bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered synaptic transmission and maturation of hippocampal CA1 neurons in a mouse model of human chr16p11.2 microdeletion
Authors: Lu Hung-Chi , Mills Alea A. , Tian Di 
Published: December 2017

The pathophysiology of neurodevelopmental disorders is often observed early in infancy and toddlerhood. Mouse models of syndromic disorders have provided insight regarding mechanisms of action, but most studies have focused on characterization in juveniles and adults. Insight into developmental trajectories, particularly those related to circuit and synaptic function, will likely yield important information regarding disorder pathogenesis that leads to symptom progression. Chromosome 16p11.2 microdeletion is one of the most common copy number variations associated with a spectrum of neurodevelopmental disorders. Yet, how haploinsufficiency of chr16p11.2 affects early synaptic maturation and function is unknown. To address this knowledge gap, the present study focused on three key components of circuit formation and function, basal synaptic transmission, local circuit function, and maturation of glutamatergic synapses, in developing hippocampal CA1 neurons in a chr16p11.2 microdeletion mouse model. The data demonstrate increased excitability, imbalance in excitation and inhibition, and accelerated maturation of glutamatergic synapses in heterozygous deletion mutant CA1 neurons. Given the critical role of early synaptic development in shaping neuronal connectivity and circuitry formation, these newly identified synaptic abnormalities in chr16p11.2 microdeletion mice may contribute to altered developmental trajectory and function of the developing brain. NEW & NOTEWORTHY The synaptic pathophysiology underlying neurodevelopmental disorders often emerges during infancy and toddlerhood. Therefore, identifying initial changes in synaptic function is crucial for gaining a mechanistic understanding of the pathophysiology, which ultimately will facilitate the design of early interventions. Here, we investigated synaptic and local circuit properties of hippocampal CA1 neurons in a human chr16p11.2 microdeletion mouse model during early postnatal development (preweaning). The data demonstrate increased neuronal excitability, excitatory/inhibitory imbalance, and accelerated maturation of glutamatergic synapses. These perturbations in early hippocampal circuit function may underlie the early pathogenesis of the heterozygous chr16p11.2 microdeletion, which is often associated with epilepsy and intellectual disability.
Rhythmic arm cycling training improves walking and neurophysiological integrity in chronic stroke: the arms can give legs a helping hand in rehabilitation
Authors: Kaupp Chelsea , Pearcey Gregory E. P. , Klarner Taryn , Sun Yao , Cullen Hilary , Barss Trevor S. , Zehr E. Paul 
Published: December 2017

Training locomotor central pattern-generating networks (CPGs) through arm and leg cycling improves walking in chronic stroke. These outcomes are presumed to result from enhanced interlimb connectivity and CPG function. The extent to which rhythmic arm training activates interlimb CPG networks for locomotion remains unclear and was assessed by studying chronic stroke participants before and after 5 wk of arm cycling training. Strength was assessed bilaterally via maximal voluntary isometric contractions in the legs and hands. Muscle activation during arm cycling and transfer to treadmill walking were assessed in the more affected (MA) and less affected (LA) sides via surface electromyography. Changes to interlimb coupling during rhythmic movement were evaluated using modulation of cutaneous reflexes elicited by electrical stimulation of the superficial radial nerve at the wrist. Bilateral soleus stretch reflexes were elicited at rest and during 1-Hz arm cycling. Clinical function tests assessed walking, balance, and motor function. Results show significant changes in function and neurophysiological integrity. Training increased bilateral grip strength, force during MA plantarflexion, and muscle activation. “Normalization” of cutaneous reflex modulation was found during arm cycling. There was enhanced activity in the dorsiflexor muscles on the MA side during the swing phase of walking. Enhanced interlimb coupling was shown by increased modulation of MA soleus stretch reflex amplitudes during arm cycling after training. Clinical evaluations showed enhanced walking ability and balance. These results are consistent with training-induced changes in CPG function and interlimb connectivity and underscore the need for arm training in the functional rehabilitation of walking after neurotrauma.NEW & NOTEWORTHY It has been suggested but not tested that training the arms may influence rehabilitation of walking due to activation of interneuronal patterning networks after stroke. We show that arm cycling training improves strength, clinical function, coordination of muscle activity during walking, and neurological connectivity between the arms and the legs. The arms can, in fact, give the legs a helping hand in rehabilitation of walking after stroke.
Reward activations and face fields in monkey cingulate motor areas
Authors: Cléry Justine , Amiez Céline , Guipponi Olivier , Wardak Claire , Procyk Emmanuel , Ben Hamed Suliann 
Published: December 2017

