Miracle-dz/UniFAR-FTUs huggingface dataset:
The Distribution of Kisspeptin (Kiss)1‐ and Kiss2‐Positive Neurones and Their Connections with Gonadotrophin‐Releasing Hormone‐3 Neurones in the Zebrafish Brain

Kisspeptin is a neuroendocrine hormone with a critical role in the activation of gonadotrophin‐releasing hormone (GnRH) neurones, which is vital for the onset of puberty in mammals. However, the functions of kisspeptin neurones in non‐mammalian vertebrates are not well understood. We have used transgenics to labell kisspeptin neurones (Kiss1 and Kiss2) with mCherry in zebrafish (Danio rerio). In kiss1:mCherry transgenic zebrafish, Kiss1 cells were located in the dorsomedial and ventromedial habenula, with their nerve fibres contributing to the fasciculus retroflexus and projecting to the ventral parts of the interpeduncular and raphe nuclei. In kiss2:mCherry zebrafish, Kiss2 cells were primarily located in the dorsal zone of the periventricular hypothalamus and, to a lesser extent, in the periventricular nucleus of the posterior tuberculum and the preoptic area. Kiss2 fibres formed a wide network projecting into the telencephalon, the mesencephalon, the hypothalamus and the pituitary. To study the relationship of kisspeptin neurones and GnRH3 neurones, these fish were crossed with gnrh3:EGFP zebrafish to obtain kiss1:mCherry/gnrh3:EGFP and kiss2:mCherry/gnrh3:EGFP double transgenic zebrafish. The GnRH3 fibres ascending to the habenula were closely associated with Kiss1 fibres projecting from the ventral habenula. On the other hand, GnRH3 fibres and Kiss2 fibres were adjacent but scarcely in contact with each other in the telencephalon and the hypothalamus. The Kiss2 and GnRH3 fibres in the ventral hypothalamus projected into the pituitary via the pituitary stalk. In the pituitary, Kiss2 fibres were directly in contact with GnRH3 fibres in the pars distalis. These results reveal the pattern of kisspeptin neurones and their connections with GnRH3 neurones in the brain, suggesting distinct mechanisms for Kiss1 and Kiss2 in regulating reproductive events in zebrafish.
Adverse health effects of children's exposure to pesticides: What do we really know and what can be done about it

Children may be exposed to pesticides in several ways, such as by transplacental transfer during foetal life, by intake of contaminated breast milk and other nutrients, or by contact with contaminated subjects and areas in the environment such as pets treated with insecticides, house dust, carpets and chemically treated lawns and gardens. Exposure early in life, and particularly during periods of rapid development, such as during foetal life and infancy, may have severe effects on child health and development by elevating the risk of congenital malformations, cancer, malabsorption, immunological dysfunction, endocrine disease, and neurobehavioural deficiencies. As pesticides can also interfere with parental reproductive health, exposure of parents may have consequences for the offspring leading to reduced chance of male birth and increased risk of childhood cancer.
Achieving utility-delay-reliability tradeoff in stochastic network optimization with finite buffers

One practical open problem is the development of a distributed algorithm that achieves near-optimal utility using only a finite (and small) buffer size for queues in a stochastic network. This paper studies utility maximization (or cost minimization) in a finite-buffer regime and considers the corresponding delay and reliability (or rate of packet drops) tradeoff. A floating-queue algorithm allows the stochastic network optimization framework to be implemented with finite buffers at the cost of packet drops. Further, the buffer size requirement is significantly smaller than previous works in this area. With a finite buffer size of B packets, the proposed algorithm achieves within O(e-B) of the optimal utility while maintaining average per-hop delay of O(B) and an average per-hop drop rate of O(e-B) in steady state. From an implementation perspective, the floating-queue algorithm requires little modification of the well-known Drift-Plus-Penalty policy (including MaxWeight and Backpressure policies). As a result, the floating-queue algorithm inherits the distributed and low complexity nature of these policies.
Correction BIOPHYSICS AND COMPUTATIONAL BIOLOGY , ENGINEERING Correction for “ Biomechanics of red blood cells in human spleen and consequences for physiology and disease

BIOPHYSICS AND COMPUTATIONAL BIOLOGY, ENGINEERING Correction for “Biomechanics of red blood cells in human spleen and consequences for physiology and disease,” by Igor V. Pivkin, Zhangli Peng, George E. Karniadakis, Pierre A. Buffet, Ming Dao, and Subra Suresh, which appeared in issue 28, July 12, 2016, of Proc Natl Acad Sci USA (113:7804–7809; first published June 27, 2016; 10.1073/pnas.1606751113). The authors note that on page 7806, the expression for red blood cell (RBC) volume (Eq. 3) appeared incorrectly. The correct exact expression for RBC volume, to be taken within Eq. 8 corresponding to the dotted line in Fig. 3, should be given as
Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment.

