VISTA as a ligand downregulates LPS-mediated inflammation in macrophages and neutrophils.

VISTA has been proposed to function both as a ligand and a receptor to dampen immune responses, although the role of VISTA as a ligand on myeloid cells has been largely ignored. We observed that a VISTA receptor is rapidly expressed on the surface of macrophages and neutrophils upon exposure to lipopolysaccharides (LPS). Importantly, treating LPS-stimulated macrophages and neutrophils ex vivo with a high-avidity agonist of the VISTA receptor (VISTA.COMP) results in the downregulation of pro-inflammatory cytokines and the increased expression of immunoregulatory genes. Finally, the in vivo administration of VISTA.COMP attenuated the rise in circulating TNFα, IL-6, and IL-12p40 in LPS-treated mice.

Predictors of neurosurgical intervention in complicated mild traumatic brain injury patients: a retrospective cohort study.

OBJECTIVES: To determine the predicting demographic, clinical and radiological factors for neurosurgical intervention in complicated mild traumatic brain injury (mTBI) patients. METHODS: Design: retrospective multicenter cohort study. Participants: patients aged ≥16 presenting to all level-I trauma centers in Quebec between 09/2016 and 12/2017 with mTBI(GCS 13-15) and complication on initial head CT (intracranial hemorrhage/skull fracture). Procedure: Consecutive medical records were reviewed and separated into two groups: no neurosurgical intervention and neurosurgical intervention (NSI). Main outcome: neurosurgical intervention. Analysis: multiple logistic regression model. RESULTS: Four hundred and seventy-eight patients were included and 40 underwent NSI. One patient had radiological deterioration but no clinical deterioration prior to surgery. Subdural hemorrhage ≥4 mm width (OR:3.755 [95% CI:1.290-10.928]) and midline shift (OR:7.507 [95% CI: 3.317-16.989]) increased the risk of NSI. Subarachnoid hemorrhage was associated with a lower risk of NSI (OR:0.312 [95% CI: 0.136-0.713]). All other intracranial hemorrhages were not associated with NSI. CONCLUSION: Radiological deterioration was not associated with the incidence of NSI. Subdural hemorrhage and midline shift should be predicting factors for neurosurgery. Some patients with isolated findings such as subarachnoid hemorrhage could be safely managed in their original center without being transferred to a level-I trauma center.

CD200 mimetic aptamer PEG-M49 markedly increases the therapeutic effects of pegylated liposomal doxorubicin in a mouse model of metastatic breast carcinoma: an effect independent of CD200 receptor 1.

We previously reported that CD200 overexpression in the host decreases progression and metastasis of the highly aggressive metastatic 4THM breast carcinoma. We have explored a possible synergistic interaction between the CD200 mimetic PEG-M49 and pegylated liposomal doxorubicin (Peg-Dox) in wild-type CD200 knockout (CD200-/-) and CD200 Receptor 1 knockout (CD200R1-/-) mice for the first time. A 4THM breast carcinoma model and three groups of BALB/c mice (wild type, CD200-/- and CD200R1-/-) were used. Five days after injection of tumor cells, mice were injected with Peg-Dox (ip, once a week) and PEG-M49 or a control aptamer (iv, every 3 days). Necropsies were performed either 12 (mid-point) or 24 (endpoint) days after injection and the extent of tumor growth, visceral metastasis and changes in the tumor-directed immune response were evaluated. PEG-M49 and Peg-Dox co-treatment induced complete tumor regression and loss of macroscopic lung metastasis in four out of seven WT mice. This synergistic anti-tumoral effect is thought to be due to Peg-M49-induced inhibition of Gr1 + CD11b + cells and Peg-Dox-induced increases in tumor-infiltrating CD8 + and CD8CD4 double-positive cells. Similar changes were observed in CD200R1-/- mice indicating that the primary effects of Peg-M49 are mediated by non-CD200R1 receptors. We also demonstrated for the first time that tumor growth, metastasis, and tumor infiltrating GR1 + CD11b + cells were markedly increased in CD200R1-/- mice, indicating an anti-inflammatory and protective role of CD200. CD200 mimetics might be a safe and effective immunomodulatory treatment in conjunction with classical chemotherapeutics for therapy of aggressive metastatic breast carcinoma.