Several premotor areas have been identified within primate cingulate cortex; however their function is yet to be uncovered. Recent brain imaging work in humans revealed a topographic anatomofunctional overlap between feedback processing during exploratory behaviors and the corresponding body fields in the rostral cingulate motor area (RCZa), suggesting an embodied representation of feedback. In particular, a face field in RCZa processes juice feedback. Here we tested an extension of the embodied principle in which unexpected or relevant information obtained through the eye or the face would be processed by face fields in cingulate motor areas, and whether this applied to monkey cingulate cortex. We show that activations for juice reward, eye movement, eye blink, and tactile stimulation on the face overlap over two subfields within the cingulate sulcus likely corresponding to the rostral and caudal cingulate motor areas. This suggests that in monkeys as is the case in humans, behaviorally relevant information is processed through multiple cingulate body/effector maps.NEW & NOTEWORTHY What is the role of cingulate motor areas? In this study we observed in monkeys that, as in humans, neural responses to face-related events, juice reward, eye movement, eye blink, and tactile stimulations, clustered redundantly in two separate cingulate subfields. This suggests that behaviorally relevant information is processed by multiple cingulate effector maps. Importantly, this overlap supports the principle that the cingulate cortex processes feedback based on where it is experienced on the body.
Done in 100 ms: path-dependent visuomotor transformation in the human upper limb
Authors: Gu Chao , Pruszynski J. Andrew , Gribble Paul L. , Corneil Brian D. 
Published: December 2017

A core assumption underlying mental chronometry is that more complex tasks increase cortical processing, prolonging reaction times. In this study we show that increases in task complexity alter the magnitude, rather than the latency, of the output for a circuit that rapidly transforms visual information into motor actions. We quantified visual stimulus-locked responses (SLRs), which are changes in upper limb muscle recruitment that evolve at a fixed latency ~100 ms after novel visual stimulus onset. First, we studied the underlying reference frame of the SLR by dissociating the initial eye and hand position. Despite its quick latency, we found that the SLR was expressed in a hand-centric reference frame, suggesting that the circuit mediating the SLR integrated retinotopic visual information with body configuration. Next, we studied the influence of planned movement trajectory, requiring participants to prepare and generate either curved or straight reaches in the presence of obstacles to attain the same visual stimulus location. We found that SLR magnitude was influenced by the planned movement trajectory to the same visual stimulus. On the basis of these results, we suggest that the circuit mediating the SLR lies in parallel to other well-studied corticospinal pathways. Although the fixed latency of the SLR precludes extensive cortical processing, inputs conveying information relating to task complexity, such as body configuration and planned movement trajectory, can preset nodes within the circuit underlying the SLR to modulate its magnitude. NEW & NOTEWORTHY We studied stimulus-locked responses (SLRs), which are changes in human upper limb muscle recruitment that evolve at a fixed latency ~100 ms after novel visual stimulus onset. We showed that despite its quick latency, the circuitry mediating the SLR transformed a retinotopic visual signal into a hand-centric motor command that is modulated by the planned movement trajectory. We suggest that the circuit generating the SLR is mediated through a tectoreticulospinal, rather than a corticospinal, pathway.
T-Cell Densities in Brain Metastases Are Associated with Patient Survival Times and Diffusion Tensor MRI Changes
Authors: Zakaria Rasheed , Platt-Higgins Angela , Rathi Nitika , Radon Mark , Das Sumit , Das Kumar , Bhojak Maneesh , Brodbelt Andrew , Chavredakis Emmanuel , Jenkinson Michael D. , Rudland Philip S. 
Published: December 2017

