical requirements for Internet of Things (IoT) end-nodes. Exploiting tightly coupled clusters of programmable processors (CMPs) has recently emerged as a suitable solution to address this challenge. One of the main bottlenecks limiting the performance and energy efficiency of these systems is the instruction cache architecture due to its criticality in terms of timing (i.e., maximum operating frequency), bandwidth, and power. We propose a hierarchical instruction cache tailored to ultralow-power (ULP) tightly coupled processor clusters where a relatively large cache (L1.5) is shared by L1 private (PR) caches through a two-cycle latency interconnect. To address the performance loss caused by the L1 capacity misses, we introduce a next-line prefetcher with cache probe filtering (CPF) from L1 to L1.5. We optimize the core instruction fetch (IF) stage by removing the critical core-to-L1 combinational path. We present a detailed comparison of instruction cache architectures' performance and energy efficiency for parallel ULP (PULP) clusters. Focusing on the implementation, our two-level instruction cache provides better scalability than existing shared caches, delivering up to 20% higher operating frequency. On average, the proposed two-level cache improves maximum performance by up to 17% compared to the state-of-the-art while delivering similar energy efficiency for most relevant applications

How do geomorphic characteristics affect the source of tree water uptake in restored river floodplains?

Alpine rivers and their floodplains have been highly modified by human activities during the last decades. River restoration projects aim to counteract these negative impacts and to restore ecosystem services provided by riparian habitats. We studied two recently restored river sites in the Ahr/Aurino and Mareit/Mareta Rivers (Italian Alps) to investigate how geomorphic conditions, soil moisture, and groundwater level affect the source of water used by grey alder (Alnus incana (L.) Moench). We compared the isotopic composition (δ2H) of tree sap at different locations (low terraces formed during bed incision and recent floodplains formed after restoration) with that of potential water sources, that is, groundwater, soil water, and rainfall. The monthly variation in the isotopic composition of rainfall was reflected in both shallow and deeper soil water, as well as in the isotopic composition of sap. The redistribution of precipitation and groundwater in the soil differed between the post-restoration floodplain sites and the post-incision terraces, leading to a different relation between the sap water, soil water, and groundwater isotopic composition. The results show that transpiration of A. incana trees growing on recent floodplains is mostly supported by stream-fed soil water, whereas trees growing on terraces mainly use precipitation-fed soil water. These marked, morphology-related differences in the source of transpiration water of grey alder highlight how channel degradation still affects the ecohydrological processes in Alpine fluvial corridors. Nonetheless, large restoration interventions—in terms of channel widening—can enable the self-formation of new floodplain areas characterized by stream water-fed riparian ecosystems

Vega: A Ten-Core SoC for IoT Endnodes with DNN Acceleration and Cognitive Wake-Up from MRAM-Based State-Retentive Sleep Mode

The Internet-of-Things (IoT) requires endnodes with ultra-low-power always-on capability for a long battery lifetime, as well as high performance, energy efficiency, and extreme flexibility to deal with complex and fast-evolving near-sensor analytics algorithms (NSAAs). We present Vega, an IoT endnode system on chip (SoC) capable of scaling from a 1.7- μW fully retentive cognitive sleep mode up to 32.2-GOPS (at 49.4 mW) peak performance on NSAAs, including mobile deep neural network (DNN) inference, exploiting 1.6 MB of state-retentive SRAM, and 4 MB of non-volatile magnetoresistive random access memory (MRAM). To meet the performance and flexibility requirements of NSAAs, the SoC features ten RISC-V cores: one core for SoC and IO management and a nine-core cluster supporting multi-precision single instruction multiple data (SIMD) integer and floating-point (FP) computation. Vega achieves the state-of-the-art (SoA)-leading efficiency of 615 GOPS/W on 8-bit INT computation (boosted to 1.3 TOPS/W for 8-bit DNN inference with hardware acceleration). On FP computation, it achieves the SoA-leading efficiency of 79 and 129 GFLOPS/W on 32- and 16-bit FP, respectively. Two programmable machine learning (ML) accelerators boost energy efficiency in cognitive sleep and active states

A Genome-Wide Screening and SNPs-to-Genes Approach to Identify Novel Genetic Risk Factors Associated with Frontotemporal Dementia

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer’s disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel SNPs-to-genes approach and functional annotation analysis. We identified two novel potential loci for FTD. Suggestive SNPs reached p-values ~10-7 and OR > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation, and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-GWAS. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis

The Efficacy of Tetracyclines in Peripheral and Intracerebral Prion Infection

We have previously shown that tetracyclines interact with and reverse the protease resistance of pathological prion protein extracted from scrapie-infected animals and patients with all forms of Creutzfeldt-Jakob disease, lowering the prion titre and prolonging survival of cerebrally infected animals. To investigate the effectiveness of these drugs as anti-prion agents Syrian hamsters were inoculated intramuscularly or subcutaneously with 263K scrapie strain at a 10−4 dilution. Tetracyclines were injected intramuscularly or intraperitoneally at the dose of 10 mg/kg. A single intramuscular dose of doxycycline one hour after infection in the same site of inoculation prolonged median survival by 64%. Intraperitoneal doses of tetracyclines every two days for 40 or 44 days increased survival time by 25% (doxycycline), 32% (tetracycline); and 81% (minocycline) after intramuscular infection, and 35% (doxycycline) after subcutaneous infection. To extend the therapeutic potential of tetracyclines, we investigated the efficacy of direct infusion of tetracyclines in advanced infection. Since intracerebroventricular infusion of tetracycline solutions can cause overt acute toxicity in animals, we entrapped the drugs in liposomes. Animals were inoculated intracerebrally with a 10−4 dilution of the 263K scrapie strain. A single intracerebroventricular infusion of 25 µg/ 20 µl of doxycycline or minocycline entrapped in liposomes was administered 60 days after inoculation, when 50% of animals showed initial symptoms of the disease. Median survival increased of 8.1% with doxycycline and 10% with minocycline. These data suggest that tetracyclines might have therapeutic potential for humans

