Search

Background In vitro and clinical observations in HIV-infected patients receiving interferon alpha therapy have shown a reduction in HIV loads. Limited investigations have explored the innate or adaptive immune responses of IFN-alpha on SIV replication in vivo. Methods Seven chronically infected rhesus macaques were given pegylated IFN-alpha 2a (n = four) or saline (n = three) injections once weekly for 14 weeks. Weekly peripheral blood samples were taken for safety parameters, viral load determinations, and measurements of innate and adaptive immune responses. Results Pharmacokinetic measurements demonstrated therapeutic peg-IFN-alpha levels for the initial period of therapy and IFN-alpha inducible antiviral molecules were increased sporadically in the PBMC mRNA of the treatment group. Despite the demonstrable effect of the IFN-alpha injections, the treatment had no effect on plasma viral RNA levels. Conclusions This work demonstrates that while short term IFN-alpha therapy induces innate antiviral immunity, it does not dramatically enhance or suppress viral replication. However, studies in the SIV model to determine therapeutic potential of chronic IFN-alpha therapy for the treatment of HIV will require macaque specific cytokines.

The primary objective of our current HIV vaccine research program is to evaluate novel alphavirus-based and Envelope (Env) protein-based vaccine formulations either alone or in prime boost regimen for improved immunogenicity and efficacy over other HIV vaccine approaches. The outcome of this work will be the production of candidate vaccine components that can be further advanced to clinical trials in human subjects. For these studies we employ viral genes derived from SF162 a primary subtype B HIV-1 isolate in alphavirus replicon particle-based vaccines. A chimeric alphavirus vector system (VEE/SIN) is used that is composed of the Venezuelan Equine Encephalitis (VEE) replicon combined with the Sindbis virus structural proteins. We have performed a proof of concept study where macaques were primed with VEE/SIN, boosted with o-gp140DV2SF162, and challenged intravenously by pathogenic SHIVSF162P4. In the next study we evaluated these recombinant VEE/SIN vaccines alone, and also in combination with DV2-trimer derived from SF162 for their ability to protect against mucosal SHIVSF162P4 challenge. Both parenteral and mucosal routes of immunization have been evaluated to identify the optimal regimen(s) for the induction of potent and protective humoral and cellular responses in rhesus macaques. In the third study, we evaluated the ability of DV2SF162 trimer to protect against against mucosal SHIVSF162P4 challenge. Both parenteral and mucosal routes of immunization have been evaluated. Results so far indicate that the recombinant VEE/SIN particles induced antigen-specific CD4+ and CD8+ T cell responses as well as neutralizing antibodies in small animals (mice and rabbits) and non-human primates. Moreover, intramuscular immunization with VEE/SIN particles encoding SIV gag or gagpol and HIV env is quite effective in priming for potent anti-Env antibody responses. However, it seems intramuscular boosting of alpha primed animals with o-gp140DV2SF162 in MF59 is critical for blocking and/or reducing acute phase viremia following either intravenous or intrarectal SHIVSF162P4 challenges of rhesus macaques. Furthermore, macaques that were immunized intranasally with o-gp140DV2SF162 protein in the LTK63 mucosal adjuvant followed by intramuscular immunization with o-gp140DV2SF162 in MF59 were also protected against SHIVSF162P4 challenge. Protection in these studies appears to occur after the induction of high titer serum neutralizing antibodies that recognize the challenge virus.

The stinging nettle (Urtica dioica) is a common weed that can cause a wide range of cutaneous reactions. Contact with the hairs or spines on the stems and leaves of the stinging nettle causes the release of several biologically active substances. The released chemicals act to cause itching, dermatitis, and urticaria within moments of contact. Extracts from the stinging nettle may provide therapeutic value for some inflammatory medical conditions. There is no standard treatment for stinging nettle dermatitis.