Latent goal models for dynamic strategic interaction.

Understanding the principles by which agents interact with both complex environments and each other is a key goal of decision neuroscience. However, most previous studies have used experimental paradigms in which choices are discrete (and few), play is static, and optimal solutions are known. Yet in natural environments, interactions between agents typically involve continuous action spaces, ongoing dynamics, and no known optimal solution. Here, we seek to bridge this divide by using a "penalty shot" task in which pairs of monkeys competed against each other in a competitive, real-time video game. We modeled monkeys' strategies as driven by stochastically evolving goals, onscreen positions that served as set points for a control model that produced observed joystick movements. We fit this goal-based dynamical system model using approximate Bayesian inference methods, using neural networks to parameterize players' goals as a dynamic mixture of Gaussian components. Our model is conceptually simple, constructed of interpretable components, and capable of generating synthetic data that capture the complexity of real player dynamics. We further characterized players' strategies using the number of change points on each trial. We found that this complexity varied more across sessions than within sessions, and that more complex strategies benefited offensive players but not defensive players. Together, our experimental paradigm and model offer a powerful combination of tools for the study of realistic social dynamics in the laboratory setting.

Adapting the Canadian CT head rule age criteria for mild traumatic brain injury.

OBJECTIVE: With the ageing population, the prevalence of mild traumatic brain injury (mTBI) among older patients is increasing, and the age criteria of the Canadian CT head rule (CCHR) is challenged by many emergency physicians. We modified the age criteria of the CCHR to evaluate its predictive capacity. METHODS: We conducted a retrospective cohort study at a level 1 trauma centre ED of all mTBI patients 65 years old and over with an mTBI between 2010 and 2014. Main outcome was a clinically important brain injury (CIBI) reported on CT. The clinical and radiological data collection was standardised. Univariate analyses were performed to measure the predictive capacities of different age cut-offs at 70, 75 and 80 years old. RESULTS: 104 confirmed mTBI were included; CT scan identified 32 (30.8%) CIBI. Sensitivity and specificity (95% CI) of the CCHR were 100% (89.1 to 100) and 4.2% (0.9 to 11.7) for a modified criteria of 70 years old; 100% (89.1 to 100) and 13.9% (6.9 to 24.1) for 75 years old; and 90.6% (75.0 to 98.0) and 23.6% (14.4 to 35.1) for 80 years old. Furthermore, modifying the age criteria to 75 years old showed a reduction of CT up to 25% (n=10/41) among the individuals aged 65-74 without missing CIBI. CONCLUSION: Adjusting the age criteria of the Canadian CT head rule to 75 years old could be safe while reducing radiation and ED resources. A future prospective study is suggested to confirm the proposed modification.

Serum-derived carcinoembryonic antigen (CEA) activates fibroblasts to induce a local re-modeling of the extracellular matrix that favors the engraftment of CEA-expressing tumor cells.

Elevated levels of the carcinoembryonic antigen (CEA; CEACAM5) in the serum of colorectal cancer (CRC) patients represent a clinical biomarker that correlates with disease recurrence. However, a mechanistic role for soluble CEA (sCEA) in tumor progression and metastasis remains to be established. In our study, we report that sCEA acts as a paracrine factor, activating human fibroblasts by signaling through both the STAT3 and AKT1-mTORC1 pathways, promoting their transition to a cancer-associated fibroblast (CaF) phenotype. sCEA-activated fibroblasts express and secrete higher levels of fibronectin, including cellular EDA+ -fibronectin (Fn-EDA) that selectively promote the implantation and adherence of CEA-expressing cancer cells. Immunohistochemical analyses of liver tissues derived from CRC patients with elevated levels of sCEA reveal that the expression of cellular Fn-EDA co-registers with CEA-expressing liver metastases. Taken together, these findings indicate a direct role for sCEA as a human fibroblast activation factor, in priming target tissues for the engraftment of CEA-expressing cancer cells, through the differentiation of tissue-resident fibroblasts, resulting in a local change in composition of the extracellular matrix.