Sphingosine-1 phosphate induces cAMP/PKA-independent phosphorylation of the cAMP response element-binding protein (CREB) in granulosa cells

Background and aims: Sphingosine-1 phosphate (S1P) is a lysosphingolipid present in the ovarian follicular fluid. The role of the lysosphingolipid in gonads of the female is widely unclear. At nanomolar concentrations, S1P binds and activates five specific G protein-coupled receptors (GPCRs), known as S1P1-5, modulating different signaling pathways. S1P1 and S1P3 are highly expressed in human primary granulosa lutein cells (hGLC), as well as in the immortalized human primary granulosa cell line hGL5. In this study, we evaluated the signaling cascade activated by S1P and its synthetic analogues in hGLC and hGL5 cells, exploring the biological relevance of S1PR-stimulation in this context. METHODS AND RESULTS. hGLC and hGL5 cells were treated with a fixed dose (0.1 \u3bcM) of S1P, or by S1P1- and S1P3-specific agonists SEW2871 and CYM5541. In granulosa cells, S1P and, at a lesser extent, SEW2871 and CYM5541, potently induced CREB phosphorylation. No cAMP production was detected and pCREB activation occurred even in the presence of the PKA inhibitor H-89. Moreover, S1P-dependent CREB phosphorylation was dampened by the mitogen-activate protein kinase (MEK) inhibitor U0126 and by the L-type Ca2+ channel blocker verapamil. The complete inhibition of CREB phosphorylation occurred by blocking either S1P2 or S1P3 with the specific receptor antagonists JTE-013 and TY52156, or under PLC/PI3K depletion. S1P-dependent CREB phosphorylation induced FOXO1 and the EGF-like epiregulin-encoding gene (EREG), confirming the exclusive role of gonadotropins and interleukins in this process, but did not affect steroidogenesis. However, S1P or agonists did not modulate granulosa cell viability and proliferation in our conditions. Conclusions: This study demonstrates for the first time that S1P may induce a cAMP-independent activation of pCREB in granulosa cells, although this is not sufficient to induce intracellular steroidogenic signals and progesterone synthesis. S1P-induced FOXO1 and EREG gene expression suggests that the activation of S1P\u2013S1PR axis may cooperate with gonadotropins in modulating follicle development

MRI data quality assessment for the RIN - Neuroimaging Network using the ACR phantoms

PURPOSE: Generating big-data is becoming imperative with the advent of machine learning. RIN-Neuroimaging Network addresses this need by developing harmonized protocols for multisite studies to identify quantitative MRI (qMRI) biomarkers for neurological diseases. In this context, image quality control (QC) is essential. Here, we present methods and results of how the RIN performs intra- and inter-site reproducibility of geometrical and image contrast parameters, demonstrating the relevance of such QC practice. METHODS: American College of Radiology (ACR) large and small phantoms were selected. Eighteen sites were equipped with a 3T scanner that differed by vendor, hardware/software versions, and receiver coils. The standard ACR protocol was optimized (in-plane voxel, post-processing filters, receiver bandwidth) and repeated monthly. Uniformity, ghosting, geometric accuracy, ellipse’s ratio, slice thickness, and high-contrast detectability tests were performed using an automatic QC script. RESULTS: Measures were mostly within the ACR tolerance ranges for both T1- and T2-weighted acquisitions, for all scanners, regardless of vendor, coil, and signal transmission chain type. All measurements showed good reproducibility over time. Uniformity and slice thickness failed at some sites. Scanners that upgraded the signal transmission chain showed a decrease in geometric distortion along the slice encoding direction. Inter-vendor differences were observed in uniformity and geometric measurements along the slice encoding direction (i.e. ellipse’s ratio). CONCLUSIONS: Use of the ACR phantoms highlighted issues that triggered interventions to correct performance at some sites and to improve the longitudinal stability of the scanners. This is relevant for establishing precision levels for future multisite studies of qMRI biomarkers

Ventricular volume expansion in presymptomatic genetic frontotemporal dementia

Objective: To characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers. Methods: Participants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. Ventricular volumes were obtained from MRI scans using FreeSurfer, with manual editing of segmentation and comparison to fully automated segmentation to establish reliability. Linear mixed models were used to identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers. Results: A total of 123 participants met the inclusion criteria and were included in the analysis (18 symptomatic carriers, 46 presymptomatic mutation carriers, and 56 noncarriers). Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings. Conclusions: Ventricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD

Multitarget CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach

Cystic fibrosis (CF) is a multiorgan disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria trigger acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients’ age, and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multitarget compounds able to “kill two birds with one stone” by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as CFTR correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multidimensional structure–activity relationship (SAR) study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor, and a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs