2 In countries with high prevalence of malaria and HIV infections, co-infection is common. Thus, in these regions, there is a very high possibility of a patient taking an antimalarial and an antiretroviral drug concurrently.3 Efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is metabolized principally Epigenetic Reader Domain inhibitor by CYP2B6 and to a lesser degree by CYP3A4.4 Although most drug interaction studies done with efavirenz have demonstrated the effects of the drug on CYP3A4 and CYP2B6 substrates, there are studies indicating that the NNRTI can also inhibit CYP2C8, CYP2C9 and CYP2C19.5, 6 and 7 For example, concurrent administration of proguanil with

efavirenz resulted in elevated plasma proguanil levels and was attributed to inhibition of CYP2C9 and CYP2C19 that mediate proguanil metabolism.8 Since

amodiaquine is mainly metabolized XL184 research buy by CYP2C8 and activity of this isozyme has been demonstrated to be modulated by efavirenz,9 there is a potential for pharmacokinetic interaction between both drugs when taken concurrently. Therefore, this study determined whether, and to what magnitude, efavirenz influences the disposition kinetics of amodiaquine in man. Fourteen Modulators healthy volunteers (8 males and 6 females) between the ages of 26 and 38 years weighing 60–78 kg were enrolled into the study after giving written informed consent. The volunteers had a Body Mass Index of 19.46 ± 1.68 (range 16–22) kg/m2 and were certified healthy by a physician on the basis of medical history, clinical examination, laboratory baseline investigations and serum chemistry tests, prior to enrollment into the study. Subjects were excluded from participating in the study if they met any Phosphatidylinositol diacylglycerol-lyase of the following

additional criteria: pregnancy, breast feeding, serum creatinine greater than 1.5 times the upper limit of normal, any liver function test more than 3 times the upper limit of normal. None of the subjects was receiving any drugs for at least one month before the study and none was a smoker. Approval for the study was obtained from the Obafemi Awolowo University Teaching Hospitals Research Ethics Board and Safety committee. The study was an open-label, randomized, multiple antiretroviral dosing, two-period crossover pharmacokinetic study. After an overnight fast, each of the 14 volunteers received a single oral dose of 600 mg amodiaquine (Amodiaquine dihydrochloride tablets, Parke-Davis, USA) either alone or with the 9th dose of efavirenz. Efavirenz (Aviranz® Capsules, Ranbaxy Laboratory Ltd, India) was given as 400 mg oral dose daily for 12 days. A washout period of 3 weeks was allowed between the two arms of the study. Blood samples (5 ml) were withdrawn by venipuncture from the forearm of each subject prior to and at 0.08, 0.25, 0.5, 1.5, 3, 5, 24, 48 and 192 h after drug administration into heparinised tubes. They were immediately centrifuged (3000 g at 20 °C for 10 min) to separate plasma. The plasma aliquots were stored at −20 °C until analyzed.

faecalis to S. inhibitors aureus 14 have been reported. Vancomycin-resistance gene acquisition

by S. aureus from Enterococcus faecium in the clinical environment has also been reported earlier. 15 In view of the increased spreading vancomycin-resistant vanA gene through conjugation, compelled us to explore chemicals that could be used as non-antibiotic adjuvants to control the spreading of resistance gene via conjugation from one gram-positive bacterial species to another species OSI-744 order of bacteria. There are no recent study regarding controlling of the spreading of vanA gene among the clinical isolates. The aim of the present study was to identify the vanA gene among clinical isolates of vancomycin-resistant S. aureus (VRSA). Thereafter, transfer of vanA gene through

conjugation from vanA positive VRSA to a vancomycin-sensitive S. aureus (VSSA) was evaluated. Next, we examined the effect of various concentrations of chemicals including ethylenediaminetetraacetic acid (disodium edetate), acid (EGTA) and boric acid on conjugation. All of the chemicals, such as ethylenediaminetetraacetic acid (disodium edetate), ethylene glycol tetraacetic acid (EGTA) and boric acid were procured from Himedia (Mumbai, India) and were reconstituted with water for injection. Working solutions were prepared using MH (Mueller Hinton, Himedia, Bombay, India) broth. A total of fourteen clinical isolates of VRSA were used in the present study of which four from patients suffering from surgical wounds and three from bacteremia and seven from patients suffering Palbociclib concentration with burns were recovered. All of the isolates were obtained from Vijayanagar Institute of Medical Sciences (VIMS), Bellary, India. Re-identification of these clinical isolates was done using standard microbiological and biochemical tests.16 and 17 The vanA positive isolate of VRSA served as donor and was grown overnight at 37 °C in Mueller-Hinton broth (MHB, Himedia, Mumbai, India) these and S. aureus (MTCC 737) obtained from

