The same pattern was observed in men and in women.

Conclusions. Leisure activities in old age may protect

against cognitive decline for both women and men, and different types of activities seem to benefit different cognitive domains.”
“A substantial proportion of individuals with obsessive-compulsive disorder (OCD) do not endorse the dysfunctional beliefs proposed by cognitive models of OCD to be important in the onset and maintenance of symptoms. Previous research has attempted to characterize Low and High obsessive IWR-1 mw beliefs groups in terms of cognitive and symptom correlates to distil potential etiological differences in these subgroups of OCD patients. The current study sought to further examine potential neurocognitive differences between obsessive beliefs subgroups. Performance on the Wisconsin Card Sorting Test (WCST) was compared between a Low Beliefs OCD subgroup, a High Beliefs OCD subgroup, and two anxious control groups: Panic Disorder with Agoraphobia (PDA) and Social Phobia (SP). The High Beliefs OCD subgroup performed significantly poorer on WCST subscales compared to the other diagnostic groups.

These findings were not accounted for by severity of OCD or depressive symptoms. The Low Beliefs OCD subgroup performed similar to the anxiety disorder control groups. The results suggest a potential interplay between heightened obsessive YAP-TEAD Inhibitor 1 beliefs and neurocognitive inflexibility. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“Purpose: Prostate specific antigen and digital rectal examination have low specificity for detecting prostate cancer and they poorly predict the BIBF 1120 supplier presence of aggressive disease.

Urine is readily available and noninvasive, and it represents a promising source of biomarkers for the early detection and prediction of prostate cancer prognosis. We identified promising biomarkers for urine based prostate cancer, examined trends and outlined potential pitfalls.

Materials and Methods: We performed PubMed (R) and Web of Science (R) database searches of the peer reviewed literature on urine based testing for prostate cancer. Original studies of this subject as well as a small number of reviews were analyzed, including the strengths and weaknesses. We provide a comprehensive review of urine based testing for prostate cancer that covers the technical aspects, including the methodology of urine collection, as well as recent developments in biomarkers spanning the fields of genomics, epigenetics, transcriptomics, proteomics and metabolomics.

Results: The process of urine collection is subject to variability, which may result in conflicting clinical results.

1038/leu.2011.48; published online 29 March 2011″
“Interleukin-10 receptor 1 (IL-10R1) single nucleotide polymorphisms, located on chromosome 11q23 – a strong candidate for linkage with Tourette’s syndrome (TS) – have been investigated for association with TS. DNA of 77 patients with a DSM-IV (Diagnostic and Statistical Manual IV) diagnosis of TS and 250 healthy controls was genotyped. IL-10R1 was not associated with TS. (c) 2007 Elsevier

Ireland Ltd. All rights reserved.”
“Aberrant neocortical DNA methylation has Epacadostat concentration been suggested to be a pathophysiological contributor to psychotic disorders. Recently, a growth arrest and DNA-damage-inducible, beta (GADD45b) protein-coordinated DNA demethylation pathway, utilizing cytidine deaminases Nirogacestat cell line and thymidine glycosylases, has been identified in the brain. We measured expression of several members of this pathway in parietal cortical samples from the Stanley Foundation Neuropathology Consortium (SFNC) cohort. We find an increase in GADD45b mRNA and protein in patients with psychosis.

In immunohistochemistry experiments using samples from the Harvard Brain Tissue Resource Center, we report an increased number of GADD45b-stained cells in prefrontal cortical layers II, III, and V in psychotic patients. Brain-derived neurotrophic factor IX (BDNF IXabcd) was selected as a readout gene to determine the effects of GADD45b expression and promoter binding. We find that there is less GADD45b selleck chemical binding to the BDNF IXabcd promoter in psychotic subjects. Further, there is reduced BDNF IXabcd mRNA expression, and an increase in 5-methylcytosine and 5-hydroxymethylcytosine at its promoter. On the basis of these results, we conclude that GADD45b may be increased in psychosis compensatory to its inability to access gene promoter regions. Neuropsychopharmacology (2012) 37, 531-542; doi:10.1038/npp.2011.221; published online 2 November 2011″
“Ecotropic viral integration

