Weak pairwise correlations imply strongly correlated network states in a neural population

Biological networks have so many possible states that exhaustive sampling is impossible. Successful analysis thus depends on simplifying hypotheses, but experiments on many systems hint that complicated, higher order interactions among large groups of elements play an important role. In the vertebrate retina, we show that weak correlations between pairs of neurons coexist with strongly collective behavior in the responses of ten or more neurons. Surprisingly, we find that this collective behavior is described quantitatively by models that capture the observed pairwise correlations but assume no higher order interactions. These maximum entropy models are equivalent to Ising models, and predict that larger networks are completely dominated by correlation effects. This suggests that the neural code has associative or error-correcting properties, and we provide preliminary evidence for such behavior. As a first test for the generality of these ideas, we show that similar results are obtained from networks of cultured cortical neurons.Comment: Full account of work presented at the conference on Computational and Systems Neuroscience (COSYNE), 17-20 March 2005, in Salt Lake City, Utah (http://cosyne.org

GSVD Comparison of Patient-Matched Normal and Tumor aCGH Profiles Reveals Global Copy-Number Alterations Predicting Glioblastoma Multiforme Survival

Despite recent large-scale profiling efforts, the best prognostic predictor of glioblastoma multiforme (GBM) remains the patient's age at diagnosis. We describe a global pattern of tumor-exclusive co-occurring copy-number alterations (CNAs) that is correlated, possibly coordinated with GBM patients' survival and response to chemotherapy. The pattern is revealed by GSVD comparison of patient-matched but probe-independent GBM and normal aCGH datasets from The Cancer Genome Atlas (TCGA). We find that, first, the GSVD, formulated as a framework for comparatively modeling two composite datasets, removes from the pattern copy-number variations (CNVs) that occur in the normal human genome (e.g., female-specific X chromosome amplification) and experimental variations (e.g., in tissue batch, genomic center, hybridization date and scanner), without a-priori knowledge of these variations. Second, the pattern includes most known GBM-associated changes in chromosome numbers and focal CNAs, as well as several previously unreported CNAs in 3% of the patients. These include the biochemically putative drug target, cell cycle-regulated serine/threonine kinase-encoding TLK2, the cyclin E1-encoding CCNE1, and the Rb-binding histone demethylase-encoding KDM5A. Third, the pattern provides a better prognostic predictor than the chromosome numbers or any one focal CNA that it identifies, suggesting that the GBM survival phenotype is an outcome of its global genotype. The pattern is independent of age, and combined with age, makes a better predictor than age alone. GSVD comparison of matched profiles of a larger set of TCGA patients, inclusive of the initial set, confirms the global pattern. GSVD classification of the GBM profiles of an independent set of patients validates the prognostic contribution of the pattern

The Clinical Impact of Copy Number Variants in Inherited Bone Marrow Failure Syndromes

Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants (CNVs) were reported in some IBMFSs. It is unclear what impact CNVs play in patients evaluated for a suspected diagnosis of IBMFS. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic CNVs (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of CNVs. Pathogenic nucleotide-level mutations were found in 157 of 303 tested patients (51.8%). Genome-wide CNV analysis by single nucleotide polymorphism arrays or comparative genomic hybridization arrays revealed pathogenic CNVs in 11 of 67 patients tested (16.4%). In four of these patients, identification of CNV was crucial for establishing the correct diagnosis as their clinical presentation was ambiguous. Eight additional patients were identified to harbor pathogenic CNVs by other methods. Of the 19 patients with pathogenic CNVs, four had compound-heterozygosity of a CNV with a nucleotide-level mutation. Pathogenic CNVs were associated with more extensive non-hematological organ system involvement

Risk-taking attitudes and their association with process and outcomes of cardiac care: a cohort study