RATIONALE Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic lesion formation is largely undefined. OBJECTIVE Because of the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand annexin A1 in atherogenesis. METHODS AND RESULTS Deletion of FPR2 or its ligand annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically, we identify annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in the presence of selective antagonists to CCR5, CCR2, or CXCR2, whereas Ac2-26 was without effect when all 3 chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation. CONCLUSIONS Instructing the annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment when compared with blocking individual chemokine receptors.
Why is it hard to induce long-term depression?

Most of the interest in computational modelling is devoted to the phenomenon of long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) of synaptic connections is often overlooked. We have found that it is in fact very difficult to induce LTD experimentally and the conditions for LTD induction are much less clear than those for induction of LTP. We concentrate on granule cells in the hippocampal dentate gyrus and using the spike-timing-dependent plasticity (STDP) rule with metaplasticity we show that to evoke homosynaptic LTD or depotentiation of previously potentiated synapses in the spiking model of granule cell is not easy similarly like in a number of experimental studies. On the other hand, heterosynaptic LTD, which accompanies homosynaptic LTP is induced readily both in the model as well as in experiments. We offer possible explanation of these phenomena from STDP, metaplasticity and spontaneous activity.
Accepted by: Annals of the Association of American Geographers Spatial Information Theory Meets Spatial Thinking - Is Topology the Rosetta Stone of Spatial Cognition?

Topology is the most commonly used spatial construct to bridge the gap between formal spatial information theory and systems on the one side and (human) spatial cognition and thinking on the other. To this end, we find topological calculi in virtually all research areas pertinent to spatial information science such as ontological modeling, geographic information retrieval, image analysis and classification. Manifold experiments have been conducted to assess the cognitive adequacy of topological calculi with varying results. Our contribution here is unique for two reasons: on the one hand, we are addressing, behaviorally, the role of topology in the crucial area of spatio-temporal information; on the other hand, we are evaluating the role of topology across different semantic domains. We report five experiments that were conducted in the framework we developed (Klippel and Li 2009), which combine critical constructs from spatial information theory and cognitive science. Topologically equivalent movement patterns were specified across five domains using paths through a conceptual neighborhood graph. This approach allows us to disentangle the role of topology from the influence of semantic context. The results show that topology plays an important yet not semanticindependent role in characterizing the cognitive conceptualization of geographic events.
A Glial Variant of the Vesicular Monoamine Transporter Is Required To Store Histamine in the Drosophila Visual System

Unlike other monoamine neurotransmitters, the mechanism by which the brain's histamine content is regulated remains unclear. In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines. We have studied the visual system of Drosophila melanogaster in which histamine is the primary neurotransmitter released from photoreceptor cells. We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe. Histamine contents are reduced by mutation of dVMAT, but can be partially restored by specifically expressing DVMAT-B in glia. Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems.
The Antioxidant Effects of a Polyphenol-Rich Grape Pomace Extract In Vitro Do Not Correspond In Vivo Using Exercise as an Oxidant Stimulus

Fruits, such as grapes, are essential food of the Mediterranean diet. Grape extracts have potent antioxidant and chemopreventive properties in vitro. Numerous studies have examined the effects of plant extract administration on redox status at rest in animals and humans but their results are controversial. However, there are no studies comparing the in vitro and in vivo effects of plant extracts on oxidative stress using exercise as an oxidant stimulus. Thus, the aim of this study was to investigate whether a polyphenol-rich grape pomace extract of the Vitis vinifera species possesses in vitro antioxidant properties and to examine whether these properties apply in an in vivo model at rest and during exercise. Our findings indicate that the tested extract exhibits potent in vitro antioxidant properties because it scavenges the DPPH• and ABTS•+ radicals and inhibits DNA damage induced by peroxyl and hydroxyl radicals. Administration of the extract in rats generally induced oxidative stress at rest and after exercise whereas exercise performance was not affected. Our findings suggest that the grape pomace extract does not behave with the same way in vitro and in vivo.
Demonstration of mRNA for five species of cytochrome P450 in human bone marrow, bone marrow‐derived macrophages and human haemopoietic cell lines

The expression of mRNA for five cytochrome P450s (CYP1A1, 2A6/7, 2D6, 2E1 and 3A4) was studied in human bone marrow, bone‐marrow‐derived macrophages and blood monocyte‐derived macrophages. Reverse transcriptase polymerase chain reaction (RT‐PCR) detected expression of all five CYPs in each of these cell populations. All five CYPs were also expressed in the haemopoietic cell lines HL‐60 and HEL and in Epstein–Barr virus (EBV)‐transformed B‐lymphoblastoid cell lines. The data suggest that bone marrow macrophages and probably other bone marrow cell types are capable of metabolizing xenobiotics. This metabolic potential may play a role in the bone marrow damage induced by some drugs and chemicals.
Protein degradation and fermentation characteristics of unwilted red clover and alfalfa silage harvested at various times during the day

