Generic advertising impacts on demands for orange juice in fifty Nielsen metropolitan regions

Agribusiness, Demand and Price Analysis,

Triple-crown advertising impacts on demands for orange juice in fifty Nielsen metropolitan regions

Agribusiness, Demand and Price Analysis,

Human sperm ion channel (dys)function:implications for fertilization

BACKGROUND: Intensive research on sperm ion channels has identified members of several ion channel families in both mouse and human sperm. Gene knock-out studies have unequivocally demonstrated the importance of the calcium and potassium conductances in sperm for fertility. In both species, the calcium current is carried by the highly complex cation channel of sperm (CatSper). In mouse sperm, the potassium current has been conclusively shown to be carried by a channel consisting of the pore forming subunit SLO3 and auxiliary subunit leucine-rich repeat-containing 52 (LRRC52). However, in human sperm it is controversial whether the pore forming subunit of the channel is composed of SLO3 and/or SLO1. Deciphering the role of the proton-specific Hv1 channel is more challenging as it is only expressed in human sperm. However, definitive evidence for a role in, and importance for, human fertility can only be determined through studies using clinical samples.OBJECTIVE AND RATIONALE: This review aims to provide insight into the role of sperm ion channels in human fertilization as evidenced from recent studies of sperm from infertile men. We also summarize the key discoveries from mouse ion channel knock-out models and contrast the properties of mouse and human CatSper and potassium currents. We detail the evidence for, and consequences of, defective ion channels in human sperm and discuss hypotheses to explain how defects arise and why affected sperm have impaired fertilization potential.SEARCH METHODS: Relevant studies were identified using PubMed and were limited to ion channels that have been characterized in mouse and human sperm. Additional notable examples from other species are included as appropriate.OUTCOMES: There are now well-documented fundamental differences between the properties of CatSper and potassium channel currents in mouse and human sperm. However, in both species, sperm lacking either channel cannot fertilize in vivo and CatSper-null sperm also fail to fertilize at IVF. Sperm-lacking potassium currents are capable of fertilizing at IVF, albeit at a much lower rate. However, additional complex and heterogeneous ion channel dysfunction has been reported in sperm from infertile men, the causes of which are unknown. Similarly, the nature of the functional impairment of affected patient sperm remains elusive. There are no reports of studies of Hv1 in human sperm from infertile men.WIDER IMPLICATIONS: Recent studies using sperm from infertile men have given new insight and critical evidence supporting the supposition that calcium and potassium conductances are essential for human fertility. However, it should be highlighted that many fundamental questions remain regarding the nature of molecular and functional defects in sperm with dysfunctional ion channels. The development and application of advanced technologies remains a necessity to progress basic and clinical research in this area, with the aim of providing effective screening methodologies to identify and develop treatments for affected men in order to help prevent failed ART cycles. Conversely, development of drugs that block calcium and/or potassium conductances in sperm is a plausible strategy for producing sperm-specific contraceptives.</p

Simultaneous interplanetary scintillation and Heliospheric Imager observations of a coronal mass ejection

We describe simultaneous Interplanetary Scintillation (IPS) and STEREO Heliospheric Imager (HI) observations of a coronal mass ejection (CME) on 16 May 2007. Strong CME signatures were present throughout the IPS observation. The IPS raypath lay within the field-of-view of HI-1 on STEREO-A and comparison of the observations shows that the IPS measurements came from a region within a faint CME front observed by HI-1A. This front may represent the merging of two converging CMEs. Plane-of-sky velocity estimates based on time-height plots of the two converging CME structures were 325 kms?1 and 550 kms?1 for the leading and trailing fronts respectively. The plane-of-sky velocities determined from IPS ranged from 420 ± 10 kms?1 to 520 ± 20 kms?1. IPS results reveal the presence of micro-structure within the CME front which may represent interaction between the two separate CME events. This is the first time that it has been possible to interpret IPS observations of small-scale structure within an interplanetary CME in terms of the global structure of the event

Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity

STUDY QUESTIONDoes a man (patient 1) with a previously described deficiency in principle cation channel of sperm (CatSper) function have a mutation in the CatSper-epsilon (CATSPERE) and/or CatSper-zeta (CATSPERZ) gene?SUMMARY ANSWERPatient 1 has a homozygous in-frame 6-bp deletion in exon 18 (c.2393_2398delCTATGG, rs761237686) of CATSPERE.WHAT IS KNOWN ALREADYCatSper is the principal calcium channel of mammalian spermatozoa. Spermatozoa from patient 1 had a specific loss of CatSper function and were unable to fertilize at IVF. Loss of CatSper function could not be attributed to genetic abnormalities in coding regions of seven CatSper subunits. Two additional subunits (CatSper-epsilon (CATPSERE) and CatSper-zeta (CATSPERZ)) were recently identified, and are now proposed to contribute to the formation of the mature channel complex.STUDY DESIGN, SIZE, DURATIONThis was a basic medical research study analysing genomic data from a single patient (patient 1) for defects in CATSPERE and CATSPERZ.PARTICIPANTS/MATERIALS, SETTING, METHODSThe original exome sequencing data for patient 1 were analysed for mutations in CATSPERE and CATSPERZ. Sanger sequencing was conducted to confirm the presence of a rare variant.MAIN RESULTS AND THE ROLE OF CHANCEPatient 1 is homozygous for an in-frame 6-bp deletion in exon 18 (c.2393_2398delCTATGG, rs761237686) of CATSPERE that is predicted to be highly deleterious.LIMITATIONS, REASONS FOR CAUTIONThe nature of the molecular deficit caused by the rs761237686 variant and whether it is exclusively responsible for the loss of CatSper function remain to be elucidated.WIDER IMPLICATIONS OF THE FINDINGSPopulation genetics are available for a significant number of predicted deleterious variants of CatSper subunits. The consequence of homozygous and compound heterozygous forms on sperm fertilization potential could be significant. Selective targeting of CatSper subunit expression maybe a feasible strategy for the development of novel contraceptives.STUDY FUNDING/COMPETING INTEREST(S)This study was funded by project grants from the MRC (MR/K013343/1 and MR/012492/1), Chief Scientist Office/NHS research Scotland. This work was also supported by NIH R01GM111802, Pew Biomedical Scholars Award 00028642 and Packer Wentz Endowment Will to P.V.L. C.L.R.B is the editor-in-chief of Molecular Human Reproduction, has received lecturing fees from Merck and Ferring, and is on the Scientific Advisory Panel for Ohana BioSciences. C.L.R.B was chair of the World Health Organization Expert Synthesis Group on Diagnosis of Male infertility (2012–2016)

On the Canonical Reduction of Spherically Symmetric Gravity

In a thorough paper Kuchar has examined the canonical reduction of the most general action functional describing the geometrodynamics of the maximally extended Schwarzschild geometry. This reduction yields the true degrees of freedom for (vacuum) spherically symmetric general relativity. The essential technical ingredient in Kuchar's analysis is a canonical transformation to a certain chart on the gravitational phase space which features the Schwarzschild mass parameter $M_{S}$, expressed in terms of what are essentially Arnowitt-Deser-Misner variables, as a canonical coordinate. In this paper we discuss the geometric interpretation of Kuchar's canonical transformation in terms of the theory of quasilocal energy-momentum in general relativity given by Brown and York. We find Kuchar's transformation to be a ``sphere-dependent boost to the rest frame," where the ``rest frame'' is defined by vanishing quasilocal momentum. Furthermore, our formalism is general enough to cover the case of (vacuum) two-dimensional dilaton gravity. Therefore, besides reviewing Kucha\v{r}'s original work for Schwarzschild black holes from the framework of hyperbolic geometry, we present new results concerning the canonical reduction of Witten-black-hole geometrodynamics.Comment: Revtex, 35 pages, no figure

New variables, the gravitational action, and boosted quasilocal stress-energy-momentum