Induction of antigen-specific TH 9 immunity accompanied by mast cell activation blocks tumor cell engraftment.

The engraftment of circulating cancer cells at distal sites represents a key step in the metastatic cascade, yet remains an unexplored target for therapeutic intervention. In this study, we establish that a vaccination strategy yielding an antigen-specific TH 9 response induces long term host surveillance and prevents the engraftment of circulating cancer cells. Specifically, we show that vaccination with a recombinant CEA IgV-like N domain, formulated with the TLR3 ligand poly I:C, elicits a CEA-specific TH 9 response, wherein IL-9 secreting TH cells act in concert with CEA N domain-specific antibodies as well as activated mast cells in preventing tumor cell engraftment. The development of this immune response was dependent on TLR3, since interference with the TLR3-dsRNA complex formation led to a reduction in vaccine-imparted protection and a shift in the resulting immune response toward a TH 2 response. These findings point to the existence of an alternate tumor targeting immune mechanism that can be exploited for the purpose of developing vaccine therapies targeting tumor dissemination and engraftment.

Slow binding kinetics of secreted protein, acidic, rich in cysteine-VEGF interaction limit VEGF activation of VEGF receptor 2 and attenuate angiogenesis.

VEGF-A (VEGF) drives angiogenesis through activation of downstream effectors to promote endothelial cell proliferation and migration. Although VEGF binds both VEGF receptor 1 (R1) and receptor 2 (R2), its proangiogenic effects are attributed to R2. Secreted protein, acidic, rich in cysteine (SPARC) is a matricellular glycoprotein thought to inhibit angiogenesis by preventing VEGF from activating R1, but not R2. Because R2 rather than R1 mediates proangiogenic activities of VEGF, the role of human SPARC in angiogenesis was reevaluated. We confirm that association of SPARC with VEGF inhibits VEGF-induced HUVEC adherence, motility, and proliferation in vitro and blocks VEGF-induced blood vessel formation ex vivo. SPARC decreases VEGF-induced phosphorylation of R2 and downstream effectors ERK, Akt, and p38 MAPK as shown by Western blot and/or phosphoflow analysis. Surface plasmon resonance indicates that SPARC binds slowly to VEGF (0.865 ± 0.02 × 10(4) M(-1) s(-1)) with a Kd of 150 nM, forming a stable complex that dissociates slowly (1.26 ± 0.003 × 10(-3) s(-1)). Only domain III of SPARC binds VEGF, exhibiting a 15-fold higher affinity than full-length SPARC. These findings support a model whereby SPARC regulates angiogenesis by sequestering VEGF, thus restricting the activation of R2 and the subsequent activation of downstream targets critical for endothelial cell functions.

Patterns of joint parasympathetic, sympathetic, and adrenocortical activity and their associations with temperament in early childhood.

Evidence has accrued to show that autonomic and adrenocortical systems act in coordination to facilitate responses to environmental opportunities and threats. In the current study, we used cluster analysis to examine whether individual differences in patterns of joint baseline activity among the parasympathetic and sympathetic branches of the autonomic nervous system with the hypothalamic-pituitary-adrenal axis are associated with parent-reported temperamental positive and negative affectivity in 36-month old children. The resulting clusters corresponded to the sensitive, buffered, and vigilant patterns as predicted by the adaptive calibration model of stress responsivity (Del Giudice et al., 2011) and included a novel pattern. Cluster memberships predicted differences in overall negative affectivity and its subscales, but no associations were found with positive affectivity. These results provide evidence that the joint activity of physiological systems at rest may underlie temperamental differences in negative affect.

Specific neural substrate linking respiration to locomotion.