Institute of Microbial Technology, Chandigarh, India, served as recipient as well as negative control was also grown overnight in MHB. These bacterial suspensions were used as the inoculum at a concentration of 106 colony-forming units/milliliter (cfu/ml). E. faecium ATCC 51559, which contains vanA gene served as a positive control. All of the clinical isolates were processed for screening of vanA gene. DNA from all of the clinical isolates, recipient, transconjugants, positive and negative controls was isolated using following methods: five ml of each at concentration of 1010 cfu/ml was centrifuged at 5000 revolutions per minute (rpm) for 4 min at 25 degree celsius (°C) and pellet was washed once in phosphate buffer saline (0.05 Molar (M) pH 7.2). After addition of 0.2 ml ice-cold solution 1 [25 millimolar (mM) Tris(hydroxymethyl)aminomethane hydrochloride (Tris–HCl) pH 8.0, 10 mM ethylenediaminete-traacetic acid (EDTA) pH 8.0 and 50 mM glucose] and 0.

In duplicated renal systems, it is the lower pole that is typically obstructed at the UPJ. Bilateral UPJ obstruction has been commonly reported, while bilateral upper pole UPJ has not been specifically reported in the literature. A case is presented with a discussion as to the therapeutic options and clinical management. A 16-year-old Caucasian girl presented with intermittent bilateral back pain aggravated by activity. She had no clinically significant medical or surgical

history. A bone scan demonstrated delayed excretion and retention of radioisotope in the upper poles of both kidneys suggesting renal obstruction click here (Fig. 1A,B). Ultrasonography revealed bilateral symmetric upper pole hydronephrosis (Fig. 2). Magnetic resonance urogram (Fig. 3) and mercaptoacetyltriglycine diuretic renogram (Fig. 4) revealed bilateral complete duplication and bilateral upper pole ureteropelvic junction (UPJ) obstructions. The lower poles appeared normal. Surgical repair was recommended, and the patient underwent bilateral robotically assisted upper pole pyeloplasties using a Y-to-V advancement repair with upper pole double-J ureteral stent placement. Postoperatively, the right ureteral stent became obstructed, requiring replacement on postoperative day 3 because of urinary ascites and pain. She did well and was inhibitors discharged on postoperative day 8 on prophylactic antibiotics. The stents were removed

6 weeks postoperatively. The patient showed complete GSK1120212 solubility dmso resolution of her symptoms despite vigorous activity. She suffered 2 minor episodes of cystitis, which resolved with treatment. Follow-up imaging showed persisting hydronephrosis, which appeared improved with more parenchyma visible between the calyces (Fig. 5). The family has deferred obtaining subsequent mercaptoacetyltriglycine scan because of her clinical improvement. At the most recent follow-up 3 years postoperatively, she is attending college and is asymptomatic. Unilateral upper pole UPJ obstruction is extremely rare1, 2, 3, 4, 5, 6 and 7; bilateral upper pole UPJ obstruction has not been reported to date. Common presentation is with flank pain,2 and 8 as well as infection, and through

prenatal detection of hydronephrosis.4 Vascular occlusion is considered a common cause, although the specific details Cell press are not well defined in the literature.1 and 2 This may have some similarity to the so-called Fraley syndrome of vascular upper infundibular obstruction.9 This patient’s diagnosis was delayed because of confusion with musculoskeletal pain in the absence of lateralizing symptoms. Modern imaging can adequately define the anatomy, but optimal treatment is not well defined. Bilateral upper pole partial nephrectomies could be a viable option. However, renal preservation seemed to be a worthwhile goal. The renal pelvises were not markedly dilated making an upper-to-lower pyelopyelostomy less likely to be feasible.

