“No template” controls and melting curves were examined to insure against contamination and primer-dimer formation. For quantitation of absolute transcript levels, a titration of TAp63 and ΔNp63 plasmids was used to make a standard curve, against which known amounts of input cDNA from YFP-positive cells (HBCs) FACS-purified from Krt5CrePR;Rosa26YFP mice were compared. Using these standard curves, we measured the amount of ΔNp63 transcript at 0.1 pg/μg input CP-673451 chemical structure cDNA, whereas the level of TAp63 mRNA was below the detection limit of our assay (0.1 fg/μg input cDNA). Quantitation of relative transcript levels was performed

using the 2−ΔΔCT method. Qualitative analysis of p63 isoforms was performed using 30 cycles of amplification. Oligonucleotides used for RT-PCR analysis are summarized in Table 1. Tissue was fixed at the indicated stages with 4% paraformaldehyde for 6–8 hr at 4°C, washed with phosphate-buffered saline (PBS), decalcified with 10% ethylenediaminetetraacetic acid in PBS at 4°C for 2–3 days, washed with distilled H2O, and equilibrated in 30% sucrose overnight at 4°C before mounting and freezing in tissue-freezing medium (Triangle Biomedical selleckchem Sciences). Tissue sections were prepared at 12 μ thickness. RNA in situ hybridization was performed using digoxigenin-labeled probes and detected with an alkaline phosphatase-conjugated anti-digoxigenin antibody and BCIP/NBT substrates, as described previously (Duggan et al., 2008).

The template for the p63 RNA in situ hybridization probe, which includes the DNA binding domain region, was isolated by RT-PCR using the following primers: 5′- GCATGGACCAGCAGATTCAG-3′

Mannose-binding protein-associated serine protease and 5′-TTGCGCTGTCCGATACTTG-3′. For immunohistochemistry, tissue sections were treated with PBS containing 0.1% Triton X-100 with primary antibodies diluted in 10% goat or donkey serum, followed by detection with Alexa 488, 568, or 594 secondary antibodies (Invitrogen), as described (Duggan et al., 2008). The primary antibodies and dilutions used were as follows: mouse anti-p63, 1:100 (4A4; Santa Cruz Biotechnology [SCBT]); rabbit anti-Ki67, 1:250 (Abcam); goat anti-SOX2, 1:100 (SCBT); guinea pig anti-Ascl1, 1:10,000 (gift from Jane Johnson); goat anti-NeuroD1, 1:100 (SCBT); Armenian hamster anti-CD54/ICAM1, 1:100 (BD Pharmingen); mouse anti-neuronal tubulin, 1:250 (TuJ1; Abcam); rabbit anti-cleaved Caspace-3, 1:250 (Cell Signaling Technology); chicken anti-GFP, 1:500 (Abcam); rabbit anti-GFP, 1:500, (Molecular Probes). Nuclei were counterstained using Hoechst 33342, and slides were coverslipped with VECTASHIELD HardSet (Vector Labs) mounting compound. An antigen retrieval step (steaming for 20 min in 0.01 M sodium citrate, pH 6.0) prior to antibody incubation was necessary for detection of P63, KRT14, and SOX2 and for enhancement of signal for neuronal tubulin (TuJ1). Imaging of processed sections was performed by epifluorescence or scanning confocal microscopy.

These aspects have been the subject of numerous reviews, including some articles in this special issue of Verteporfin supplier Neuron, and will not be discussed here in any detail, except in cases where they may serve to help understand the history of the subject. The terminology of various subtypes of dividing cells and their offspring, however, was never clearly defined, and each investigator now chooses the terms that he or she likes, with the hope that others will understand what he or she means. Heackel

originated the term “stem cell” (“Stammzelle”) (Haeckel, 1868); the more specific name “neural stem cell” became popular only in the early 1990s (e.g., Chu-LaGraff and Doe, 1993 and Mackay-Sim and Kittel, 1991), and though widely used, it is not precisely defined (see Breunig et al., 2007 for discussion). Embryonically, the term usually refers to the early population of dividing cells, traditionally called neuroepithelial cells, which line the VZ and have the potential to give rise to both neurons and glial cells; it is also sometimes used, however, to describe the HDAC inhibitor cells