Extensive proteolysis during fermentation of highprotein legumes reduces dietary N-use efficiency in ruminants. Research has demonstrated that enhancing the level of fermentable carbohydrates in crops entering the silo may reduce protein degradation by increasing the rate of decline in pH. The objective was to evaluate whether delaying cutting time during the day, to allow accumulation of total non-structural carbohydrates (TNC), would inhibit proteolysis in the silo. Red clover (Trifolium pratense L.) and alfalfa (Medicago sativa L.) were harvested at 06.00, 10.00, 14.00 and 18.00 hours in 1993, 1994 and 1995, and ensiled without wilting. TNC accumulated in fresh forage during the day, with starch accounting for more than 0AE50 of the daily change in TNC in fresh herbage of both species, except in red clover in 1995. The level of TNC in fresh forage did not consistently affect the extent of protein degradation in either species and, in all instances, alfalfa underwent more extensive proteolysis than red clover. Silage pH typically decreased and starch concentration increased as cutting time was delayed from 06.00 to 18.00 hours. Although the extent of proteolysis was largely unaffected by inherent increases in TNC, harvesting in the afternoon did provide several benefits including increased dry-matter content, lower silage pH and higher starch concentrations. Effluent production is a concern in any unwilted silage system; there was therefore an added advantage of lower moisture content from cutting in the afternoon.
Preparation and In Vitro Release Study of Quaternized Chitosan Nanoparticles

In order to exploit a novel drug carrier for 5-fluorocrai (5-Fu) with improved entrapment efficiency (EE) and loading capacity (LC) determined by UV/Vis spectrophotometer, N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) nanoparticles were prepared via the ionic gelation based on the electrostatic interactions between positively charged HTCC and negatively charged sodium tripolyphosphate (TPP). The in vitro release behavior of 5-Fu molecules encapsulated within HTCC nanoparticles took a controlled manner in PBS buffer solution (pH 7.4), initiating from a rapid release within 2 hours following a slower sustained release. A higher substitution degree of quaternary ammonium group (DQ) along HTCC chain generated a stronger electrostatic interaction between positively charged HTCC and negatively charged 5-Fu as a result of a higher positively charge density, and contributed to the controlled release of 5-Fu from HTCC nonaparticles. The formation mechanism of HTCC nanoparticles and 5-Fu-loaded HTCC nanoparticles was probed based on the results of fourier transforms infrared spectroscopy (FTIR), transmission electron microscopy (TEM), and size and zeta potential analysis.
Opinion Mining of Spanish Customer Comments with Non-Expert Annotations on Mechanical Turk

One of the major bottlenecks in the development of data-driven AI Systems is the cost of reliable human annotations. The recent advent of several crowdsourcing platforms such as Amazon's Mechanical Turk, allowing requesters the access to affordable and rapid results of a global workforce, greatly facilitates the creation of massive training data. Most of the available studies on the effectiveness of crowdsourcing report on English data. We use Mechanical Turk annotations to train an Opinion Mining System to classify Spanish consumer comments. We design three different Human Intelligence Task (HIT) strategies and report high inter-annotator agreement between non-experts and expert annotators. We evaluate the advantages/drawbacks of each HIT design and show that, in our case, the use of non-expert annotations is a viable and cost-effective alternative to expert annotations.
Managing strategic alliances: what do we know now, and where do we go from here?

Executive Overview Alliances present a paradox for firms. On the one hand, firms engage in a large number of alliances to secure and extend their competitive advantage and growth; on the other hand, their alliances exhibit surprisingly low success rates. In this paper, we discuss how firms can address these failures by identifying some of the primary drivers of alliance success. First, we discuss how firms can achieve success with any individual alliance by considering critical factors at each phase of the alliance life cycle. Second, we show how firms can increase their overall alliance success by developing and institutionalizing firm-level capabilities to manage alliances. Third, we highlight emerging issues in the alliance context, including the need to recognize a new class of alliances between firms and not-for-profit organizations or individuals, the benefits of taking a “portfolio approach” to alliance strategy and management, and the opportunity to transfer one’s alliance capabilities to the effective management of other interfirm relationships, including acquisitions.
Dynamic RON Characterization Technique for the Evaluation of Thermal and Off-State Voltage Stress of GaN Switches