For this purpose, a dedicated production facility is being constructed within the Bio Farma premises in Bandung. In parallel, Bio Farma was selected as a grantee of the WHO influenza vaccine technology transfer initiative, which sought to increase access of developing countries to a pandemic influenza vaccine through domestic production capacity. The WHO seed funding for transfer of the technology, procurement of equipment for quality control and production, and formulation and

filling training for seasonal vaccine imported from Biken, complemented the financial contributions of Bio Farma and the Indonesian Government. This article describes the progress made towards the following four objectives of the project: (i) technology transfer for the production of influenza vaccine; (ii) installation and operationalization of a formulation and filling unit; (iii) registration in Indonesia of seasonal vaccine developed from imported bulk antigen;

selleck (iv) production of bulk inactivated influenza antigen for seasonal and pandemic use. Since the existing formulation and filling lines at Bio Farma were fully occupied for routine vaccine production, a new unit was established and fully equipped. Following the transfer from Biken, Japan of the technology to formulate, fill and quality control trivalent seasonal influenza vaccine, three monovalent bulks each of the following strains were received from Biken in December 2007: A/Hiroshima/52/205 (H3N2); A/Solomon Islands/3/2006

Ceritinib purchase (H1N1); B/Malaysia/2506/2004. In 2008, three consecutive Modulators batches were successfully produced from the imported bulk antigen in two presentations: single-dose ampoules for use in clinical trials, and multi-dose vials for stability studies. Within 1 year of the start of the project, candidate seasonal influenza vaccine lots prepared for clinical trial were approved by the National Agency of Drug and Food Control (NADFC) in Indonesia. The results of analyses performed in Indonesia on clinical trial lots were confirmed in samples sent to Biken. In response to a request from NADFC, Bio Farma also carried Phosphatidylinositol diacylglycerol-lyase out a prelicensure bridging study to assess the safety and immunogenicity of the vaccine in 405 adolescents and adults (12–64 years old), randomly assigned to above three bulk batches. A single 0.5 mL dose was administered intramuscularly and blood samples taken before and 28 days after immunization. Results showed that the vaccine induced high antibody titres against influenza antigens in all subjects (≥1:40 haemagglutination inhibition to A/Hiroshima, A/Solomon Island and B/Malaysia strains 97.8%, 98.2% and 95.5%, respectively; p = 0.025). The geometric mean titres after immunization increased (A/Hiroshima: 66.16–323.37; A/Solomon Islands: 41.89–554.26; B/Malaysia: 24.02–231.83), and subjects with a fourfold increase in antibody titre were 61.2%; 85.5%; 81.5%, respectively.

, 2004 and Modulators Clarke et al., 2013). However, similar changes were not observed following restraint of conventionally housed mice suggesting that the absence of the early microbiota influences stress responsivity into adulthood. Further, monoassociation with Bifidobacterium infantis, a bacterium commonly isolated from the neonate gut, partially rescued the HPA stress activation, and gnotobiotic mice reconstituted with normal specific pathogen-free microbiota exhibited decreased anxiety-like behaviors ( Sudo et al., 2004, Clarke et al., 2013 and Nishino et al., 2013). Further evidence

of the role of microbiota in shaping stress pathway regulation comes from the study Z-VAD-FMK molecular weight of serotonergic dysregulation, a common feature ZD1839 molecular weight in sex-specific affective disorders (Ressler and Nemeroff, 2000 and Goel and Bale, 2010). Consistent with previous reports of sex differences in serotonergic neurocircuitry and established sex differences in the HPA axis stress response (Goel and Bale, 2010), hippocampal serotonin and 5-HIAA, the main metabolite of serotonin, concentrations were higher in conventionally colonized (CC) female mice than in males (Clarke et al., 2013). Interestingly, serotonin and 5-HIAA levels remain unchanged in GF females relative to CC females, while concentrations of these monoamines

and metabolites were increased to female-typical levels in GF male mice (Clarke et al., 2013), suggesting potential dysmasculinization of hippocampal serotonergic neurocircuitry in GF males. Consistent with previous work on early life stress and sex-specific dysregulation of neuroplasticity (Mueller and

Bale, 2008), BDNF expression was decreased in the hippocampus of GF male, but not GF female mice (Clarke et al., 2013). While bacterial colonization of GF males during the post-weaning period did not rescue hippocampal serotonergic alterations, this treatment successfully rescued altered anxiety-like behaviors observed in male GF mice (Clarke et al., 2013). This demonstration of the absence of a normal gut microbiota exhibiting consequences on neurodevelopment and adult behavior in males but not females introduces the possibility that the microbiome may also contribute to a larger extent to sex differences in the susceptibility to disease. Of great importance to stress Endonuclease pathway regulation, a direct interaction between gonadal hormones and microbial exposure in mediating sex-specific disease risk has been recently illustrated (Markle et al., 2013 and Yurkovetskiy et al., 2013). The incidence of autoimmune disorders such as type 1 diabetes (T1D) displays a strong female bias, with nearly twice as many females affected as males (Pozzilli et al., 1993). Similar sex-specific susceptibility is observed in the non-obese diabetes (NOD) mouse model where female NOD mice exhibit increased incidence of T1D pathogenesis relative to NOD males (Pozzilli et al., 1993).