that translocate to the SVZ, which are also called intermediate amplifying progenitors (IAPs) or intermediate neuronal progenitors (INPs). Recent studies have also provided more detail about the transient neurons and proliferative cells outside the classical neuroepithelium and those in additional “abventricular” cellular compartments (Bielle et al., 2005, Bystron et al., 2006, Carney et al., 2007, Smart et al., 2002 and Zecevic et al., 2005), e.g., subpial granular layer (SPG) (reviewed in Bystron et al., aminophylline 2008) and outer subventricular zone (OSVZ) in primate and rodent (Fietz et al., 2010, Hansen et al., 2010, Reillo et al., 2010, Shitamukai et al., 2011 and Wang et al., 2011). Some of these latter cell types already have multiple names in the literature, so providing consistent definitions and labels for the many cells present in the developing

system remains an important task. Although developmental neurobiologists have spent the last decade increasingly finding that NSCs have intrinsic properties related to their spatial and temporal characteristics, adult NSCs, beginning more from a standing start, are only recently becoming progressively better characterized. It is now understood that the adult brain contains a large number of stem cells throughout virtually all regions (Gage, 2000). In addition, new neurons are produced in discrete sites—even in the human brain (Eriksson et al., 1998). Furthermore, human embryonic stem cell (hESC) and induced pluripotent stem cell (IPS) technology offers a potentially unlimited source of NSCs for clinical use (Mattis and Svendsen, 2011).

Still visual function is relatively unaffected, with the exception of nystagmus and the absence of stereopsis. In line with previously reported achiasmic subjects (Apkarian et al., 1994, 1995; Prakash et al., 2010; Victor et al., 2000), the subjects made effective use of their vision in daily life, including sport activities and reading. They performed normal on various clinical tasks, including largely normal visual field sensitivities and

no visual field defects associated with the abnormal representation of the nasal retina. Further, there was no apparent confusion between left and right visual fields, in line with previous reports that have found no evidence for perceptual crosstalk across the opposing hemifields, neither in achiasma (Victor et al., 2000) nor albinism (Klemen et al., 2012). In order to make the selleck chemicals abnormally represented visual information available for perception, neural plasticity is required. We propose that instead of large-scale reorganizations, comparatively subtle intracortical mechanisms

mediate the achiasmic subjects’ ability to cope with the abnormal visual input. For example, normally binocular information is integrated to yield stereovision. In achiasma, however, these integrative Sirolimus datasheet mechanisms would result in major sensory conflicts such as confusions between the two hemifields. Plasticity of intracortical mechanisms is therefore required ADP ribosylation factor to selectively block such integrative processes while supporting others, e.g., those required to shape monocular spatial receptive field properties. Remarkably, conservative geniculostriate and cortico-cortical mapping of abnormal retinogeniculate

input provides a sufficient scope of developmental plasticity in humans to make substantially abnormal representations available for relatively normal visual perception. Data of two male achiasmic patients and their respective controls were acquired at two sites, at Magdeburg University, Germany (AC1 and four controls), and Stanford University, USA (AC2 and 34 controls). The control subjects were visually and neurologically normal. The procedures followed the tenets of the declaration of Helsinki, and the participants gave their written consent. The ethical committees of the University of Magdeburg and the Stanford Institutional Review Board approved the respective protocols. AC1 (aged 22) was referred with the clinical diagnosis of severe hypoplasia of the optic chiasm based on a T1 weighted MRI and functional achiasma was confirmed with VEPs (Apkarian et al., 1983, 1995). He made effective use of his vision including reading and the diagnosis of the chiasmic malformation was incidental (age 20). His best-corrected decimal visual acuity was 0.5 for the dominant right and 0.17 for the left eye, and there was no foveal hypoplasia. He had alternating exotropia (2 deg), dissociated vertical deviation (5 deg), and was stereoblind.