site 1 (EVI1) is an oncogenic transcription factor in human acute myeloid leukemia (AML) with chromosomal alterations at 3q26. Because a high expression of EVI1 protein in AML cells predicts resistance to chemotherapy with a poor outcome, we have searched for molecular targets that will treat these patients with AML. In this study, we determined that CD52, which is mainly expressed on lymphocytes, is highly expressed in most cases of AML with a high EVI1 expression (EVI1(High)). CAMPATH-1H, a humanized monoclonal antibody against CD52, has been used to prevent graft-versus-host disease and treat CD52-positive lymphopro-liferative disorders. Here, we investigated the antitumor effect of CAMPATH-1H on EVI1(High) AML cells. CAMPATH-1H significantly inhibited cell growth and induced apoptosis in CD52-positive EVI1(High) leukemia cells. Furthermore, CAMPATH-1H induced complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity against CD52-positive EVI1(High) leukemia cells.

Results. – The results of four neurophysiological studies, performed on Days 14, 26, 35 and 125 after symptomatic onset are reported. All immunological determinations including antiganglioside antibodies (GM1, GM2, GM3, asialoGM1, GD1a, GD1b, GD3, GQ1b and GT1b) were negative. The patient had a favorable evolution

following FRAX597 treatment with intravenous immunoglobulins (IVIg).

Conclusions. – We conclude that the electrophysiologic hallmark of AMCBN may occur in the course of AIDP. Serial investigation including proximal, intermediate and distal segments of all nerves from upper and lower Limbs is essential for its detection. (c) 2008 Elsevier Masson SAS. All rights reserved.”
“Objectives. Age greater than 80 has been identified as a risk factor for complications, including stroke and death, in patients undergoing carotid artery angioplasty

and stenting (CAS). This study evaluates other potential predictors of perioperative complications in patients undergoing CAS.

Methods. All cerebrovascular endovascular procedures performed by the vascular surgery division at our university hospital between July 2003 and December 2005 were retrospectively examined. During the course of 212 admissions, 198 patients Selisistat concentration underwent 215 procedures. Patient age, comorbidities, and admission status were analyzed as independent (predictor) variables. Complication rate, discharge disposition, and length of hospital stay were considered dependent (outcome) variables. Logistic regression and Fisher exact test or Student t test were performed, as appropriate.

Results: Complications included major and minor stroke, TGF-beta inhibitor myocardial infarction, femoral artery pseudoaneurysm, and death. The rates of perioperative major and minor stroke were 0.5% and 2.8%, respectively. Chronic renal insufficiency was a predictor of perioperative complications, including stroke: patients with serum

creatinine greater than 1.3 mg/dL had a 37% complication rate and a 11.1% stroke rate, while those with normal renal function had a 13% complication rate (P = .003) and a 0.6% stroke rate (P = .001). Similar association was seen between creatinine clearance and both stroke and complications. Obesity was a risk factor for complications, but not stroke: obese patients had a complication rate of 28%, while others had a 16% complication rate (P = .024). Emergency admission predicted both extended hospital stay (P < .001) and requirement for further inpatient care in a rehabilitation or nursing facility (P = .007). There was no significant difference in complication rate or stroke rate between octogenarians and others.

Conclusion: This experience demonstrates that chronic renal insufficiency, obesity, and emergent clinical setting are risk factors for patients undergoing CAS.”
“Introduction.

4 to 6.0 with a half-maximum inhibitory concentration of 26 mu M. The inhibition of ASIC1b currents by pre-applied zinc was independent of pH, voltage, or extracellular Ca(2+). Further, we showed that the effect CRT0066101 molecular weight of zinc is dependent on the extracellular cysteine, but not histidine residue. Mutating cysteine 149, but not cysteine 58 or cysteine 162, located in the extracellular domain of the ASIC1b subunit abolished the zinc inhibition. These findings suggest that cysteine 149 in

the extracellular finger domain of ASIC1b subunit is critical for zinc-mediated inhibition and provide the basis for future mechanistic studies addressing the functional significance of zinc inhibition of ASIC1b. Published by Elsevier Ltd on behalf of IBRO.”
“Purpose: To compare long-term outcomes of systematic primary stent placement between Trans-Atlantic Inter-Society Consensus (TASC)-II C/D disease and TASC-II A/B disease.