All animal studies had the approval of the Institutional Animal Ethics Committee of Advinus Therapeutics Ltd. (an Association for Assessment and Accreditation of Laboratory Animal Care accredited facility) and were in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments INCB018424 molecular weight on Animals (Government of India). Animals were acclimatized in study rooms for at least three days prior to dosing. Hamsters and mice were housed in polypropylene cages (3 per cage, marked for identification), rats were housed singly and dogs were housed in individual pens maintained in controlled environmental conditions

(22 ± 3 °C; 40–70% Relative Humidity; 10–15 fresh air change cycles/h) with 12 h light and dark cycles. All animals were bred in-house except hamsters which were obtained from the Central Drugs Research Institute, Lucknow,

India. Hamsters, mouse and rats were given Ssniff® Rodent pellet food (ssniff Spezialdiäten GmbH, Germany) ad selleckchem libitum and dogs were given Pedigree® standard dog chow (manufactured by Effem India Private Limited, India) 300 g once a day. Good quality water passed through activated charcoal filter and exposed to UV rays was provided ad libitum throughout the study to all animals. In hamsters and mice, blood samples were collected through retro-orbital plexus using a sparse sampling design. In rats and dogs, a serial sampling design was used

with blood samples withdrawn through jugular vein in rats and cephalic vein in dogs. In rats, surgery was performed 48 h before study Libraries conduct and no surgery was performed in dogs. The IV solution vehicle comprised 20% (v/v) N-methyl-2-pyrrolidinone else (NMP) and 40% (v/v) polyethylene glycol 400 (PEG-400) in 100 mM citrate buffer pH 3. The PO vehicle comprised 7% (v/v) Tween® 80 and 3% (v/v) ethanol in water for hamster and mouse studies. Oral solutions in rat and dog used the same vehicle as IV. Suspension formulations comprised 0.08% (v/v) Tween® 80 in 0.5% (w/v) sodium carboxymethyl cellulose (medium viscosity). The IV dose volume was 1 mL/kg for hamsters, rats and dog and 2 mL/kg for mice. The oral dose volume was 10 mL/kg for hamsters and mice, 5–10 mL/kg for rats and 2–5 mL/kg for dogs. Formulations were prepared on the day of dosing. Rats were anesthetized using 1 mL/kg body weight of a mixture of ketamine (40 mg/mL) and xylazine (4 mg/mL). The depth of anesthesia was assessed by sensory and motor responses. Rats were placed in supine position and a 2 cm ventral cervical skin incision was made on the right side. Tissues were cleaned to visualize jugular vein following which a sterile PE-50 cannula was inserted into the vein and secured in place with a suture. The cannula was exteriorized through the scapulae.

When data permit, specific rules of evidence – such as those followed by the US Preventive Services Task Force – are used to judge the quality of data and to make

decisions regarding the inhibitors nature and strength of recommendations. In the absence of data or when Selleckchem VE821 data are inadequate, expert opinions of voting members and other experts are used to make recommendations. Other considerations and inputs used in formulating policy recommendations include clinical trial results and information provided in the manufacturer’s labeling or package insert; equity in access to the vaccine and responsible management of public funds; recommendations of other professional liaison organizations; and the feasibility of incorporating the vaccine into existing immunization programs. ACIP WGs often review WHO recommendations as a secondary source of information in their deliberations. In the U.S. setting WHO recommendations (vaccine position papers) may not be as relevant as they are in the WHO Wnt assay Regions and countries. In general, differences between ACIP’s recommendations