Because of the many conditions (23 figure positions and 2 attention conditions) we averaged responses

across recording sessions on different days. We only included recording sites with at least three figure-detection and three curve-tracing sessions in the analysis (the average Doxorubicin ic50 number of sessions in every task was 5). This resulted in a sample of 59 recording sites in V1 (18 in monkey B, 15 in monkey C, and 26 in monkey J) and 46 in V4 (18 in monkey B, 9 in monkey C, and 19 in monkey J). The average number of trials per condition was 484. We did not observe significant differences in visual responsiveness between the figure-detection and the curve-tracing tasks (paired t test; V1 and V4, p > 0. 05). We separately analyzed the V1 responses evoked by the texture background, the figure edge and the figure Screening Library screening center. To create the space-time plots in Figures 4C, 4D,

6C, and 6D we first computed for every RF the distance of the figure center to the RF center in all stimulus conditions and rounded these distances to the nearest multiple of 0.5°. We then computed for every figure position (0.5° steps) an average response across RFs. In area V1, background responses were obtained by averaging across conditions where the RF-center was separated from the nearest figure edge by at least 2°. Edge responses were averaged across conditions where one of the two edges fell in the RF, and center responses across conditions where the RF-center was within 0.5 degrees of the figure center. In V4, we did not distinguish between edge and figure responses, because the large RFs typically did not fit entirely within the figure. Instead, we compared figure positions where the figure completely or partially MTMR9 covered the RF to background positions where the figure was outside the RF. We took as background responses those conditions where the RF border was separated from the nearest figure edge by at least 2° (except for 5 recording sites with distance <1.8°, and 3 with distance <1°) and as figure responses those configurations

where the RF hot spot (point in V4 RF with maximum response) was within 2° from the figure center. To compute the population responses, we first normalized the responses before averaging across recording sites by subtracting Sp and dividing the result by (Pe-Sp) (Sp and Pe were defined above). As a measure of the reliability of the FGM across trials, we computed the FGM d  -prime: dFGM′=(y¯Fig−y¯Bck)/sAct, where y¯Fig and y¯Bck is the average response evoked by the figure and background, respectively, and sActsAct is the pooled standard deviation across the two conditions. For each recording site, we obtained an estimate of the FGM d-prime during figure detection and curve tracing by averaging d-prime values across the corresponding sessions. The model consists of areas V1m, V2m, and V4m (the subscript “m” stands for model). The input signal arrives in two maps.

Care should be taken to distinguish research papers from reviews, which although important are not signs by themselves of research accomplishment. Although quality

of the research papers is paramount, number selleck kinase inhibitor is also important, keeping in mind that large labs should obviously be publishing more papers per year than a small lab, so some normalization for that factor is important. If your prospective advisor has not published a good research paper in over 5 years, this is a serious warning sign (what is the chance you will just happen to be the one student in that lab to publish?). Another measure of the overall productivity and impact of a scientist’s work as a whole is known as the H-index, which is a single number that rates a scientist’s most cited papers and the number of citations that they have received (http://en.wikipedia.org/wiki/H-index). Any scientist’s H-index can be found at the Web of Science (http://thomsonreuters.com/web-of-science). Keep in mind that older scientists will have higher H-indexes than younger scientists. Second, a student can learn much about a potential advisor’s research productivity and accomplishments

by simply reading the advisor’s curriculum vitae. You should not be shy to ask for a prospective advisor’s CV. This does not reflect poorly on you but rather shows unusual maturity and that you are Hormones antagonist being careful about how you select your thesis advisor. In some cases, the candidate advisor may be a Nobel Laureate, National Academy member, HHMI investigator, or have won some other distinguished scientific award or prize, such as an NIH Pioneer Award, which is generally an excellent sign that they are a good scientist. ADP ribosylation factor Most good scientists, however, lack these awards and this should not be considered a negative factor. Indeed, working with a young faculty member who is skilled in the latest techniques, still has a small lab, and therefore much time to mentor you, can often be an excellent choice. Another objective measure of the

quality of science a lab is doing is whether they have established National Institutes of Health (NIH) (or other) grant support. If this information is not listed on his or her CV, it can easily be checked by going to the NIH grant database (http://www.report.nih.gov). Unless your prospective advisor is in his first several years of starting his or her own lab, lack of NIH support in the form of one or more R01 grants would be a sign that he or she has not been sufficiently productive to merit further support. That said, without doubt obtaining grant funding is highly competitive these days, and this means that many good scientists may sometimes fail to obtain or renew a highly deserving grant application. Nonetheless, it is important for your training that you select an advisor who has sufficient funds to support your graduate research.