Methods: Between 1997 and 2009, endovascular treatments with primary stent placement were performed for 533 lesions in 413 consecutive

patients with iliac artery occlusive disease. Median follow-up term was 72 months (range, 1-144 months). Lesion severity in this retrospective study was classified according to TASC-II as type A in 134 patients (32%), type B in 154 patients (37%), type C in 64 patients (16%), and type D in 61 patients (15%). Technical success AS1842856 supplier rates, procedure time, complication rates, and cumulative primary patency MK-4827 mw rates were compared between the complex lesion group (TASC-II type C/D) and the simple lesion group (TASC-II type A/B). Risk factors for in-stent restenosis were also analyzed.

Results: Technical success rates in TASC-II C/D and A/B were both 99%. Procedure times for TASC-II type A, B, C, and D lesions were 98 +/- 40, 124 +/- 50, 152 +/- 55, and 183 +/- 68 minutes, respectively. Procedure time was significantly longer in TASC-II C/D (167 +/- 63 minutes) than in TASC-II A/B (112 +/- 47 minutes; P < .001). The complication rate was significantly higher in TASC-II C/D (9%) than

in TASC-II A/B (3%; P = .014). Cumulative primary patency rates at 1, 3, 5, and 10 years were 90%, 88%, 83%, and 71% in TASC-II C/D and 95%, 91%, 88%, and 83% in TASC-II A/B, respectively. No significant differences were apparent between groups (P = .17; Kaplan-Meier method, log-rank test). In multivariate analysis, lesion length was an independent risk factor for in-stent restenosis (hazard ratio, 1.12, P = .03; 95% confidence interval, 1.01-1.24).

Conclusions: Primary stent placement for complex iliac artery occlusive disease provides acceptable long-term outcomes, although the procedure takes relatively longer and is associated with a higher frequency of complications than for simple disease. (J Vasc Surg 2011;53:992-9.

Five-minute pretreatment with 10-50 nM 17 beta-estradiol protected female but not male neurons from glutamate toxicity 24 h later. Both estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) are expressed in these cultures. Experiments using an ER alpha selective agonist or antagonist indicate that this receptor is important check details for neuroprotection in female cortical neurons. The ER beta selective agonist conveys a small degree of neuroprotection to both male and female cortical neurons. Interestingly, we found that 17 alpha estradiol and the novel membrane estrogen receptor (mER) agonist STX, but not bovine serum albumin conjugated

estradiol or the GPR30 agonist G1 were neuroprotective in both male and female neurons. Taken together these data highlight a role for ER alpha in sexually dimorphic neuroprotection. Published by Elsevier Torin 1 chemical structure Ltd on behalf of IBRO.”
“Poliovirus (PV) 2A(pro) has been considered important for PV replication and is known to be toxic to host cells. A 2A(pro)-deficient PV would potentially be less toxic and ideal as a vector. To examine whether 2A(pro) is needed to form progeny virus, a full-length cDNA of dicistronic (dc) PV with (pOME) or without (pOME Delta 2A) 2A(pro) was constructed in the strain PV1(M)OM. RNAs of both pOME and pOME Delta 2A were capable of forming

progeny viruses, called OME and OME Delta 2A, respectively. In their ability to induce a cytopathic effect (CPE), the strains ranked as OME Delta 2A < OME is approximately equal

to PV1(M) OM. These results suggest that 2A(pro) is not essential for full-length dc PV to form progeny virus and that it contributes to the efficient viral replication and/or induction of a CPE. To clarify whether 2A(pro) is essential for P1-null however (lacking the entire coding sequence for capsid proteins) PV, the RNA replication activity of P1-null PV (pOM Delta P1) or P1-null PV without 2A(pro) (pOM Delta P1 Delta 2A) or without both 2A(pro) and 2B (pOM Delta P1 Delta 2A Delta 2B) was examined. The RNAs of pOM Delta P1 and pOM Delta P1 Delta 2A could replicate and form progeny viruses under a trans supply of P1 protein, whereas the RNA of pOM Delta P1 Delta 2A Delta 2B could not. These results suggest that 2A(pro) is not needed for the replication of P1-null PV, although it is important for PV RNA replication and inducing a CPE. To know whether a 2A(pro)-deficient PV can be used as a vector, a P1-null PV containing the enhanced green fluorescent protein (EGFP) coding sequence with or without 2A(pro) was examined. It expressed fluorescent protein. This result suggests that 2A(pro)-deficient PV can express foreign genes.”
“Estrogens are important in the development, maintenance and physiology of the CNS.