This paper presents a complete set of quasilocal densities which describe the stress-energy-momentum content of the gravitational field and which are built with Ashtekar variables. The densities are defined on a two-surface $B$ which bounds a generic spacelike hypersurface $\Sigma$ of spacetime. The method used to derive the set of quasilocal densities is a Hamilton-Jacobi analysis of a suitable covariant action principle for the Ashtekar variables. As such, the theory presented here is an Ashtekar-variable reformulation of the metric theory of quasilocal stress-energy-momentum originally due to Brown and York. This work also investigates how the quasilocal densities behave under generalized boosts, i. e. switches of the $\Sigma$ slice spanning $B$. It is shown that under such boosts the densities behave in a manner which is similar to the simple boost law for energy-momentum four-vectors in special relativity. The developed formalism is used to obtain a collection of two-surface or boost invariants. With these invariants, one may ``build" several different mass definitions in general relativity, such as the Hawking expression. Also discussed in detail in this paper is the canonical action principle as applied to bounded spacetime regions with ``sharp corners."Comment: Revtex, 41 Pages, 4 figures added. Final version has been revised and improved quite a bit. To appear in Classical and Quantum Gravit

Depolarization of sperm membrane potential is a common feature of men with subfertility and is associated with low fertilization rate at IVF

STUDY QUESTION. Are significant abnormalities in outward (K+) conductance and resting membrane potential (Vm) present in the spermatozoa of patients undertaking IVF and ICSI and if so, what is their functional effect on fertilization success? SUMMARY ANSWER. Negligible outward conductance (≈5% of patients) or an enhanced inward conductance (≈4% of patients), both of which caused depolarization of Vm, were associated with a low rate of fertilization following IVF. WHAT IS KNOWN ALREADY. Sperm-specific potassium channel knockout mice are infertile with defects in sperm function, suggesting that these channels are essential for fertility. These observations suggest that malfunction of K+ channels in human spermatozoa might contribute significantly to the occurrence of subfertility in men. However, remarkably little is known of the nature of K+ channels in human spermatozoa or the incidence and functional consequences of K+ channel defects. STUDY DESIGN, SIZE AND DURATION. Spermatozoa were obtained from healthy volunteer research donors and subfertile IVF and ICSI patients attending a hospital assisted reproductive techniques clinic between May 2013 and December 2015. In total, 40 IVF patients, 41 ICSI patients and 26 normozoospermic donors took part in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS. Samples were examined using electrophysiology (whole-cell patch clamping). Where abnormal electrophysiological characteristics were identified, spermatozoa were further examined for Ca2+ influx induced by progesterone and penetration into viscous media if sufficient sample was available. Full exome sequencing was performed to specifically evaluate potassium calcium-activated channel subfamily M α 1 (KCNMA1), potassium calcium-activated channel subfamily U member 1 (KCNU1) and leucine-rich repeat containing 52 (LRRC52) genes and others associated with K+ signalling. In IVF patients, comparison with fertilization rates was done to assess the functional significance of the electrophysiological abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE. Patch clamp electrophysiology was used to assess outward (K+) conductance and resting membrane potential (Vm) and signalling/motility assays were used to assess functional characteristics of sperm from IVF and ICSI patient samples. The mean Vm and outward membrane conductance in sperm from IVF and ICSI patients were not significantly different from those of control (donor) sperm prepared under the same conditions, but variation between individuals was significantly greater (P&lt; 0.02) with a large number of outliers (&gt;25%). In particular, in ≈10% of patients (7/81), we observed either a negligible outward conductance (4 patients) or an enhanced inward current (3 patients), both of which caused depolarization of Vm. Analysis of clinical data from the IVF patients showed significant association of depolarized Vm (≥0 mV) with low fertilization rate (P= 0.012). Spermatozoa with electrophysiological abnormities (conductance and Vm) responded normally to progesterone with elevation of [Ca2+]i and penetration of viscous medium, indicating retention of cation channel of sperm (CatSper) channel function. LIMITATIONS, REASONS FOR CAUTION. For practical, technical, ethical and logistical reasons, we could not obtain sufficient additional semen samples from men with conductance abnormalities to establish the cause of the conductance defects. Full exome sequencing was only available in two men with conductance defects. WIDER IMPLICATIONS OF THE FINDINGS. These data add significantly to the understanding of the role of ion channels in human sperm function and its impact on male fertility. Impaired potassium channel conductance (Gm) and/or Vm regulation is both common and complex in human spermatozoa and importantly is associated with impaired fertilization capacity when the Vm of cells is completely depolarized