, 1995). Crossing the midline may be an easier option than turning back into the ipsilateral optic tract. The tripartite system described here, as with VEGF/neuropilin signaling, could provide a Navitoclax cost necessary molecular “boost” that augments this inertial midline tendency. All animal procedures followed the regulatory guidelines of the Columbia University Institutional Animal Care and Use Committee. Noon of the day on which a plug was found was considered E0.5. Generation, breeding, and genotyping of Nr-CAM−/−, Plexin-A1−/−, and Sema6D−/−

mutants were described previously by Sakurai et al., 2001 and Takamatsu et al., 2010, and Yoshida et al. (2006). Mice were maintained on a 129SvEvS6 (Nr-CAM−/−) or a C57BL/6 (Plexin-A1−/− and Sema6D−/−) genetic background. Plexin-A1−/−;Nr-CAM−/− double mutants were generated from these mutants

resulting in a 129SvEvS6/C57BL/6 background. These mice are born at roughly Mendelian ratios, are fertile, and survive to adulthood. Whole-anterograde and retrograde labeling was performed on fixed tissue using DiI (Molecular Probes) as described previously by Pak et al. (2004) and Plump et al. (2002). Bortezomib manufacturer For quantification of the ipsilateral projection in mutants anterogradely labeled with DiI, pixel intensity of DiI+ ipsilateral and contralateral optic tracts adjacent to chiasm midline in a 500 × 500 μm area Digestive enzyme was measured with MetaMorph image analysis software. The ipsilateral index was obtained by dividing the intensity of the ipsilateral projection as seen in whole mounts by the sum of the contralateral and ipsilateral pixel intensities. Each of the ipsilateral indexes in mutants was normalized to the WT ipsilateral index. Details are shown in Figure 7B. Retinal explants were dissected from E14.5 WT C57BL/6 or mutant embryos as described previously by Wang et al. (1996). To harvest chiasm cells, a 400 × 400 μm area of the ventral diencephalon that included the chiasm midline was dissected, dissociated, and plated at a density

of 140,000 cells/dish shortly after retinal explants were plated, in DMEM/F12 serum-free medium containing 0.4% methylcellulose with 80 μg/ml αSema6D or preimmune serum added. Cultures were grown for 18 hr and then fixed for 30 min with 4% PFA. Neurites were visualized with a monoclonal neurofilament antibody (2H3). The total area covered by neurites of individual explants was quantified by measuring pixel intensity with OpenLab image analysis software. The amount of axon growth was normalized with respect to the outgrowth of DT or VT explants under control conditions, and indicated in the leftmost bar in graphs in Figures 2, 3, and 5. Each experiment was carried out at least three times, and in each experiment at least four explants were treated in each experimental group.

, 2010). However, in absolute numbers the majority of these receptors are localized in the extrasynaptic space, which greatly

exceeds the synaptic membrane area. Moreover, not all γ2-containing receptors are concentrated at synapses. In particular, α5βγ2 receptors are found almost exclusively at extrasynaptic sites (Brünig et al., 2002a, Crestani et al., 2002 and Serwanski selleck inhibitor et al., 2006) and contribute to tonic GABAergic currents (Caraiscos et al., 2004 and Glykys et al., 2008), although synaptic α5βγ2 receptors have been reported also (Serwanski et al., 2006 and Zarnowska et al., 2009). The most prominent population of nonsynaptic GABAARs mediating tonic inhibition consists of α4βδ receptors in the forebrain and α6βδ receptors in the cerebellum. In addition, α1βδ receptors underlie tonic inhibition of hippocampal interneurons (Glykys et al., 2007). The δ-containing receptor subtypes exhibit high agonist affinity and therefore are tailored to function at ambient submicromolar

concentrations of GABA outside of synapses (Saxena and Macdonald, 1996, Haas and Macdonald, 1999, Ke et al., 2000, Bianchi et al., 2001, Brown et al., 2002 and Terpstra et al., 2002). Lastly, GABAARs also are present on axons, including the axon initial segment of pyramidal cells (Nusser et al., 1996, Brünig et al., 2002a and Szabadics et al., 2006), mossy fiber Palbociclib chemical structure Levetiracetam terminals of hippocampal granule cells (Ruiz et al., 2003, Jang et al., 2006 and Alle and Geiger, 2007), axon terminals of retinal bipolar neurons (Shields et al., 2000), and cerebellar parallel fibers (Stell et al., 2007). Axonal GABAARs are thought to modulate action potential conductance and neurotransmitter release (Kullmann et al., 2005). Regulated expression