The realization that induction of immune responses at mucosal surfaces may prevent colonization, invasion or dissemination of pathogenic microorganisms has spurred intensive efforts to develop vaccines which elicit effective mucosal immunity. In this paper, recent results are discussed for mice given cholera toxin as both an immunogen and as an adjuvant for inducing both humoral and gastrointestinal mucosal immune responses. Oral administration of cholera toxin alone or with a co-administered protein vaccine tetanus toxoid induces a strong T helper type 2 (TH2) cell response in both Peyer's patches and spleen. Both serum IgG and secretory IgA antibodies specific for cholera toxin or for the co-administered protein tetanus toxoid were induced. When administered parentally, however, no mucosal antibody responses were evident and a mixed TH1- and TH2-type CD4+ T cell response was noted in the spleen. Various vectors are being employed in an effort not only to induce mucosal immune responses but also to direct the response to a TH1-type response, thought to promote strong cell-mediated immune responses, or to a TH2-type response for maximum B cell antibody responses. The ability to manipulate the TH cell responses may provide a more rational approach for the design of vaccines. Although lymphoid tissues of the female reproductive tract differ from that of the gut, many of the strategies and evolving principles may be directly applicable to the development of vaccines designed to prevent sexually transmitted diseases.

In the report "Free energy and temperature dependence of electron transfer at the metal-electrolyte interface" by C. E. D. Chidsey (22 Feb., p.919), the axis label in figure 3B should have been "Time (s)," not "Time (ms)." Also, the text following equation 8 should have read, "where C = [See equation in the PDF file]

The steady-level distribution coefficients (r values) between the cell water and the incubation solution are measured for a variety of small, hydrophilic, nonmetabolized nonelectrolytes in a red muscle preparation, the mouse diaphragm. Four distinct groups of solutes are discerned: large surgars, with r = 0.08; many monosaccharides, with r = 0.36; some sugars in the presence of insulin at 20 °C, and d-ribose, with r = 0.80; and all compounds tested with four carbons or less, and some sugars in the presence of insulin at 34 °C, with r = 1.00. The results can be interpreted in terms of a four-compartment model of the muscle fiber. The model requires that 64% of the cell volume be noncytoplasmic. The results are considered difficult to interpret in terms of the association-induction hypothesis of Ling. Special conditions are found under which d-xylose moves out of the muscle fiber against its concentration gradient. This observation requires either that insulin-sensitive xylose be adsorbed in the cytoplasm or that an active extrusion mechanism for sugars exists in the muscle.

SUMMARYThe expression of toxigenicity byVibrio cholerae, before and after exposure to various conditions of salinity, pH and cation composition and concentration, has been measured. Exposure to these conditions did not select for hyper- or hypo-toxigenic strains. This suggests that toxigenicV. choleraeO 1 are unlikely to lose their toxigenicity when exposed to environmental stress and thatV. choleraetoxin production is not a response to the stresses included in this study. These results are consistent with an aquatic reservoir for toxigenicV. choleraeO 1.

This paper demonstrates that local electric fields originating from negatively charged groups on a K+-specific ion channel modify its behavior. Single high-conductance, Ca2+-activated K+ channels were studied in neutral phospholipid bilayers. The channel protein surface charges were manipulated experimentally by carboxyl group esterification using trimethyloxonium (TMO) or by electrolyte screening. Three channel properties--ion conduction, ion blockade, and voltage-dependent gating--are affected by surface electrostatics. Negative charges increase the affinity of cationic pore blockers by establishing a local negative potential at the pore entrance; these charges modify channel gating by establishing a potential gradient across the ion channel; finally, both effects influence ion permeation through the pore.

Addition of membrane vesicles prepared from the electric organ of Torpedo californica to the aqueous phase of a planar phospholipid bilayer system results in a large (up to 3 orders of magnitude) stepwise increase in membrane conductance. This increased conductance consists of two components: an ohmic background "leak" and a voltage-dependent, ideally anion-selective conductance. The anion conductance is low at voltages greater than +10 mV, rises sharply as the voltage becomes negative, and then saturates as the voltage becomes highly negative. (The trans side of the bilayer, to which vesicles are not added, is defined as ground.) Under high amplification, the anion conductance shows single channel behavior with a voltage-independent, single channel conductance of 13.9 +/- 0.1 pmho in 0.1 M Cl-. Furthermore, the anion channel, but not the background conductance, is inhibited by submillimolar concentrations of SITS and DIDS, two well known anion transport inhibitors. The inhibition is seen only when SITS or DIDS is added to the cis side. No cholinergic agents tested have any effect on the channel.