Gold Nanoparticle (AuNP) as a Therapeutic Enhancer for Radio – And Immunotherapy Therapy Combination in Triple Negative Breast Cancer

Purpose/Objective(s): Triple negative breast cancer (TNBC) is the most aggressive breast cancer (BC) form, with a high metastases rate and a very low survival. The aggressiveness of TNBC coupled with a significant toxicity and suboptimal chemotherapy outcomes underscores the urgency for new TNBC treatments. In recent years, immunotherapy has emerged as a promising option. In particular, immune checkpoint blockers (ICB) targeting PD-L1/PD1 inhibitory T cell check point pathway showed clinical responses and have been explored for TNBC. Unfortunately, the response rates to standalone ICB therapy are low (15-20%), indicating the presence of inhibitory immune mechanisms. Radiation therapy (RT) has been widely used in BC therapies. In addition to antitumor (antiproliferative) effects, RT has been evidenced to stimulate immune tumor rejection through immunomodulation of the tumor microenvironment (TME) that has been shown to enhance the response to immunotherapy in mouse BC models. Antitumor RT effects, including TME immunomodulation, can be improved by using radiosensitizers, such as gold nanoparticles (AuNPs). We hypothesize that AuNP potentiates RT-induced immunomodulatory effects, leading to a more efficient response to ICB in TNBC. To test this hypothesis, we used AuNP as an enhancer of RT-induced immunological TME changes, to improve ICB therapy response in murine orthotopic syngeneic 4T1Luc TNBC model. Materials/Methods: Female Balb/c mice bearing 4T1Luc tumors received intratumoral injections of 14 nm AuNPs. After 24h mice were irradiated with fractionated regimen of 3 × 6 Gy dose using 225 kV photons. After the 3rd RT dose, mice received 3 doses of anti-PD-L1 antibody that were 4 days apart. Therapeutic efficiency was determined by assessing the tumor growth and animal survival. Tumor tissue immunohistochemistry determined the expression of TME immunological markers and immune cell tumor infiltration. Results: AuNPs improved response to anti PD-L1 treatment in mice receiving RT, shown by significant delay in tumor growth and increase in survival compared to the animals receiving RT+ AuNP (p\u3c0.01) and to the animals receiving RT+ anti PD-L1 or RT alone (p\u3c0.05). These results were accompanied with changes in the expression of TME immunological markers and T cell and macrophage infiltration. Conclusion: In TNBC patients, induction of antitumor immune response may play a critical role in improving clinical outcomes. Here we show that AuNP enhanced the effect of a fractionated RT regimen that has significantly improved the response to anti PD-L1 treatment in 4T1Luc TNBC mouse model. This effect was measured by a delay in tumor growth and an increase in animal survival. These findings support the role of immunological mechanisms in TNBC and provide a platform for designing multimodal TNBC RT formulations with novel radiosensitizers or immunotherapy

Molecular elasticity and the geometric phase

We present a method for solving the Worm Like Chain (WLC) model for twisting semiflexible polymers to any desired accuracy. We show that the WLC free energy is a periodic function of the applied twist with period 4 pi. We develop an analogy between WLC elasticity and the geometric phase of a spin half system. These analogies are used to predict elastic properties of twist-storing polymers. We graphically display the elastic response of a single molecule to an applied torque. This study is relevant to mechanical properties of biopolymers like DNA.Comment: five pages, one figure, revtex, revised in the light of referee's comments, to appear in PR