of GABAAR subunit genes determines cell type-specific and developmental changes in the subunit composition and function of GABAARs. In addition, significant changes in subunit mRNA levels are observed in adulthood. For example, the subunit gene expression of α4βδ receptors in granule cells of the dentate gyrus is dynamically altered during epileptogenesis in a rat model of epilepsy (Brooks-Kayal et al., 1998 and Peng et al., 2004) and during the estrus cycle of the mouse (Maguire et al., 2005). The levels of mRNAs encoding subunits of these receptors in CA1 pyramidal cells of rats is changed during puberty (Shen et al., 2007 and Shen et al., 2010a), at the end of pregnancy (Sanna et al., 2009), and in a progesterone withdrawal model of premenstrual syndrome (Sundstrom-Poromaa et al., 2002). These studies in rodents indicate that alterations in subunit mRNA levels are generally paralleled by corresponding changes in the surface accumulation and function of GABAARs that contribute to changes in neural excitability.

Study participants over estimated the sero-prevalence of WNv in Saskatchewan at 20%. Recently completed sero-prevalence studies from 2003 to 2007 estimate the sero-prevalence AZD5363 mw in Saskatchewan at 3.3% (range: 2:0–5.3% depending on geographic area) (unpublished data, J. Tataryn and P. Curry), with one specific geographic area of Saskatchewan as high as 8.5% [2]. Risk perceptions of the

public are likely influenced by media coverage and personal knowledge of individuals directly affected by WNv. The main concern for public health is the burden of illness to WNv patients and their families as well as the impact on the health care system. For example, in 2007, the Saskatoon Health Region reported

358 cases, including 32 neurological cases and 2 deaths; 15% of all cases were hospitalized. In that year, WNv was a leading cause of human encephalitis and aseptic meningitis in the region (Saskatoon Health Region Health Status Report, 2008; http://www.saskatoonhealthregion.ca/your_health/documents/PHO/shr_health_status_report_2008_full.pdf). Adults, seniors, and individuals who have chronic illnesses or who are immunosuppressed were perceived by study participants selleck products to be at greater risk of WNv disease and complications. Literature from across North America suggests that certain co-morbidity groups are at higher risk of prolonged recovery due to WNv, even the more mild form of West Nile fever [10]. Other factors, identified by study participants, believed to increase the risk of contracting WNv included living Sodium butyrate in the southern part of the province, living

in a rural setting, working primarily outdoors, or participating in outdoor recreational activities. Again, these risk factors are reported in other studies from across North America [2] and [10]. Nearly all public health practitioners personally recommended preventive strategies against contracting WNv. The methods most commonly suggested by study participants included using mosquito repellent with DEET, wearing covering clothing such as long sleeves and pants, and avoiding exposure to mosquitoes during peak mosquito activity time periods. The 2004 sero-prevalence study conducted in southern Saskatchewan reported that study participants were highly knowledgeable about personal protective measures with over 95% of participants believing the protective measures prevent WNv; however, less than 50% reported practicing the behaviours all of most of the time [2]. This disconnect between knowledge and action for the personal prevention of WNv makes the introduction of a vaccine an extremely tangible method to prevent all forms of WNv disease which does not have to be applied on a daily basis. The majority of health care professionals felt confident in the potential efficacy of vaccination for prevention of WNv.

Access (7–18 MΩ) and membrane resistance (see Table S1) were monitored before and after mEPSC recordings and data were rejected if changes greater than 20% occurred. The behavioral experiments started 3 weeks after stereotaxic delivery of rAAVs. Mice were habituated to the experimental room and handled once a day for 3 consecutive days before testing started. Two different sets of mice were used for

Morris water maze Dasatinib clinical trial and contextual fear conditioning experiments. At the end of the experiments, virus infection was assessed. For details on the behavioral experiments see Supplemental Information. All plotted data represent mean ± SEM. ANOVA with Tukey’s post hoc test was used for statistical analyses except where stated otherwise. In those experiments where only two conditions are tested, comparisons were made by using a Student’s t test for independent samples. In the Morris water maze experiment,