SummaryThe survival and growth of toxigenicVibrio cholerae01 in water under various conditions of salinity, pH, temperature and cation composition and concentration were studied in an extensive series of laboratory experiments. Inter- and intra-strain variation in stress response (of 01 and non-01 strains) and the ability ofV. choleraeto adapt to stressful environments were also studied. ToxigenicV. cholerae01 were able to survive for at least 70 days at 25 °C in solutions of sea salt. The optimal salt concentration was 2·0% though all solutions in the range 0·25–3·0% gave good support. Substrains with enhanced capacity to persist at sub-optimal salinity (0·1%) were demonstrated. A great degree of inter-strain variation in stress response at low salinity (0·05%) was found among 59 strains, and this variation was unrelated to serogroup (01 or non-01), source (clinical or environmental) or country of origin (Tanzania or Bangladesh). At optimal salinity, inter-strain variation was less and 18 out of 20 strains remained viable at high concentrations for at least 40 months at 25 °C.V. cholerae01 could not survive beyond 45 days at 4 °C and optimal salinity, either with or without nutrients. The optimal pH range for survival at 25 °C was 7·0–8·5 at optimal salinity, and 7·5–9·0 at low salinity.V. cholerae01 require Na+for survival in the absence of nutrients, and for enhanced growth in their presence. The presence of Ca2+or Mg2+, in addition to Na+, further enhanced survival. These, and other results reported in this paper, suggest that toxigenicV. cholerae01 are able to survive for extended periods in warm water containing no nutrients but having a salinity of 0·25–3·0% and a pH of around 8·0. With added nutrients and under the same conditions, rapid growth is possible. The implications of these findings for the identification of putative aquatic reservoirs ofV. cholerae01, and for the epidemiology of cholera, are considerable.

An animal model for the heterosexual transmission of human immunodeficiency virus (HIV) was developed by the application of simian immunodeficiency virus (SIV) onto the genital mucosas of both mature and immature, male and female rhesus macaques. Virus preparations were infused into the vaginal vaults or the urethras (males) of the animals through a soft plastic pediatric nasogastric feeding tube. The macaques that were infected by this route (six males and nine females) developed SIV-specific antibodies, and SIV was isolated from peripheral mononuclear cells of all seropositive animals. One male and one female infected by this route developed severe acquired immunodeficiency syndrome-like disease with retroviral giant-cell pneumonia. As few as two inoculations of cell-free SIV containing 50 50% tissue culture infective doses induced persistent viremia. Cell-free virus preparations were capable of producing infection by the genital route. Much higher doses of virus were required to transmit SIV by this route than are required for transmission by intravenous inoculation. Thus, it appears that the mucous membranes of the genital tract act as a barrier to SIV infection. Spermatozoa and seminal plasma were not required for the genital transmission of SIV. Rarely, SIV was recovered from mononuclear cells in semen and vaginal secretions. The SIV-rhesus macaque model is suitable for assessing the role of cofactors in heterosexual transmission of HIV and will be useful for testing the effectiveness of spermicides, pharmacologic agents, and vaccines in preventing the heterosexual transmission of HIV.

The d -xylose equilibrium distribution ratio ( r value) and the relative cell volume are measured in the mouse diaphragm muscle at 34 °C in incubation media made hypertonic with varying concentrations of d -xylose. Under basal conditions, r increases with external xylose concentration, and the muslce fiber shrinks. The xylose r value does not rise if the muscles are shrunken by hypertonic addition of NaCl or mannitol instead of xylose. In the presence of insulin, both r and the cell volume remain constant as external xylose is increased. All observations conform quantitatively to the a priori predictions of the compartmentation theory of sugar exclusion and insulin action. The data contradict predictions of the association-induction hypothesis. The results indicate strongly that intracellular water behaves like normal water aqueous solution and that no significant amount of intracellular xylose is adsorbed. The results also suggest that sugars are excluded from intracellular compartments via an active extrusion mechanism and that insulin causes inhibition of this mechanism.