and WHO recommendations are relatively minor and reflect differences in epidemiology and clinical presentations between the US and the developing country setting. Draft recommendations are subjected to extensive review by scientific staff of the CDC, other relevant federal agencies, ACIP members, liaison representatives and external expert consultants. WG members or ACIP members may identify a need for additional data, corrections in data content and modifications of the interpretation of the data and may critique or challenge expert opinions. Occasionally surveys are considered, e.g. surveys of parents CYTH4 concerning acceptance/knowledge of a vaccine or surveys of immunization

providers. Public comments are solicited during each ACIP meeting and are considered in the decision-making process. These inputs are synthesized by the WG in an iterative process, and options are presented to the ACIP for final consideration and vote. WG meeting minutes are not available to the public, as WGs are not governed by the laws and procedures of the US Federal Advisory Committee Act. WG meetings are closed, internal meetings for the purpose of fact-finding and data review; neither involve deliberation nor voting on specific policy recommendations; nor do they include the entire membership of the ACIP.

, 2008). Thus, the appearance of structural contacts between GABAergic

amacrine cells and RBC axon terminals coincides with the emergence of sIPSCs in RBCs. This suggests that functional postsynaptic GABA receptor clusters are already present on RBC terminals before eye opening (P15). Previous studies demonstrated that GABAA and GABAC receptors are present on axon terminals of RBCs across species (Fletcher et al., 1998; Koulen et al., 1997, 1998; Lukasiewicz, 1996, 2004; Enz Epigenetics activator et al., 1996; McCall et al., 2002). To monitor the appearance of GABA receptor clusters on RBC axonal boutons during circuit assembly, we labeled for GABAA and GABAC receptors at two developmental time points, before eye opening (P12) and at maturity (P30). We found abundant GABAC receptor clusters on PKC-labeled axon terminals of RBCs as early as P12 and at P30 (Figures 1E and 1F). To determine the subunit composition of the GABAA receptor clusters located at these terminals, we performed immunostaining for GABAA α1–α3 subunits together with PKC. α2-containing GABAA receptors were not present on RBC axon terminals

(Figure S2A), supporting past findings (Fletcher et al., 1998). In contrast, both α1- and α3-containing GABAA receptor clusters were localized on RBC axonal boutons at both ages examined (Figures 1E and 1F). GABAA synapses containing α1 or α3 subunits did not colocalize with GABAC receptors selleck compound (Figure S2B) as found previously in adult retina (Koulen et al., 1996; Wässle et al.,

1998). Furthermore, these three GABA receptor cluster types (α1-GABAA, α3-GABAA, and GABAC) on RBC Idoxuridine boutons were each apposed to large GAD67-GFP amacrine cell varicosities ( Figure S1C). Coimmunolabeling for GAD67 and GABA receptors revealed that 93.27% ± 0.48% of GABAAα1 (n = 2 animals), 93.89% ± 0.66% of GABAC (n = 2), and 79.30% ± 2.04% of GABAAα3 (n = 3) receptor clusters on RBC terminals were apposed to GAD67-positive terminals. Thus, all three GABA receptor types are present on RBC terminals before eye opening, suggesting that synapses comprising these receptor types develop concurrently. To determine the role of neurotransmission in the structural development of inhibitory synapses onto RBC axon terminals, we used two transgenic mouse lines (Figure 2A). First, we asked whether suppressing glutamatergic transmission onto amacrine cells that likely contact RBCs affects the development of amacrine cell synapses onto RBC axons. This was achieved using the grm6-TeNT line in which neurotransmission from all ON-bipolar cells, including RBCs, is suppressed by expression of the light chain of tetanus toxin ( Kerschensteiner et al., 2009). Next, we assessed the outcome when GABA release from amacrine cells is diminished from development onward. To do so, we crossed GAD1 conditional knockout (KO) mice ( Chattopadhyaya et al.

Finally, we computed each decoder’s

predictions for MT-pursuit correlations with the same analysis procedures we had applied to our recordings from area MT. Most of the decoding computations we used are structured as “vector averaging,” a family of decoding computations that can reproduce much of pursuit behavior, defined by S→ in Equation 1. Vector averaging computes the vector sum of MT responses (R  i) weighted by their preferred speed (s  i) and a unit vector in their preferred direction ( θ→i) in the numerator; it divides by the sum of MT responses for normalization: equation(Equation 1) S→=∑iRiθ→isi∑jRj The equations for our decoders, by using the subscripts i versus j in the numerator and denominator, include the possibility of using different populations of model neurons for the numerator and denominator. This feature allows implementation of the principle that normalization might be based on an estimate rather LDK378 chemical structure than a calculation of total population activity ( Chaisanguanthum and Lisberger, 2011). It also allows