Here, we report that two human polyomaviruses associated with serious disease in immunocompromised individuals, JC virus and BK virus, encode miRNAs with the same function

as that of the monkey polyomavirus simian virus 40 miRNAs. These miRNAs are expressed late during AP24534 supplier infection to auto-regulate early gene expression. We show that the miRNAs generated from both arms of the pre-miRNA hairpin are active at directing the cleavage of the early mRNAs. This finding suggests that despite multiple differences in the miRNA seed regions, the primary target (the early mRNAs) and function ( the downregulation of early gene expression) are evolutionarily conserved among the primate polyomavirus-encoded miRNAs. Furthermore, we show that these miRNAs are expressed in individuals diagnosed with polyomavirus-associated

disease, suggesting their potential as targets for therapeutic intervention.”
“The resting brain shows high neural activity in various regions, the default-mode network, chief among them the Z-IETD-FMK clinical trial cortical midline structures (CMS). The psychological correlate of high resting state neural activity in CMS remains however unclear though speculatively it has been associated with processing of internally-oriented self-relatedness. We used functional MRI to examine internally-oriented self-relatedness during the resting state period. This was indirectly done by letting subjects perceive emotional pictures followed by a fixation cross; the very same pictures were then rated subjectively according to their degree of self-relatedness

in a postscanning session. This allowed us to correlate the picture ratings of self-relatedness with signal changes in the subsequent resting state period, i.e. fixation period. The emotional pictures’ degree of self-relatedness parametrically modulated subsequent resting state signal changes in various CMS, including ventro- and dorsomedial prefrontal cortex and posterior cingulate cortex. This modulation could be distinguished from effects of emotion dimensions (e.g. valence, intensity) and evoked effects of self-relatedness Selleck 8-Bromo-cAMP during the stimulus period itself the latter being observed rather in subcortical regions, e.g. amygdala, ventral striatum, and tectum. In sum, our findings suggest that resting state neural activity in CMS is parametrically and specifically modulated by the preceding stimulus’s degree of self-relatedness. This lends further support to the presumed involvement of these regions in processing internally-oriented self-relatedness as distinguished from externally-oriented self-relatedness. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.”
“The coronavirus mouse hepatitis virus (MHV) induces a minimal type I interferon (IFN) response in several cell types in vitro despite the fact that the type I IFN response is important in protecting the mouse from infection in vivo.

This view had been based on studies which have assumed cooperation to be discrete rather than continuous

(i.e., individuals can either fully cooperate or else fully defect, but they cannot continuously vary their level of cooperation). In real world cooperation, however, cooperation is often continuous. In this paper, we re-examine the evolution of reciprocity in sizable groups by presenting a model of the n-person prisoner’s dilemma that assumes continuous rather than discrete cooperation. This model shows that continuous reciprocity has a dramatically wider basin of attraction than discrete reciprocity, and that this basin’s size increases with efficiency of cooperation (marginal per capita return). Further, we find that assortative see more interaction interacts synergistically with continuous reciprocity to a much greater extent than it does with discrete reciprocity. These results suggest that previous models may have underestimated reciprocity’s adaptiveness in groups. BIX 1294 price However, we also find that the invasion of continuous reciprocators into a population of unconditional defectors

becomes realistic only within a narrow parameter space in which the efficiency of cooperation is close to its maximum bound. Therefore our model suggests that continuous reciprocity can evolve in large groups more easily than discrete reciprocity only under unusual circumstances. (C) 2010 Elsevier Ltd. All rights reserved.”
“13-Cis-retinoic acid (13-cis-RA) causes depression-related behavior in mice. Hypothalamic dysregulation has been implicated in clinical depression. In fact, apoptosis of hypothalamic neurons may lead ATM inhibitor to depression after myocardial infarction. Our objective was to determine if 13-cis-RA affects cultured hypothalamic cell number. Treatment of GT1-7 hypothalamic cells with 10 mu M 13-cis-RA for 48 h decreased cell growth to 45.6 +/- 13% of control. To determine if this decrease in cell number was due to 13-cis-RA acting as an oxidant, cells were treated with I 3-cis-RA and ascorbic acid or butylated hydroxyanisole (BHA) for 24 or 48 h. Neither antioxidant alleviated the inhibitory affects