Abstract
Brain metastases are common and are usually detected by MRI. Diffusion tensor imaging (DTI) is a derivative MRI technique that can detect disruption of white matter tracts in the brain. We have matched preoperative DTI with image-guided sampling of the brain–tumor interface in 26 patients during resection of a brain metastasis and assessed mean diffusivity and fractional anisotropy (FA). The tissue samples were analyzed for vascularity, inflammatory cell infiltration, growth pattern, and tumor expression of proteins associated with growth or local invasion such as Ki67, S100A4, and MMP2, 9, and 13. A lower FA in the peritumoral region indicated more white matter tract disruption and independently predicted longer overall survival times (HR for death = 0.21; 95% confidence interval, 0.06–0.82; P = 0.024). Of all the biological markers studied, only increased density of CD3+ lymphocytes in the same region correlated with decreased FA (Mann–Whitney U, P = 0.037) as well as confounding completely the effect of FA on multivariate survival analyses. We conclude that the T-cell response to brain metastases is not a surrogate of local tumor invasion, primary cancer type, or aggressive phenotype and is associated with patient survival time regardless of these biological factors. Furthermore, it can be assayed by DTI, potentially offering a quick, noninvasive, clinically available method to detect an active immune microenvironment and, in principle, to measure susceptibility to immunotherapy.
Significance: These findings show that white matter tract integrity is degraded in areas where T-cell infiltration is highest, providing a noninvasive method to identify immunologically active microenvironments in secondary brain tumors. Cancer Res; 78(3); 610–6. ©2017 AACR.
Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors
Authors: Jardim Denis L. , de Melo Gagliato Débora , Giles Francis J. , Kurzrock Razelle 
Published: December 2017

Abstract
Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785–94. ©2017 AACR.
A Serum Protein Signature Associated with Outcome after Anti–PD-1 Therapy in Metastatic Melanoma
Authors: Weber Jeffrey S. , Sznol Mario , Sullivan Ryan J. , Blackmon Shauna , Boland Genevieve , Kluger Harriet M. , Halaban Ruth , Bacchiocchi Antonietta , Ascierto Paolo A. , Capone Mariaelena , Oliveira Carlos , Meyer Krista , Grigorieva Julia , Asmellash Senait G. , Roder Joanna , Roder Heinrich 
Published: December 2017

AbstractA mass spectrometry analysis was performed using serum from patients receiving checkpoint inhibitors to define baseline protein signatures associated with outcome in metastatic melanoma. Pretreatment serum was obtained from a development set of 119 melanoma patients on a trial of nivolumab with or without a multipeptide vaccine and from patients receiving pembrolizumab, nivolumab, ipilimumab, or both nivolumab and ipilimumab. Spectra were obtained using matrix-assisted laser desorption/ionization time of flight mass spectrometry. These data combined with clinical data identified patients with better or worse outcomes. The test was applied to five independent patient cohorts treated with checkpoint inhibitors and its biology investigated using enrichment analyses. A signature consisting of 209 proteins or peptides was associated with progression-free and overall survival in a multivariate analysis. The test performance across validation cohorts was consistent with the development set results. A pooled analysis, stratified by set, demonstrated a significantly better overall survival for “sensitive” relative to “resistant” patients, HR = 0.15 (95% confidence interval: 0.06–0.40, P &lt; 0.001). The test was also associated with survival in a cohort of ipilimumab-treated patients. Test classification was found to be associated with acute phase reactant, complement, and wound healing pathways. We conclude that a pretreatment signature of proteins, defined by mass spectrometry analysis and machine learning, predicted survival in patients receiving PD-1 blocking antibodies. This signature of proteins was associated with acute phase reactants and elements of wound healing and the complement cascade. This signature merits further study to determine if it identifies patients who would benefit from PD-1 blockade. Cancer Immunol Res; 6(1); 79–86. ©2017 AACR.
Genetic Testing in Pediatric Left Ventricular Noncompaction
Authors: Miller Erin M. , Hinton Robert B. , Czosek Richard , Lorts Angela , Parrott Ashley , Shikany Amy R. , Ittenbach Richard F. , Ware Stephanie M. 
Published: December 2017

Background—
Left ventricular noncompaction (LVNC) can occur in isolation or can co-occur with a cardiomyopathy phenotype or cardiovascular malformation. The yield of cardiomyopathy gene panel testing in infants, children, and adolescents with a diagnosis of LVNC is unknown. By characterizing a pediatric population with LVNC, we sought to determine the yield of cardiomyopathy gene panel testing, distinguish the yield of testing for LVNC with or without co-occurring cardiac findings, and define additional factors influencing genetic testing yield.