When animals move, respiration increases to adapt for increased energy demands; the underlying mechanisms are still not understood. We investigated the neural substrates underlying the respiratory changes in relation to movement in lampreys. We showed that respiration increases following stimulation of the mesencephalic locomotor region (MLR) in an in vitro isolated preparation, an effect that persists in the absence of the spinal cord and caudal brainstem. By using electrophysiological and anatomical techniques, including whole-cell patch recordings, we identified a subset of neurons located in the dorsal MLR that send direct inputs to neurons in the respiratory generator. In semi-intact preparations, blockade of this region with 6-cyano-7-nitroquinoxaline-2,3-dione and (2R)-amino-5-phosphonovaleric acid greatly reduced the respiratory increases without affecting the locomotor movements. These results show that neurons in the respiratory generator receive direct glutamatergic connections from the MLR and that a subpopulation of MLR neurons plays a key role in the respiratory changes linked to movement.

Parenting behaviors and vagal tone at six months predict attachment disorganization at twelve months.

The authors investigated the relationships among parenting behaviors, infant vagal tone, and subsequent attachment classification. Vagal tone was assessed among 6-month olds (n = 95) during the still-face paradigm (SFP) via respiratory sinus arrhythmia (RSA), while attachment security and disorganization were measured at 12 months during the strange situation procedure (SSP). Infants demonstrating higher levels of RSA during the normal interaction and reunion episodes of the SFP whose mothers were also rated as negative-intrusive exhibited higher levels of attachment disorganization at 12 months, while infants with lower RSA and mothers who were negative-intrusive did not exhibit higher levels of disorganization. These results suggest that high levels of RSA may not be adaptive within the context of negative-intrusive parenting.

NEURO.TV: Neuroscience Education on the Internet.

NEURO.tv is a new educational project that seeks to bring advanced concepts in neuroscience to the general public. We film one-hour discussions with leading neuroscientists, philosophers, and psychologists who have had significant impact on our current understanding of brain function, and we publish these discussions on YouTube, iTunes, and other social media outlets. Here, we explain the motivations behind this new program.

Broadly Applicable Bispecific Linker Approach to Noncovalently Target Therapeutic Nanoparticles to Tumor Cells Expressing Carcinoembryonic Antigen.

Design strategies that lead to a more focused in vivo delivery of functionalized nanoparticles (NPs) and their cargo can potentially maximize their therapeutic efficiency while reducing systemic effects, broadening their clinical applications. Here, we report the development of a noncovalent labeling approach where immunoglobulin G (IgG)-decorated NPs can be directed to a cancer cell using a simple, linear bispecific protein adaptor, termed MFE23-ZZ. MFE23-ZZ was created by fusing a single-chain fragment variable domain, termed MFE23, recognizing carcinoembryonic antigen (CEA) expressed on tumor cells, to a small protein ZZ module, which binds to the Fc fragment of IgG. As a proof of concept, monoclonal antibodies (mAbs) were generated against a NP coat protein, namely, gas vesicle protein A (GvpA) of Halobacterium salinarum gas vesicles (GVs). The surface of each GV was therapeutically derivatized with the photoreactive agent chlorin e6 (Ce6GVs) and anti-GvpA mAbs were subsequently bound to GvpA on the surface of each Ce6GV. The bispecific ligand MFE23-ZZ was then bound to mAb-decorated Ce6GVs via their Fc domain, resulting in a noncovalent tripartite complex, namely, MFE23.ZZ-2B10-Ce6GV. This complex enhanced the intracellular uptake of Ce6GVs into human CEA-expressing murine MC38 colon carcinoma cells (MC38.CEA) relative to the CEA-negative parental cell line MC38 in vitro, making them more sensitive to light-induced cell killing. These results suggest that the surface of NP can be rapidly and noncovalently functionalized to target tumor-associated antigen-expressing tumor cells using simple bispecific linkers and any IgG-labeled cargo. This noncovalent approach is readily applicable to other types of functionalized NPs.

Derivation of the Quebec Brain Injury Categories for complicated mild traumatic brain injuries.