GaN power switches provide remarkable performance in terms of power-density, reduced parasitics, and high-thermal handling capability that enable the realization of very efficient and compact dc/dc converters. Despite exhibiting state-of-the-art channel conductivity, GaN high electron mobility transistor (HEMT) devices are affected by the degradation of the dynamic <sc>on</sc>-Resistance (<italic>R</italic><sub>ON</sub>) at increasing <sc>off</sc>-state voltages and operative temperatures. In this paper, a novel laboratory setup and characterization procedure for the dynamic <italic>R</italic><sub>ON</sub> of GaN HEMT switches in the presence of thermal- and trapping-effects is presented. The proposed setup allows the study of <italic>R</italic><sub>ON</sub> transients after the switching event at variable <sc>off</sc>-state voltages and temperatures. The use of custom-designed differential amplification stages and a voltage-controlled current source enables the accurate characterization of <italic>R</italic><sub>ON</sub> even on large periphery devices. At first, the proposed setup is tested with a well-established and mature device technology such as a Si MOSFET. Degradation of the <italic>R</italic><sub>ON</sub> up to 120% due to temperature variation is observed with the presented setup. The setup is then used for the characterization of commercial-grade GaN-on-SiC and GaN-on-Si HEMTs. For both technologies dynamic <italic>R</italic><sub>ON</sub> degradations up to 75% and 20% are observed for temperature and <sc>off</sc>-state voltage variations, respectively. These characterization data are fundamental for the accurate estimation of conduction losses during the design of switching-mode power converters.
Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL).

LBA9000^ Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. METHODS A nonrandomized cohort of ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) pts treated with MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W and randomized cohorts of IPI-N and IPI-T pts treated with 2 Q3W or 10 Q3W were included. Response was assessed every 12 wk by RECIST 1.1 by independent central review and by immune-related response criteria (irRC) by investigator. RESULTS 162 pts were treated at 2 Q3W, 192 at 10 Q3W, and 57 at 10 Q2W. 190 pts were IPI-N and 221 were IPI-T. As of the 10/18/2013 cutoff, all pts had ≥6 mo follow-up and >75% had ≥9 mo follow-up. Among the 365 pts with measurable disease at baseline, ORR by RECIST was 40% (95% CI 32%-48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T pts. Responses were durable (88% ongoing at analysis). Median PFS by RECIST was 24 wk in IPI-N and 23 wk in IPI-T pts. Median OS was not reached, with 1-y OS of 71% in all pts. Benefit was observed by both RECIST and irRC at all doses and schedules in IPI-N and IPI-T pts (Table). MK-3475 demonstrated activity in all major subgroups irrespective of ECOG PS, LDH levels, BRAFmutation, M stage, and number and type of prior therapy. Overall, 12% of pts experienced drug-related grade 3/4 AEs and 4% discontinued due to a drug-related AE. There were no drug-related deaths. CONCLUSIONS MK-3475 showed durable responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T MEL pts. The observed efficacy and safety suggest MK-3475 may be an appropriate treatment for all pts with MEL. CLINICAL TRIAL INFORMATION NCT01295827. [Table: see text].
Arabidopsis cryptochrome 1 functions in nitrogen regulation of flowering

Significance Overapplication of nitrogen (N) fertilizer causes delayed flowering and negatively impacts the function and composition of natural ecosystems and climate. In this study, we demonstrate that flowering time variations regulated by altered nitrogen levels are mediated by two key factors: ferredoxin-NADP+-oxidoreductase (FNR1) and the blue-light receptor cryptochrome 1 (CRY1). Nitrogen regulates FNR1 expression, thereby contributing to changes in NADPH/NADP+ and ATP/AMP ratios, which in turn activates adenosine monophosphate-activated protein kinase to modulate nuclear CRY1 abundance, which further acts in the N signal input pathway to affect central clock function and flowering time. A better understanding of N-regulated floral transition will offer biotechnological solutions to improve sustainable agriculture. The phenomenon of delayed flowering after the application of nitrogen (N) fertilizer has long been known in agriculture, but the detailed molecular basis for this phenomenon is largely unclear. Here we used a modified method of suppression-subtractive hybridization to identify two key factors involved in N-regulated flowering time control in Arabidopsis thaliana, namely ferredoxin-NADP+-oxidoreductase and the blue-light receptor cryptochrome 1 (CRY1). The expression of both genes is induced by low N levels, and their loss-of-function mutants are insensitive to altered N concentration. Low-N conditions increase both NADPH/NADP+ and ATP/AMP ratios, which in turn affect adenosine monophosphate-activated protein kinase (AMPK) activity. Moreover, our results show that the AMPK activity and nuclear localization are rhythmic and inversely correlated with nuclear CRY1 protein abundance. Low-N conditions increase but high-N conditions decrease the expression of several key components of the central oscillator (e.g., CCA1, LHY, and TOC1) and the flowering output genes (e.g., GI and CO). Taken together, our results suggest that N signaling functions as a modulator of nuclear CRY1 protein abundance, as well as the input signal for the central circadian clock to interfere with the normal flowering process.