Selleck HIF inhibitor us to explore the new idea that there need not be neuron-neuron correlations between the populations of model units that contribute to the population vector sum and the normalization. In all models, however, we created neuron-neuron correlations within the numerator or denominator populations. There were two important ingredients of decoding models that predicted our data successfully. One was an opponent Ergoloid computation in the numerator, to create different signs of MT-pursuit correlations for neurons with preferred directions near versus opposite to the direction of target motion. The other was the lack of correlation between the model neurons that contribute to the weighted population vector in the numerator versus the normalization in the denominator, to create mostly positive MT-pursuit correlations for neurons with preferred directions within 90 degrees of target direction. Figure 4B provided a good qualitative match to the data in Figure 4A, for a form of vector averaging

that used opponent motion signals in the numerator and the sum of activity in a different population of model neurons in the denominator (Churchland and Lisberger, 2001, Huang and Lisberger, 2009 and Yang and Lisberger, 2009): equation(Equation 2) sh=∑icos(θi)Rilog2(si)k∑jRj equation(Equation 3) sv=∑isin(θi)Rilog2(si)k∑jRj equation(Equation 4) s=2sh2+sv2 We created opponent motion signals by weighting responses by the sine and cosine of preferred direction (Equations (Equation 2) and (Equation 3)), effectively computing: the response of a model unit with a given preferred direction minus the response of a model unit with the same preferred speed but the opposite preferred direction. Horizontal and vertical eye speeds sh and sv were decoded separately and combined to obtain the speed s ( Equation 4).

, 2009), possibly due to

the effect of additional regulatory mechanisms—for example, it is possible that Syt1 may become inhibited by phosphorylation or that Syt7 may be constitutively activated by phosphorylation or by alternative splicing ( Sugita et al., 2001). The simple model of Syt1 and Syt7 function that we propose accounts for all of the available observations but raises new questions. What precisely are the mechanisms mediating the functions of Syt1 and Syt7 in Ca2+ triggering of evoked release and in clamping minirelease? SNARE and phospholipid binding by Syt1 and Syt7 are probably involved (Perin et al., 1990, Bennett et al., 1992, Li et al., 1995, Chapman et al., 1995 and Sugita et al., 2002), but the precise nature of the protein selleck products complexes that mediate these functions remains to be established. In particular, the clamping function of Syt1 and of Syt7 probably operates upstream of Ca2+ influx and thus implies that Syt1 and Syt7 perform Ca2+-independent BYL719 mouse actions in release. A second question regards the identity of the Ca2+ sensor for the increased

minirelease in Syt1 KO synapses that is not mediated by Syt7. This sensor has a lower apparent Ca2+ cooperativity than the Ca2+ sensor for evoked release (Xu et al., 2009) and is also clamped by complexin (Yang et al., 2010), suggesting that it is not a synaptotagmin. It is tempting to speculate that this Ca2+ sensor may

catalyze SNARE complex assembly and could be involved in Munc13 function upstream of regular Ca2+ triggering by Syt1 and Syt7 (Augustin et al., 1999 and Varoqueaux et al., 2002), but this possibility has not been tested. Furthermore, not all asynchronous release is blocked in Syt1/Syt7 double-deficient neurons (see Figures 2, 3, and 6). The residual asynchronous release may be mediated by remaining Syt1 or Syt7 protein or by other synaptotagmin isoforms. Alternatively, of the remaining asynchronous release may reflect an additional, qualitatively different release process that may be driven by the same molecular mechanisms as those that lead to the increased minirelease in Syt1 KO synapses. Finally, our data do not rule out additional functions for Syt1 and Syt7. For example, Syt1 and Syt7 could additionally contribute to vesicle priming and/or regulate the repriming rate of synaptic vesicles. However, the phenotypes we observed cannot be explained solely by a potential function of Syt7 in priming or in regulating repriming. Specifically, impairments in priming or in the Ca2+-dependent regulation of repriming could not account for the sustained increased minifrequency in Syt1/Syt7 double-deficient neurons (Figure 4), for the decrease in isolated single responses in these neurons (Figure 3) and for the selective loss of asynchronous responses in Syt7 KO neurons still expressing Syt1 (Figure 7).