Methods and Results—

One hundred twenty-eight individuals diagnosed with LVNC at ≤21 years of age were identified, including 59% with idiopathic etiology, 32% with familial disease, and 9% with a syndromic or metabolic diagnosis. Overall, 75 individuals had either cardiomyopathy gene panel (n=65) or known variant testing (n=10). The yield of cardiomyopathy gene panel testing was 9%. The severity of LVNC by imaging criteria was not associated with positive genetic testing, co-occurring cardiac features, etiology, family history, or myocardial dysfunction. Individuals with isolated LVNC were significantly less likely to have a positive genetic testing result compared with those with LVNC and co-occurring cardiomyopathy (0% versus 12%, respectively;
P
<0.01).

Conclusions—
Genetic testing should be considered in individuals with cardiomyopathy co-occurring with LVNC. These data do not suggest an indication for cardiomyopathy gene panel testing in individuals with isolated LVNC in the absence of a family history of cardiomyopathy.
Functional Metabolomics Characterizes a Key Role for
N
-Acetylneuraminic Acid in Coronary Artery Diseases
Authors: Zhang Lei , Wei Ting-Ting , Li Yong , Li Jing , Fan Yong , Huang Feng-Qing , Cai Yuan-Yuan , Ma Gaoxiang , Liu Jin-Feng , Chen Qian-Qian , Wang Shi-Lei , Li Honglin , Alolga Raphael N. , Liu Baolin , Zhao Dong-Sheng , Shen Jian-Hua , Wang Xiang-Ming , Zhu Wei , Li Ping , Qi Lian-Wen 
Published: December 2017

Background:
As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms.

Methods:

A cohort of 2324 patients who underwent coronary angiography from 4 independent centers was studied. A combination of ultra–performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode was used for untargeted analysis of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liquid chromatography-mass spectrometry–based approach using isotope-labeled standard addition was subsequently performed for targeted analysis of the metabolic marker
N
-acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models.

Results:

We identified a total of 36 differential metabolites, 35 of which were confirmed with reference compounds. Elevation of Neu5Ac was observed in plasma during CAD progression in center 1 (
P
=4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-associated coiled-coil containing protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation–induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacological inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury.

Conclusions:
Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.
Astrocytic Lrp4 (Low-Density Lipoprotein Receptor–Related Protein 4) Contributes to Ischemia-Induced Brain Injury by Regulating ATP Release and Adenosine-A
2A
R (Adenosine A2A Receptor) Signaling
Authors: Ye Xin-Chun , Hu Jin-Xia , Li Lei , Li Qiang , Tang Fu-Lei , Lin Sen , Sun Dong , Sun Xiang-Dong , Cui Gui-Yun , Mei Lin , Xiong Wen-Cheng 
Published: December 2017

Background and Purpose—
Lrp4 (low-density lipoprotein receptor–related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis.

Methods—

The brain-specific Lrp4 conditional knockout mice (Lrp4
GFAP-Cre
), astrocytic-specific Lrp4 conditional knockout mice (Lrp4
GFAP-creER
), and their control mice (Lrp4
f/f
) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A
2A
R (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate,
d
-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured.

Results—

Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4
GFAP-Cre
and Lrp4
GFAP-creER
mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P
2
X
7
R or adenosine-A
2A
R signaling diminished Lrp4
GFAP-creER
’s protective effect.

Conclusions—

The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A
2A
R signaling.
Caring and Carers: Diplomatic Personnel and the Duty of Care
Authors: Leira Halvard 
Published: December 2017

Summary
This article deals with the duty of care that states hold in relation to their citizens abroad — more specifically, the double role of diplomatic personnel, as both providers and recipients of care. The focus of discussion is states’ duty of care for diplomatic personnel, raising questions of how this care can be balanced with the duty of care for citizens and how far this duty stretches. The article first emphasizes the threats, before focusing on the means of protection: evacuation; physical structures; and psychological care. A tension remains, for as states fulfil their duty of care towards personnel through increasing security, they might at the same time reduce their personnel’s capacity to provide care for citizens. One solution for this tension — outsourcing and local personnel — tests the limits of care.