In non-human primate models of AIDS, attenuated lentiviruses provide the most reliable protection from challenge with pathogenic virus but the extent to which the vaccine virus replicates after challenge is unclear. At 7 and 14 days after vaginal challenge with pathogenic SIVmac239, plasma SIV env RNA levels were significantly lower in female macaques immunized 6 months earlier with live, attenuated SHIV89.6 compared to unimmunized control animals. In 2 SHIV-immunized, unprotected macaques SIV replication produced moderate-level plasma viremia with dissemination of challenge virus to all tissues on day 14 after challenge. In protected, SHIV-immunized monkeys, SIV replication was controlled in all tissues, from the day of challenge through 14 days post-challenge. Further, in CD8 + T cell-depleted SHIV-immunized animals, SIV replication and dissemination were more rapid than in control animals. These findings suggest that replication of a pathogenic AIDS virus can be controlled at the site of mucosal inoculation by live-attenuated lentivirus immunization.

Six macaques, apparently uninfected, following low-dose exposure to the pathogenic SIV mac251 and SIV SME660 by the mucosal route, were used in a pilot study to investigate whether infectability of ex vivo lymph nodes could predict resistance and/or susceptibility to SIV infection in vivo. Of six macaques exposed to the less-pathogenic virus SIV MNE , four resisted viral infection. Analysis of the susceptibility of the PBMC of these four animals before SIV MNE challenge indicated that all of them were resistant to infection by the SIV BK28 isolate and, in three of them, this resistance was dependent on CD8+ T cells. Blocks of lymph nodes of these four macaques were resistant to SIV MNE infection ex vivo following SIV MNE viral challenge exposure. However, the same blocks from the same animals were permissive to the more virulent SIV 251(32H) . Accordingly, three of these macaques were readily infected following challenge exposure with SIV 251(32H) . Lymphoproliferative responses in blood or lymph nodes, local C-C chemokine production in the lymph-node explants, and cytotoxic T-cell activity measured throughout the study did not correlate with ex vivo resistance or susceptibility to in vivo infection. In conclusion, PBMC and lymph-node resistance or susceptibility to infection ex vivo appeared to correlate with in vivo infectivity and, thus, these approaches should be further tested for their predictive value for in vivo infection.

The HIV vaccines tested in the halted Step efficacy trial and the modestly successful phase 3 RV144 trial were designed to elicit strong systemic immune responses; therefore, strategies to direct immune responses into mucosal sites should be tested in an effort to improve AIDS vaccine efficacy. However, as increased CD4(+) T-cell activation and recruitment to mucosal sites have the potential to enhance HIV transmission, mucosal immune responses to HIV vaccines should primarily consist of effector CD8(+) T cells and plasma cells. Controlling the level of mucosal T-cell activation may be a critical factor in developing an effective mucosal AIDS vaccine. Immunization routes and adjuvants that can boost antiviral immunity in mucosal surfaces offer a reasonable opportunity to improve AIDS vaccine efficacy. Nonhuman primate models offer the best system for preclinical evaluation of these approaches.

Solid organ transplant recipients (SOTRs) have a 2.4-fold increased risk for melanoma.1 Renal transplant recipients have an incidence of melanoma up to 8 times greater than the comparison immunocompetent population.2 Posttransplant melanomas diagnosed at a later stage (Breslow depth 1.51-3.00 mm3 and T3/T4 stage tumors4) have worse survival rates than non-SOTRs with melanoma. Immunosuppressive therapy for kidney transplantation or autoimmune disease at the time of melanoma diagnosis is associated with a greater risk of death from melanoma, suggesting that melanomas in the setting of immunosuppression are more likely to metastasize.5 The following case report documents the aggressive behavior of a melanoma in a kidney transplant patient. Because later stage melanomas in SOTRs have a high risk for metastasis, practitioners will benefit from understanding how immunosuppression influences the choice of treatment among the growing number of systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma.

