Psychiatric blood biomarkers: avoiding jumping to premature negative or positive conclusions

Blood biomarkers may provide a scientifically useful and clinically usable peripheral signal in psychiatry, as they have been doing for other fields of medicine. Jumping to premature conclusions, negative or positive, can create confusion in this field. Reproducibility is a hallmark of good science. We discuss some recent examples from this dynamic field, and show some new data in support of previously published biomarkers for suicidality (SAT1, MARCKS and SKA2). Methodological clarity and rigor in terms of biomarker discovery, validation and testing is needed. We propose a set of principles for what constitutes a good biomarker, similar in spirit to the Koch postulates used at the birth of the field of infectious diseases

Direct Observation of Quark-Hadron Duality in the Free Neutron F\u3csub\u3e2\u3c/sub\u3e Structure Function

Using the recently published data from the BONuS(Barely Off-shell Nucleon Structure) experiment at Jefferson Lab, which utilized a spectator tagging technique to extract the inclusive electron-free neutron scattering cross section, we obtain the first direct observation of quark-hadron duality in the neutron F2 structure function. The data are used to reconstruct the lowest few (N = 2, 4, and 6) moments of F2 in the three prominent nucleon resonance regions, as well as the moments integrated over the entire resonance region. Comparison with moments computed from global parametrizations of parton distribution functions suggest that quark-hadron duality holds locally for the neutron in the second and third resonance regions down to Q2 approximate to 1 GeV2, with violations possibly up to 20% observed in the first resonance region

Precision medicine for suicidality: from universality to subtypes and personalization

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a ‘liquid biopsy’ approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator

Significance of solutions of the inverse Biot-Savart problem in thick superconductors

The evaluation of current distributions in thick superconductors from field profiles near the sample surface is investigated theoretically. A simple model of a cylindrical sample, in which only circular currents are flowing, reduces the inversion to a linear least squares problem, which is analyzed by singular value decomposition. Without additional assumptions about the current distribution (e.g. constant current over the sample thickness), the condition of the problem is very bad, leading to unrealistic results. However, any additional assumption strongly influences the solution and thus renders the solutions again questionable. These difficulties are unfortunately inherent to the inverse Biot-Savart problem in thick superconductors and cannot be avoided by any models or algorithms

Moments of the Proton F2 Structure Function at Low Q2

The Q^2 dependence of inclusive electron-proton scattering F_2 structure function data in both the nucleon resonance region and the deep inelastic region, at momentum transfers below 5 (GeV/c)^2, is investigated. Moments of F_2 are constructed, down to momentum transfers of Q^2 ~ 0.1 (GeV/c)^2. The second moment is only slowly varying with Q^2 down to Q^2 ~ 1 (GeV/c)^2, which is a reflection of duality. Below Q^2 of 1 (GeV/c)^2, the Q^2 dependence of the moments is predominantly governed by the elastic contribution, whereas the inelastic channels still seem governed by local duality.Comment: 11 page paper, 1 LaTeX file, 10 postscript figure file

All Who Wander: On the Prevalence and Characteristics of Multi-community Engagement

Although analyzing user behavior within individual communities is an active and rich research domain, people usually interact with multiple communities both on- and off-line. How do users act in such multi-community environments? Although there are a host of intriguing aspects to this question, it has received much less attention in the research community in comparison to the intra-community case. In this paper, we examine three aspects of multi-community engagement: the sequence of communities that users post to, the language that users employ in those communities, and the feedback that users receive, using longitudinal posting behavior on Reddit as our main data source, and DBLP for auxiliary experiments. We also demonstrate the effectiveness of features drawn from these aspects in predicting users' future level of activity. One might expect that a user's trajectory mimics the "settling-down" process in real life: an initial exploration of sub-communities before settling down into a few niches. However, we find that the users in our data continually post in new communities; moreover, as time goes on, they post increasingly evenly among a more diverse set of smaller communities. Interestingly, it seems that users that eventually leave the community are "destined" to do so from the very beginning, in the sense of showing significantly different "wandering" patterns very early on in their trajectories; this finding has potentially important design implications for community maintainers. Our multi-community perspective also allows us to investigate the "situation vs. personality" debate from language usage across different communities.Comment: 11 pages, data available at https://chenhaot.com/pages/multi-community.html, Proceedings of WWW 2015 (updated references