of 13-cis-RA. In addition, 13-cis-RA treatment did not increase superoxide anion production, indicating 13-cis-RA was not acting as an oxidant. To determine if 13-cis-RA was acting via retinoic acid receptors (RARs) to decrease cell number, GT1-7 cells were treated with 13-cis-RA and the RAR pan-antagonist, AGN 193109. Treatment with the RAR-antagonist blocked the ability of 13-cis-RA to decrease cell number, indicating this phenomenon was a RAR-independent mechanism. We hypothesize that the ability of I 3-cis-RA to decrease hypothalamic cell number may contribute to the increased depression-related behaviors observed in mice. (C) 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

These data show that ligands that activate RAGE present in the circulation of patients with type 2 diabetes and nephropathy are predominantly of high molecular weight. Kidney International (2010) 78, 287-295; doi: 10.1038/ki.2010.134; published online 12 May 2010″
“Alzheimer’s disease (AD) is well known as a disease characterized by degeneration of cholinergic neuronal activity in the brain. It follows that patients with AD would be sensitive to an ‘anticholinergic burden’, and also that medicine with anticholinergic properties

would promote various clinical symptoms of AD. Despite the relevance of this important phenomenon to the clinical therapeutics of AD patients, few reports have been seen concerning PRN1371 cost the relationship between anticholinergic burden selleck chemicals llc and clinical AD symptoms. Therefore,

we wished to investigate the relationship between serum anticholinergic activity (SAA) and the severity of clinical symptoms of AD patients. Twenty-six out of 76 AD patients referred by practitioners to our hospital were positive for anticholinergic activity in their serum, and the remaining 50 patients were negative. Cognitive and psychiatric symptoms in AD patients were compared between the positive SAA (SAA+) group and the negative SAA (SAA) group. The SAA+ group showed a significantly (p < 0.05) lower total score on the Mini-Mental State Examination, and significantly (p < 0.05) higher scores on the Functional Assessment Staging and the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD). In particular, certain subscales of the BEHAVE-AD, i.e. the items of paranoid and delusional ideation,

hallucinations Fosbretabulin mouse and diurnal rhythm disturbances, had higher scores in the SAA+ group. Moreover, it was shown that many more psychotropic medicines were prescribed to the SAA+ group. By means of logistic regression analysis, the items of paranoid and delusional ideation and diurnal rhythm disturbances in the BEHAVE-AD were positively correlated with SAA in patients. We hypothesized that SAA in AD patients would be associated with clinical symptoms, especially delusion and diurnal rhythm disturbances. Copyright (C) 2011 S. Karger AG, Basel”
“Controversy exists as to whether minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) represent different diseases or are manifestations within the same disease spectrum. Urinary excretion of CD80 (also known as B7.1) is elevated in patients with MCD and hence we tested whether urinary CD80 excretion might distinguish between patients with MCD from those with FSGS. Urinary CD80 was measured in 17 patients with biopsy-proven MCD and 22 with proven FSGS using a commercially available enzyme-linked immunosorbent assay and its molecular size determined by western blot analysis.

Four hexadentate salicylaldimine

ligands derived from bis(3-aminopropyl)ethylenediamine (BAPEN) that showed promise in previous rat experiments were selected for this study.

Methods: Following an evaluation of myocardial blood flow with [O-15]water PET, the pigs (total n=14) underwent a dynamic 90-min PET study with one of four Ga-68-labeled BAPEN derivatives (n=3-5 per tracer) either at rest or under adenosine stress. Serial arterial blood samples were collected during the imaging selleck chemicals llc for the measurements of total radioactivity, radiometabolites, plasma protein binding and blood-to-plasma ratio for the Ga-68 chelates. Time-activity curves of the left ventricular blood pool and myocardium were derived from PET images, and metabolite-corrected arterial input function was used for kinetic

modeling. Also, ex vivo biodistribution of Ga-68 radioactivity CX-6258 was analyzed.