OBJECTIVE: Approximately 10% of patients with mild traumatic brain injury (TBI) present with intracranial bleeding, and only 3.5% eventually require neurosurgical intervention, which often necessitates interhospital transfer. Better guidelines and recommendations are needed to manage complicated mild TBI in the emergency department (ED). The main objective of this study was to derive a clinical decision rule, the Quebec Brain Injury Categories (QueBIC), to predict the risk of adverse outcomes for complicated mild TBI in the ED. The secondary objective was to compare the QueBIC's performance with those of other existing guidelines. METHODS: The authors conducted a retrospective multicenter cohort study in 3 level I trauma centers. Consecutive patients with complicated mild TBI (Glasgow Coma Scale [GCS] score 13-15) who were aged ≥ 16 years were included. The primary outcome was a combination of neurosurgical intervention, mild TBI-related death, and clinical deterioration. Statistical analyses included set covering machine analyses. RESULTS: In total, 477 patients were included in the study. The mean age was 62.9 years, and 68.1% were male. The algorithm classified patients into three risk categories (low, moderate, and high risk). The high-risk group (128 patients) (subdural hemorrhage [SDH] width > 7 mm or any midline shift) presented a sensitivity of 84% (95% CI 71%-93%) and a specificity of 80% (95% CI 76%-84%) to detect neurosurgical intervention and mild TBI-related death, leaving 8 undetected cases. Patients in the moderate-risk group (169 patients) had at least 1 variable: SDH width > 4 mm, initial GCS score ≤ 14, > 1 intraparenchymal hemorrhage, or intraparenchymal hemorrhage width > 4 mm. The combined QueBIC high- and moderate-risk category had a sensitivity of 100% (95% CI 63%-100%) and a specificity of 53% (95% CI 47%-58%) to detect mild TBI-related death or neurosurgical intervention. The sensitivity and specificity values for clinical deterioration when no death or neurosurgical intervention occurred were 81% (95% CI 64%-93%) and 44% (95% CI 39%-49%), respectively. The remaining 180 patients (37.7%) did not meet any high-risk or moderate-risk criteria and were considered low risk. None had neurosurgical intervention or mild TBI-related death. Only 6 (3.3%) low-risk patients showed clinical deterioration. CONCLUSIONS: QueBIC is a safe and effective tool to guide the management of patients presenting to the ED with complicated mild TBI. It accurately identifies patients at low risk for specialized neurotrauma or neurosurgical care. Further validation is required before its use in EDs.

Brain games: toward a neuroecology of social behavior.

In the target article, Schilbach et al. defend a "second-person neuroscience" perspective that focuses on the neural basis of social cognition during live, ongoing interactions between individuals. We argue that a second-person neuroscience would benefit from formal approaches borrowed from economics and behavioral ecology and that it should be extended to social interactions in nonhuman animals.

Emerging insights into ethnic-specific TP53 germline variants.

The recent expansion of human genomics repositories has facilitated the discovery of novel TP53 variants in populations of different ethnic origins. Interpreting TP53 variants is a major clinical challenge because they are functionally diverse, confer highly variable predisposition to cancer (including elusive low-penetrance alleles), and interact with genetic modifiers that alter tumor susceptibility. Here, we discuss how a cancer risk continuum may relate to germline TP53 mutations on the basis of our current review of genotype-phenotype studies and an integrative analysis combining functional and sequencing datasets. Our study reveals that each ancestry contains a distinct TP53 variant landscape defined by enriched ethnic-specific alleles. In particular, the discovery and characterization of suspected low-penetrance ethnic-specific variants with unique functional consequences, including P47S (African), G334R (Ashkenazi Jewish), and rs78378222 (Icelandic), may provide new insights in terms of managing cancer risk and the efficacy of therapy. Additionally, our analysis highlights infrequent variants linked to milder cancer phenotypes in various published reports that may be underdiagnosed and require further investigation, including D49H in East Asians and R181H in Europeans. Overall, the sequencing and projected functions of TP53 variants arising within ethnic populations and their interplay with modifiers, as well as the emergence of CRISPR screens and AI tools, are now rapidly improving our understanding of the cancer susceptibility spectrum, leading toward more accurate and personalized cancer risk assessments.

The IgV domain of the poliovirus receptor alone is immunosuppressive and binds to its receptors with comparable affinity.