repeated-measures ANOVA and Baf-A1 datasheet one-way ANOVA were used to analyze acquisition curves and probe trials, respectively. We thank I. Bünzli-Ehret for her help with the preparation of hippocampal cultures; U. Weiss for western blot analysis; Drs. S. Oliviero, B.L. Sabatini, and A. Asano for providing plasmids; Drs. S.J. Zhang, D. Lau, and S. Romorini for discussions; and Dr. A.M. Hagenston for comments on the manuscript. All images of Golgi-impregnated tissues were taken at the Nikon Imaging Center at Heidelberg University. This work was supported by the Alexander von Humboldt Foundation (Wolfgang Paul Prize to H.B.), a European Research Council (ERC) Advanced Grant (to H.B.), the Sonderforschungsbereich (SFB) 488 and SFB 636 of the Deutsche Forschungsgemeinschaft (DFG),

the European Network of Excellence NeuroNE, and the Histone demethylase European Union Project Glutamate Receptor Interacting Proteins as Novel Neuroprotective Targets (EU Project GRIPANNT). H.B. is a member of the Excellence Cluster “CellNetworks” at Heidelberg University. D.M. is recipient of a European Molecular Biology Organization (EMBO) Long-Term Fellowship; A.M.M.O. is recipient of a Postdoctoral Fellowship from the Foundation for Science and Technology, Portugal. “
“PSD-95, the principal protein of postsynaptic densities (PSD), is a major scaffolding protein that impacts synaptic plasticity (Cho et al., 1992 and Migaud et al., 1998). In addition to maintaining the molecular architecture of the PSD (Chen et al., 2008), PSD-95 enhances long-term depression (Stein et al., 2003) and is required for spatial learning in mouse models (Migaud et al., 1998). N-terminal palmitoylation targets PSD-95 to synapses, where it clusters AMPA-type glutamate receptors (Chen et al., 2000) and physically links NMDA receptors to neuronal nitric oxide synthase (nNOS) (Brenman et al., 1996 and Christopherson et al., 1999). This interaction enables calcium that permeates NMDA receptors to activate nNOS by binding calmodulin associated with the enzyme (Bredt and Snyder, 1990).

Interviews with a selection of countries from each group will be conducted later to ascertain explanatory factors for increased or decreased distribution rates. The study’s results were compiled uniformly on a global basis from a standardized source. The vaccine producers that manufacture the majority of the world’s influenza vaccines (IFPMA IVS members)

accounted for approximately 79% of the global seasonal influenza vaccine production reported by a 2011 WHO survey [10], or 489 million doses out of 620 million doses, with the remainder manufactured by non-IFPMA IVS members. However, some limitations to the survey methods must be noted. Some error may have occurred due to inaccurate reporting by distributors, but this error should be small. It is also recognized that dose distribution is not synonymous with vaccination coverage rates, but provides a reasonable proxy to assess vaccine utilization. Also, increases in absolute BMS354825 numbers of doses distributed

may in some cases reflect changes in Olaparib supplier target populations (i.e., new target groups), and not increased coverage. Global distribution of IFPMA IVS seasonal influenza vaccine doses in 2011 represents an approximate 87% increase over absolute number of doses distributed in 2004 (489.1 versus 261.7 million doses) as seen in Fig. 1, but only an approximate 12% increase over doses distributed in 2008 (489.1 versus 436.5 million doses). Thus, while there is a positive trend in global distribution of doses, and a majority of countries (56%) have increased doses distributed per 1000 population between 2008 and 2011, the rate of growth has slowed

considerably. In 2011, only 24% of 115 countries had achieved or surpassed the hurdle rate of 159 doses per 1000 population. Using vaccine dose distribution as a proxy for vaccine coverage would therefore suggests that the majority of countries have not achieved national or supranational targets for influenza vaccination where they exist. Low coverage rates cannot be attributed to lack of vaccine supply as global manufacturing capacity for influenza vaccines has grown steadily but remains underutilized with only about half the capacity being consumed annually [10]. Hence, many vulnerable patients are not protected against Phosphatidylinositol diacylglycerol-lyase the potential serious implications of an influenza infection. Furthermore, there are significant regional disparities in dose distribution. Increases in distributed doses have been predominantly steady in all WHO regions since 2004, except in EURO and EMRO where distributed doses have been declining since 2009. AFRO, SEARO and EMRO constitute 47% of the global population but account for only 14.1 million doses of the more than 489 million IFPMA IVS doses (3.7%) distributed in 2011. And within these 3 regions, further inequities in distribution exist with only 4 countries having distributions of >70 doses per 1000 population and the vast majority of countries having considerably lower per capita distributions.