Cascades: A view from Audience

Cascades on online networks have been a popular subject of study in the past decade, and there is a considerable literature on phenomena such as diffusion mechanisms, virality, cascade prediction, and peer network effects. However, a basic question has received comparatively little attention: how desirable are cascades on a social media platform from the point of view of users? While versions of this question have been considered from the perspective of the producers of cascades, any answer to this question must also take into account the effect of cascades on their audience. In this work, we seek to fill this gap by providing a consumer perspective of cascade. Users on online networks play the dual role of producers and consumers. First, we perform an empirical study of the interaction of Twitter users with retweet cascades. We measure how often users observe retweets in their home timeline, and observe a phenomenon that we term the "Impressions Paradox": the share of impressions for cascades of size k decays much slower than frequency of cascades of size k. Thus, the audience for cascades can be quite large even for rare large cascades. We also measure audience engagement with retweet cascades in comparison to non-retweeted content. Our results show that cascades often rival or exceed organic content in engagement received per impression. This result is perhaps surprising in that consumers didn't opt in to see tweets from these authors. Furthermore, although cascading content is widely popular, one would expect it to eventually reach parts of the audience that may not be interested in the content. Motivated by our findings, we posit a theoretical model that focuses on the effect of cascades on the audience. Our results on this model highlight the balance between retweeting as a high-quality content selection mechanism and the role of network users in filtering irrelevant content

Trk: a neuromodulator of age-specific behavioral and neurochemical responses to cocaine in mice.

Responses to psychostimulants vary with age, but the molecular etiologies of these differences are largely unknown. The goal of the present research was to identify age-specific behavioral and molecular adaptations to cocaine and to elucidate the mechanisms involved therein. Postweanling, periadolescent, and adult male CD-1 mice were exposed to cocaine (20 mg/kg) for 7 d. The rewarding effects of cocaine were assessed, as were the response to a Trk antagonist and the regulation of dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32). Cocaine was rewarding in both periadolescent and adult mice using a conditioned place preference procedure. In contrast, postweanling mice failed to demonstrate significant cocaine-induced place preference. Because components of the neurotrophin system including brain-derived neurotrophic factor and TrkB are developmentally regulated, their role in the age-specific effects of cocaine was determined using the Trk receptor antagonist K252a. Postweanling mice that received K252a before daily cocaine showed a significant place preference to the cocaine-paired environment that was not seen in the absence of K252a. DARPP-32 protein levels were significantly upregulated in the lateral region of the caudate-putamen exclusively in postweanling mice after chronic cocaine. Daily pretreatment with K252a attenuated the induction of DARPP-32 in the postweanling striatum. These data indicate that Trk neurotransmission plays a role in age-specific behavioral and molecular responses to cocaine and concurrently modulates DARPP-32 levels

Local Duality Predictions for x ~ 1 Structure Functions

Recent data on the proton F_2 structure function in the resonance region suggest that local quark-hadron duality works remarkably well for each of the low-lying resonances, including the elastic, to rather low values of Q^2. We derive model-independent relations between structure functions at x ~ 1 and elastic electromagnetic form factors, and predict the x -> 1 behavior of nucleon polarization asymmetries and the neutron to proton structure function ratios from available data on nucleon electric and magnetic form factors.Comment: 10 pages, 2 figures, typos in Eq. (2) correcte

Comment on "Nucleon elastic form factors and local duality"

We comment on the papers "Nucleon elastic form factors and local duality" [Phys. Rev. {\bf D62}, 073008 (2000)] and "Experimental verification of quark-hadron duality" [Phys. Rev. Lett. {\bf 85}, 1186 (2000)]. Our main comment is that the reconstruction of the proton magnetic form factor, claimed to be obtained from the inelastic scaling curve thanks to parton-hadron local duality, is affected by an artifact.Comment: to appear in Phys. Rev.