Recent work has demonstrated the propulsive efficiency improvement available from single- and counter-rotation propfans as compared with current technology high bypass ratio turbofans. The concept known as swirl recovery vanes (SRV) is examined through the use of a 3-D Euler code. At high speed cruise conditions, the SRV can improve the efficiency level of a single-rotation propfan, but a concern is to have adequate hub choke margin. The SRV was designed with 2-D methods and was predicted to have hub choking at Mach 0.8 cruise. The 3-D Euler analysis properly accounts for sweep effects and 3-D relief, and predicts that at cruise the SRV will recover roughly 5 percent of the 10 percent efficiency loss due to swirl and have a good hub choke margin.

A preliminary design tool for advanced propellers was developed combining a fast vortex lattice aerodynamic analysis, a fast subsonic point source noise analysis, and an optimization scheme using a conjugate directions method. Twist, chord and sweep distributions are optimized to simultaneously improve both the aerodynamic performance and the noise observed at a fixed relative position. The optimal noise/performance tradeoffs for straight and advanced concept blades are presented. The techniques used include increasing the blade number, blade sweep, reducing the rotational speed, shifting the spanwise loading and diameter changes.

The inhibition by 4,4'-diisothiocyano-2,2'-stilbenedisulfonate (DIDS) of Cl- channels from Torpedo electroplax incorporated in planar phospholipid bilayer membranes is studied. DIDS irreversibly and rapidly inhibits the macroscopic conductance of membranes containing many channels. At the single-channel level, the effect of DIDS is more complicated. The uninhibited single channel displays three "substates" of conductances 20, 10, and 0 pS. Short exposure (5-30 s) to 10 microM DIDS converts this three-level active channel into a "conventional" channel of 10-pS conductance. Longer exposure eliminates all channel fluctuations. The results are taken as strong evidence that the Cl- channel is constructed as a functional dimer of identical protein subunits.

The open-channel conductance properties of a voltage-gated Cl- channel derived from Torpedo californica electroplax and incorporated into planar bilayers were studied by several approaches. In neutral bilayers the channel conductance saturates with Cl- activity according to a rectangular hyperbolic relation with a half-saturation activity of 75 mM and a maximum conductance of 32 pmho. The observation of identical behavior in charged membranes implies that ions permeating the channel do not sense the surface potential of the bulk membrane. The Cl-:Br- permeability ratio, measured under biionic conditions, is independent of salt concentration. SCN- ion reversibly blocks the channel. The voltage dependence of the block implies the existence of two separate blocking sites within the channel: one accessible from the cis side only (the side to which vesicles are added) and the other accessible from the trans side only. The block at each site is competitive with Cl-. The results are consistent with a single-ion Eyring model of the conduction process in which the ion must traverse three kinetic barriers as it permeates the channel and in which the channel can accommodate at most one ion at a time.

We report initial results of a deep search for an optical counterpart to the gravitational wave event GW150914, the first trigger from the Advanced LIGO gravitational wave detectors. We used the Dark Energy Camera (DECam) to image a 102 deg$^2$ area, corresponding to 38% of the initial trigger high-probability sky region and to 11% of the revised high-probability region. We observed in i and z bands at 4-5, 7, and 24 days after the trigger. The median $5\sigma$ point-source limiting magnitudes of our search images are i=22.5 and z=21.8 mag. We processed the images through a difference-imaging pipeline using templates from pre-existing Dark Energy Survey data and publicly available DECam data. Due to missing template observations and other losses, our effective search area subtends 40 deg$^{2}$, corresponding to 12% total probability in the initial map and 3% of the final map. In this area, we search for objects that decline significantly between days 4-5 and day 7, and are undetectable by day 24, finding none to typical magnitude limits of i= 21.5,21.1,20.1 for object colors (i-z)=1,0,-1, respectively. Our search demonstrates the feasibility of a dedicated search program with DECam and bodes well for future research in this emerging field., Comment: 6 pages, 1 figure. Updated references. Submitted to ApJL