<p>Abstract</p> <p>Background</p> <p>Prior research reveals that processes and outcomes of cardiac care differ across sociodemographic strata. One potential contributing factor to such differences is the personality traits of individuals within these strata. We examined the association between risk-taking attitudes and cardiac patients' clinical and demographic characteristics, the likelihood of undergoing invasive cardiac procedures and survival.</p> <p>Methods</p> <p>We studied a large inception cohort of patients who underwent cardiac catheterization between July 1998 and December 2001. Detailed clinical and demographic data were collected at time of cardiac catheterization and through a mailed survey one year post-catheterization. The survey included three general risk attitude items from the Jackson Personality Inventory. Patients' (n = 6294) attitudes toward risk were categorized as risk-prone versus non-risk-prone and were assessed for associations with baseline clinical and demographic characteristics, treatment received (i.e., medical therapy, coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention (PCI)), and survival (to December 2005).</p> <p>Results</p> <p>2827 patients (45%) were categorized as risk-prone. Having risk-prone attitudes was associated with younger age (p < .001), male sex (p < .001), current smoking (p < .001) and higher household income (p < .001). Risk-prone patients were more likely to have CABG surgery in unadjusted (Odds Ratio [OR] = 1.21; 95% CI 1.08–1.36) and adjusted (OR = 1.18; 95% CI 1.02–1.36) models, but were no more likely to have PCI or any revascularization. Having risk-prone attitudes was associated with better survival in an unadjusted survival analysis (Hazard Ratio [HR] = 0.78 (95% CI 0.66–0.93), but not in a risk-adjusted analysis (HR = 0.92, 95% CI 0.77–1.10).</p> <p>Conclusion</p> <p>These exploratory findings suggest that patient attitudes toward risk taking may <b>contribute to </b>some of the documented differences in use of invasive cardiac procedures. An awareness of these associations could help healthcare providers as they counsel patients regarding cardiac care decisions.</p

Geographical variation in radiological services: a nationwide survey

BACKGROUND: Geographical variation in health care services challenges the basic principle of fair allocation of health care resources. This study aimed to investigate geographical variation in the use of X-ray, CT, MRI and Ultrasound examinations in Norway, the contribution from public and private institutions, and the impact of accessibility and socioeconomic factors on variation in examination rates. METHODS: A nationwide survey of activity in all radiological institutions for the year 2002 was used to compare the rates per thousand of examinations in the counties. The data format was files/printouts where the examinations were recorded according to a code system. RESULTS: Overall rates per thousand of radiological examinations varied by a factor of 2.4. The use of MRI varied from 170 to 2, and CT from 216 to 56 examinations per 1000 inhabitants. Single MRI examinations (knee, cervical spine and head/brain) ranged high in variation, as did certain other spine examinations. For examination of specific organs, the counties' use of one modality was positively correlated with the use of other modalities. Private institutions accounted for 28% of all examinations, and tended towards performing a higher proportion of single examinations with high variability. Indicators of accessibility correlated positively to variation in examination rates, partly due to the figures from the county of Oslo. Correlations between examination rates and socioeconomic factors were also highly influenced by the figures from this county. CONCLUSION: The counties use of radiological services varied substantially, especially CT and MRI examinations. A likely cause of the variation is differences in accessibility. The coexistence of public and private institutions may be a source of variability, along with socioeconomic factors. The findings represent a challenge to the objective of equality in access to health care services, and indicate a potential for better allocation of overall health care resources. PREVIOUS PUBLICATION: The data applied in this article was originally published in Norwegian in: Børretzen I, Lysdahl KB, Olerud HM: Radiologi i Noreg – undersøkingsfrekvens per 2002, tidstrendar, geografisk variasjon og befolkningsdose. StrålevernRapport 2006:6. Østerås: The Norwegian Radiation Protection Authority. The Norwegian Radiation Protection Authority has given the authors permission to republish the data