PVR (poliovirus receptor) functions as a ligand that signals through TIGIT and CD96 to induce suppression of T-cell and NK-cell responses. Alternatively, PVR binds to CD226, resulting in a co-stimulatory signal. To date, TIGIT antibody antagonists have been developed to restore immune functions and allow PVR to signal though CD226 in the context of cancer immunotherapy. Due to PVR receptor heterogeneity, agonizing either of these pathways with a recombinant form of the PVR extracellular domain represents a therapeutic strategy for either immunosuppression or activation. Here, we developed a minimal murine PVR-Fc fusion construct, consisting of only the IgV domain of PVR (vdPVR-Fc), and assessed its ability to dampen inflammatory responses in a murine model of psoriasis. vdPVR-Fc and PVR-Fc containing the full-length extracellular domain bound to TIGIT, CD96 and CD226 with similar low nanomolar affinities as defined by surface plasmon resonance. vdPVR-Fc was also able to suppress the in-vitro proliferation of murine CD4+ and CD8+ T-cells in mixed splenocyte cultures. Importantly, vdPVR-Fc delayed the onset, and reduced inflammatory responses (scaling and thickness) in a murine model of psoriasis. Collectively, our results suggest that the minimal IgV domain of PVR is sufficient to dampen immune responses in-vitro and attenuate symptoms of psoriasis in-vivo.

VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway.

Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases.

Residual flow after cerebral aneurysm coil occlusion: diagnostic accuracy of MR angiography.

BACKGROUND AND PURPOSE: The purpose of this study was to estimate the performance measures of MR angiography (MRA) in the diagnosis of aneurysm residual flow after coil occlusion. METHODS: Patients having at least 1 cerebral aneurysm treated with coil occlusion were prospectively and consecutively enrolled. Time of flight and contrast-enhanced MRA were performed the same day of the DSA follow-up. The degree of aneurysm occlusion and dimensions of the residual flow were evaluated by independent readers at MRA and digital subtraction angiogram. MRA performance measures were estimated in a cross-sectional analysis and repeated in subgroups of aneurysm sizes and locations. MRA predictive values for recurrence were also estimated using a longitudinal design. RESULTS: We obtained 167 aneurysm evaluations for each imaging modality. Class 3 residual flow was seen on digital subtraction angiogram follow-up in 27%. The sensitivity and specificity of MRA was 88% (95% CI, 80-94) and 79% (95% CI, 67-88), respectively. The positive predictive value for a Class 3 recurrence was 67% (95% CI, 51-80) and the negative predictive value was 93% (95% CI, 86-97). Time-of-flight MRA underestimated the length of the residual flow (P=0.039), whereas contrast-enhanced MRA overestimated its width (P<0.0001). MRA sensitivity for a Class 3 residual flow was lower for aneurysms <6 mm (P=0.01). CONCLUSIONS: MRA has sufficient accuracy for screening of aneurysm residual flow after coil occlusion. Due to its lower negative predictive value, recurrent aneurysms should be confirmed with digital subtraction angiogram before planning a retreatment. Routine use of MRA to follow small aneurysms should wait better estimation of its performance in this particular subgroup.

A focused immune response targeting the homotypic binding domain of the carcinoembryonic antigen blocks the establishment of tumor foci in vivo.

Metastatic forms of cancers remain the main cause of death in cancer patients. In this study, we demonstrate that directing a sustained antibody response towards the homotypic binding function of CEA interferes with the implantation and development of tumor foci in CEA-expressing transgenic (CEA.Tg) mice. Specifically, vaccinating CEA.Tg mice with a recombinant, altered self-form of the CEA Ig V-like N domain led to the production of circulating IgG1 and IgG2a antibodies that inhibited CEA-mediated adhesion of murine carcinoma expressing CEA (MC38.CEA) and mediated antibody-dependent lysis of tumor cells. Moreover, vaccinated CEA.Tg mice were resistant to the development of tumor nodules in the lungs and the peritoneal cavity, suggesting that mounting a focused antibody response to the CEA N domain may represent a simple therapeutic strategy to control the establishment of metastatic foci in cancer patients.