HIV-specific CD8+ T cells that secrete multiple cytokines in response to Ag stimulation are associated with the control of virus replication during chronic HIV infection. To determine whether the presence of polyfunctional CD8+ T cell responses distinguishes protected and unprotected monkeys in a live attenuated lentivirus model, SIV Gag peptide-specific CD8+ T cell responses of simian HIV (SHIV) 89.6-vaccinated, SIVmac239-challenged rhesus macaques were compared in two monkeys that controlled challenge virus replication and two that did not. The ratio of Bcl-2+ Gag-specific CD8+ T cells to caspase-3+ Gag-specific CD8+ T cells was higher in the vaccinated-protected animals compared with unprotected monkeys. In addition, polyfunctional SIV-specific CD8+ T cells were consistently detected through 12 wk postchallenge in the protected animals but not in the unprotected animals. In the unprotected monkeys, there was an increased frequency of CD8+ T cells expressing markers associated with effector memory T cells. Further, there was increased annexin V expression in central memory T cells of the unprotected animals before challenge. Thus, monkeys that control viral replication after live attenuated SHIV infection have polyfunctional SIV-specific CD8+ T cells with an increased survival potential. Importantly, the differences in the nature of the SIV-specific CD8+ T cell response in the protected and unprotected animals are present during acute stages postchallenge, before different antigenic levels are established. Thus, the polyfunctional capacity and increased survival potential of CD8+ SIV-specific T cells may account for live attenuated, SHIV89.6-mediated protection from uncontrolled SIV replication.

We measure the weak lensing shear around galaxy troughs, i.e. the radial alignment of background galaxies relative to underdensities in projections of the foreground galaxy field over a wide range of redshift in Science Verification data from the Dark Energy Survey. Our detection of the shear signal is highly significant (10 to 15$\sigma$ for the smallest angular scales) for troughs with the redshift range z in [0.2,0.5] of the projected galaxy field and angular diameters of 10 arcmin...1{\deg}. These measurements probe the connection between the galaxy, matter density, and convergence fields. By assuming galaxies are biased tracers of the matter density with Poissonian noise, we find agreement of our measurements with predictions in a fiducial Lambda cold dark matter model. The prediction for the lensing signal on large trough scales is virtually independent of the details of the underlying model for the connection of galaxies and matter. Our comparison of the shear around troughs with that around cylinders with large galaxy counts is consistent with a symmetry between galaxy and matter over- and underdensities. In addition, we measure the two-point angular correlation of troughs with galaxies which, in contrast to the lensing signal, is sensitive to galaxy bias on all scales. The lensing signal of troughs and their clustering with galaxies is therefore a promising probe of the statistical properties of matter underdensities and their connection to the galaxy field., Comment: 15 pages, 8 figures; matches accepted version; high-resolution versions of figures can be downloaded from http://deswl.github.io

The chameleon gravity model postulates the existence of a scalar field that couples with matter to mediate a fifth force. If it exists, this fifth force would influence the hot X-ray emitting gas filling the potential wells of galaxy clusters. However, it would not influence the clusters' weak lensing signal. Therefore, by comparing X-ray and weak lensing profiles, one can place upper limits on the strength of a fifth force. This technique has been attempted before using a single, nearby cluster (Coma, $z=0.02$). Here we apply the technique to the stacked profiles of 58 clusters at higher redshifts ($0.1, Comment: 14 pages, 7 figures