Results: All four Ga-68 tracers showed undesirably slow myocardial accumulation over time, but their in vivo stability, clearance from blood and the kinetics of the myocardium uptake varied. [Ga-68][Ga-(sal)(2)BAPDM EM](I+) showed the highest myocardial uptake in PET images and tissue samples (myocardium-to-blood ratio 7.63+/-1.89, myocardium-to-lung ratio 3.03+/-0.33 and myocardium-to-liver ratio 1.80+/-0.82). However, there was no correlation between the myocardial perfusion measured with [O-15]water and the net uptake rates or K-1 values of the Ga-68 chelates.

Conclusion: Our results revealed that myocardial accumulation of the Ga-68 chelates proposed for myocardial perfusion imaging with PET was slow and not determined by myocardial perfusion in a large animal model. These findings suggest that the studied tracers are not suitable for clinical imaging of myocardial perfusion. (C) 2012 Elsevier Inc. All rights NU7026 reserved.”
“The authors present the context maintenance and retrieval (CMR) model of memory search, a generalized version of the temporal context model of M. W. Howard and M. J. Kahana (2002a), which

proposes that memory search is driven by,in internally maintained context representation composed of stimulus-related and source-related features. In the CMR model, organizational effects (the tendency for related items to cluster during the recall sequence) arise as a consequence of associations between active context elements and features of the studied material. Semantic clustering is due to longstanding context-to-item associations. whereas temporal clustering and source clustering are both due to associations formed during the study episode. A behavioral investigation of the three forms of organization provides data to constrain the CMR model, revealing interactions between the organizational factors. Finally, the authors discuss the implications of CMR for their understanding of a broad class of episodic memory phenomena and Suggest ways in which this theory may guide exploration of the neural correlates of memory search.

During development, network-constitutive neurons undergo dramatic rearrangements, involving their intrinsic properties, such as the blend of ion channels see more governing their firing activity,

and their synaptic interactions. The spinal cord is no exception to this rule; in fact, in the ventral horn the maturation of motor networks into functional circuits is a complex process where several mechanisms cooperate to achieve the development of motor control. Elucidating such a process is crucial in identifying neurons more vulnerable to degenerative or traumatic diseases or in developing new strategies aimed at rebuilding damaged tissue.

The focus of this review is on recent advances in understanding the spatio-temporal expression of the glycinergic/GABAergic system and on the contribution of this system to early network function and to motor pattern transformation along with spinal buy GSK923295 maturation. During antenatal development, the operation of mammalian spinal networks strongly depends on the activity of glycinergic/GABAergic neurons, whose action is often excitatory until shortly before birth

when locomotor networks acquire the ability to generate alternating motor commands between flexor and extensor motor neurons. At this late stage of prenatal development, GABA-mediated excitation is replaced by synaptic inhibition mediated by glycine and/or GABA. At this stage of spinal maturation, the large majority of GABAergic neurons are located https://www.selleck.cn/products/epz-5676.html in the dorsal horn. We propose that elucidating the role of inhibitory

systems in development will improve our knowledge on the processes regulating spinal cord maturation. (C) 2009 Elsevier Ltd. All rights reserved.”
“Endocrine disruption, the guiding theme of the 27th International Neurotoxicology Conference, merged into the neurotoxicology agenda largely because hormones help steer the process of brain development. Although the disruption motif first attracted public health attention because of reproductive anomalies in both wildlife and humans, the neurobehavioral implications had been planted decades earlier. They stemmed from the principle that sex differences in behavior are primarily the outcomes of differences in how the brain is sexually differentiated during early development by gonadal hormones (the Organizational Hypothesis). We also now understand that environmental chemicals are capable of altering these underlying events and processes. Among those chemicals, the group labeled as endocrine disrupting chemicals (EDCs) offers the clearest evidence of such selectivity, a consequence of their actions on the endogenous sex steroids, androgens and estrogens. Two EDCs in particular offer useful and intriguing examples. One is phthalate esters. The other is bisphenol A. Both agents are used extensively in plastics manufacture, and are pervasive in the environment. Both are produced in immense quantities. Both are found in almost all humans.