HIV-1 superinfection results in broad polyclonal neutralizing antibodies

<div><p>HIV-1 vaccines designed to date have failed to elicit neutralizing antibodies (Nabs) that are capable of protecting against globally diverse HIV-1 subtypes. One relevant setting to study the development of a strong, cross-reactive Nab response is HIV-1 superinfection (SI), defined as sequential infections from different source partners. SI has previously been shown to lead to a broader and more potent Nab response when compared to single infection, but it is unclear whether SI also impacts epitope specificity and if the epitopes targeted after SI differ from those targeted after single infection. Here the post-SI Nab responses were examined from 21 Kenyan women collectively exposed to subtypes A, C, and D and superinfected after a median time of ~1.07 years following initial infection. Plasma samples chosen for analysis were collected at a median time point ~2.72 years post-SI. Because previous studies of singly infected populations with broad and potent Nab responses have shown that the majority of their neutralizing activity can be mapped to 4 main epitopes on the HIV-1 Envelope, we focused on these targets, which include the CD4-binding site, a V1/V2 glycan, the N332 supersite in V3, and the membrane proximal external region of gp41. Using standard epitope mapping techniques that were applied to the previous cohorts, the present study demonstrates that SI did not induce a dominant Nab response to any one of these epitopes in the 21 women. Computational sera delineation analyses also suggested that 20 of the 21 superinfected women’s Nab responses could not be ascribed a single specificity with high confidence. These data are consistent with a model in which SI with diverse subtypes promotes the development of a broad polyclonal Nab response, and thus would provide support for vaccine designs using multivalent HIV immunogens to elicit a diverse repertoire of Nabs.</p></div

Comparison of data-merging methods with SVM attribute selection and classification in breast cancer gene expression

Background: DNA microarray data are used to identify genes which could be considered prognostic markers. However, due to the limited sample size of each study, the signatures are unstable in terms of the composing genes and may be limited in terms of performances. It is therefore of great interest to integrate different studies, thus increasing sample size.Results: In the past, several studies explored the issue of microarray data merging, but the arrival of new techniques and a focus on SVM based classification needed further investigation. We used distant metastasis prediction based on SVM attribute selection and classification to three breast cancer data sets.Conclusions: The results showed that breast cancer classification does not benefit from data merging, confirming the results found by other studies with different technique

Renal Effects of the Novel Selective Adenosine A1 Receptor Blocker SLV329 in Experimental Liver Cirrhosis in Rats

Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A1 receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A1 receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (−36.5%, p<0.05), especially in those receiving furosemide (−41.9%, p<0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17% vs. 54%, p<0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A1 receptor antagonists are clinically beneficial at different stages of liver cirrhosis

Characteristics of the Earliest Cross-Neutralizing Antibody Response to HIV-1

Recent cross-sectional analyses of HIV-1+ plasmas have indicated that broadly cross-reactive neutralizing antibody responses are developed by 10%–30% of HIV-1+ subjects. The timing of the initial development of such anti-viral responses is unknown. It is also unknown whether the emergence of these responses coincides with the appearance of antibody specificities to a single or multiple regions of the viral envelope glycoprotein (Env). Here we analyzed the cross-neutralizing antibody responses in longitudinal plasmas collected soon after and up to seven years after HIV-1 infection. We find that anti-HIV-1 cross-neutralizing antibody responses first become evident on average at 2.5 years and, in rare cases, as early as 1 year following infection. If cross-neutralizing antibody responses do not develop during the first 2–3 years of infection, they most likely will not do so subsequently. Our results indicate a potential link between the development of cross-neutralizing antibody responses and specific activation markers on T cells, and with plasma viremia levels. The earliest cross-neutralizing antibody response targets a limited number of Env regions, primarily the CD4-binding site and epitopes that are not present on monomeric Env, but on the virion-associated trimeric Env form. In contrast, the neutralizing activities of plasmas from subjects that did not develop cross-neutralizing antibody responses target epitopes on monomeric gp120 other than the CD4-BS. Our study provides information that is not only relevant to better understanding the interaction of the human immune system with HIV but may guide the development of effective immunization protocols. Since antibodies to complex epitopes that are present on the virion-associated envelope spike appear to be key components of earliest cross-neutralizing activities of HIV-1+ plasmas, then emphasis should be made to elicit similar antibodies by vaccination