[Abridged] We present here a new and homogeneous sample of 3340 galaxies selected from the Sloan Digital Sky Survey (SDSS) based solely on the observed strength of their Hdelta absorption line. These galaxies are commonly known as ``post-starburst'' or ``E+A'' galaxies, and the study of these galaxies has been severely hampered by the lack of a large, statistical sample of such galaxies. In this paper, we rectify this problem by selecting a sample of galaxies which possess an absorption Hdelta equivalent width of EW(Hdelta_max) - Delta EW(Hdelta_max) > 4A from 106682 galaxies in the SDSS. We have performed extensive tests on our catalog including comparing different methodologies of measuring the Hdelta absorption and studying the effects of stellar absorption, dust extinction, emission-filling and measurement error. The measured abundance of our Hdelta-selected (HDS) galaxies is 2.6 +/- 0.1% of all galaxies within a volume-limited sample of 0.05

A voltage-dependent, K+-selective ionic channel from sarcoplasmic reticulum of rabbit skeletal muscle has been studied in a planar phospholipid bilayer membrane. The purpose of this work is to study the mechanism by which the channel undergoes transitions between its conducting and nonconducting states. Thermody- namic studies show that the "open" and "closed" states of the channel exist in a voltage-dependent equilibrium, and that the channel displays only a single open state; the channel conductance is 120 pmho in 0.1 M K +. The channel's gating process follows single exponential kinetics at all voltages tested, and the individual opening and closing rate constants are exponentially dependent on voltage. The individual rate constants may also be determined from a stochastic analysis of channel fluctua- tions among multiple conductance levels. Neither the thermodynamic nor the kinetic parameters of gating depend on the absolute concentration of channels in the bilayer. The results are taken as evidence that the channel gates by an unusually simple two- state conformational mechanism in which the equivalent of 1.1 net charges are moved across the membrane during the formation of the open channel. Of the events leading to the contraction of vertebrate skeletal muscle, those involved in the release of Ca ++ from the sarcoplasmic reticulum (SR) mem- brane are the least understood. It is clear that the permeability of the SR membrane to Ca ++ is greatly increased during the release process (Endo, 1977), but it is not known to what extent other ions participate in any voltage and conductance changes that may occur during Ca ++ release. One obvious question to arise from any consideration of Ca ++ movements is: what other ions move across the SR membrane to maintain electroneutralit y and, hence, to permit the rapid, massive fluxes of Ca ++ into and out of the SR throughout the contraction-rela xation cycle? Indirect approaches have yielded estimates of the overall SR conductance (Vergara et al., 1978), but the ionic basis of this is entirely unknown. In particular, the role of K +, the overwhelmingly abundant ion on both sides of the SR membrane in vivo (Somlyo et al., 1977)) is obscure.

Shortly after its discovery, General Relativity (GR) was applied to predict the behavior of our Universe on the largest scales, and later became the foundation of modern cosmology. Its validity has been verified on a range of scales and environments from the Solar system to merging black holes. However, experimental confirmations of GR on cosmological scales have so far lacked the accuracy one would hope for — its applications on those scales being largely based on extrapolation and its validity there sometimes questioned in the shadow of the discovery of the unexpected cosmic acceleration. Future astronomical instruments surveying the distribution and evolution of galaxies over substantial portions of the observable Universe, such as the Dark Energy Spectroscopic Instrument (DESI), will be able to measure the fingerprints of gravity and their statistical power will allow strong constraints on alternatives to GR. In this paper, based on a set of N-body simulations and mock galaxy catalogs, we study the predictions of a number of traditional and novel summary statistics beyond linear redshift distortions in two well-studied modified gravity models — chameleon f(R) gravity and a braneworld model — and the potential of testing these deviations from GR using DESI. These summary statistics employ a wide array of statistical properties of the galaxy and the underlying dark matter field, including two-point and higher-order statistics, environmental dependence, redshift space distortions and weak lensing. We find that they hold promising power for testing GR to unprecedented precision. The major future challenge is to make realistic, simulation-based mock galaxy catalogs for both GR and alternative models to fully exploit the statistic power of the DESI survey (by matching the volumes and galaxy number densities of the mocks to those in the real survey) and to better understand the impact of key systematic effects. Using these, we identify future simulation and analysis needs for gravity tests using DESI.