Humans often rank craniofacial pain as more severe than body pain. Evidence suggests that a stimulus of the same intensity induces stronger pain in the face than in the body. However, the underlying ...neural circuitry for the differential processing of facial versus bodily pain remains unknown. Interestingly, the lateral parabrachial nucleus (PB
), a critical node in the affective pain circuit, is activated more strongly by noxious stimulation of the face than of the hindpaw. Using a novel activity-dependent technology called CANE developed in our laboratory, we identified and selectively labeled noxious-stimulus-activated PB
neurons and performed comprehensive anatomical input-output mapping. Surprisingly, we uncovered a hitherto uncharacterized monosynaptic connection between cranial sensory neurons and the PB
-nociceptive neurons. Optogenetic activation of this monosynaptic craniofacial-to-PB
projection induced robust escape and avoidance behaviors and stress calls, whereas optogenetic silencing specifically reduced facial nociception. The monosynaptic circuit revealed here provides a neural substrate for heightened craniofacial affective pain.
BACKGROUND:Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain conditions to a variant of ...the catechol-O-methyltransferase (COMT), ValMet. This variant confers reduced enzymatic activity and results in higher synaptic dopamine levels. Here we examined the role of ValMet as a predictor of DNP in HIV-SN.
METHODS:In 1044 HIV-infected individuals enrolled in CNS HIV Antiretroviral Therapy Effects Research, an observational study across six US institutions, we characterized the relationship between ValMet and DNP in HIV-SN. Participants underwent neurologic examination and genotyping. Stratification into genetic ancestry groups was employed to eliminate bias due to genetic background.
FINDINGS:Of 590 participants with HIV-SN, 38% endorsed DNP, 24% reported nonpainful symptoms of neuropathy (paresthesia and numbness), and 38% were asymptomatic. Compared with asymptomatic HIV-SN, ValMet was associated with 2.3 higher odds of DNP. There were no increased odds of nonpainful symptoms. The association remained significant after controlling for other risk factors for DNPlifetime diagnosis of depression, older age, ancestry, cumulative exposure to dideoxynucleoside antiretrovirals, diabetes, and nadir CD4. Stratified by genetic ancestry, the association between ValMet and DNP was significant in European and African genetic ancestry.
INTERPRETATION:ValMet may be a genetic marker for susceptibility to DNP in HIV-SN. Our findings support the notion that differences in pain processing mediated by COMT-related dopamine signaling play a role in susceptibility to DNP in HIV-SN. Because prior studies suggest that the COMT allele may influence dose-response relationships with opioid treatment, knowing COMT genotype could influence management.
We developed a strategy to harness alkyl amines as alkylating agents via C–N bond activation. This Suzuki–Miyaura cross coupling of alkylpyridinium salts, readily formed from primary amines, is the ...first example of a metal-catalyzed cross coupling via C–N bond activation of an amine with an unactivated alkyl group. This reaction enjoys broad scope and functional group tolerance. Primary and secondary alkyl groups can be installed. Preliminary studies suggest a NiI/NiIII catalytic cycle.
Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) ...overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBMxenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.
Individuals do not respond uniformly to treatments, such as events or interventions. Sociologists routinely partition samples into subgroups to explore how the effects of treatments vary by selected ...covariates, such as race and gender, on the basis of theoretical priors. Data-driven discoveries are also routine, yet the analyses by which sociologists typically go about them are often problematic and seldom move us beyond our biases to explore new meaningful subgroups. Emerging machine learning methods based on decision trees allow researchers to explore sources of variation that they may not have previously considered or envisaged. In this article, the authors use tree-based machine learning, that is, causal trees, to recursively partition the sample to uncover sources of effect heterogeneity. Assessing a central topic in social inequality, college effects on wages, the authors compare what is learned from covariate and propensity score–based partitioning approaches with recursive partitioning based on causal trees. Decision trees, although superseded by forests for estimation, can be used to uncover subpopulations responsive to treatments. Using observational data, the authors expand on the existing causal tree literature by applying leaf-specific effect estimation strategies to adjust for observed confounding, including inverse propensity weighting, nearest neighbor matching, and doubly robust causal forests. We also assess localized balance metrics and sensitivity analyses to address the possibility of differential imbalance and unobserved confounding. The authors encourage researchers to follow similar data exploration practices in their work on variation in sociological effects and offer a straightforward framework by which to do so.
PDF
