Synchronized activation of striatal direct and indirect pathways underlies the behavior in unilateral dopamine‐depleted mice

For more than three decades it has been known, that striatal neurons become hyperactive after the loss of dopamine input, but the involvement of dopamine (DA) D1‐ or D2‐receptor‐expressing neurons has only been demonstrated indirectly. By recording neuronal activity using fluorescent calcium indicators in D1 or D2 eGFP‐expressing mice, we showed that following dopamine depletion, both types of striatal output neurons are involved in the large increase in neuronal activity generating a characteristic cell assembly of particular neurons that dominate the pattern. When we expressed channelrhodopsin in all the output neurons, light activation in freely moving animals, caused turning like that following dopamine loss. However, if the light stimulation was patterned in pulses the animals circled in the other direction. To explore the neuronal participation during this stimulation we infected normal mice with channelrhodopsin and calcium indicator in striatal output neurons. In slices made from these animals, continuous light stimulation for 15 s induced many cells to be active together and a particular dominant group of neurons, whereas light in patterned pulses activated fewer cells in more variable groups. These results suggest that the simultaneous activity of a large dominant group of striatal output neurons is intimately associated with parkinsonian symptoms.     

The Neutrophil to Lymphocyte Ratio Predicts the Response to Neoadjuvant Chemotherapy in Luminal B Breast Cancer

Objective: Tumor response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients is a predictor foroverall survival. The aim of our study was to determine a relationship between the neutrophil to lymphocyte ratio(NLR) prior to NAC, BC subtypes and the probability of a pathologic complete response (pCR). Materials andMethods: Medical records were collected retrospectively from Centro de Cancer at Red Salud UC-Christus. Clinicaldata collected included peripheral blood cell counts, BC subtype at diagnosis and the pathology report of surgeryafter chemotherapy. Results: A total of 88 patients were analyzed. Approximately, a 25% had a pCR, and displayed asignificant correlation between BC subtype and pCR (p= 0.0138 Chi2); this was more frequent in epidermal growthfactor receptor type 2 (HER2) enriched subtype patients (54%). Luminal B BC patients with a pCR had significantlylower NLR levels (t test, p= 0.0181). Conclusions: HER2-enriched tumors had a higher probability of pCR. In LuminalB tumors, NLR had a statistically significant relationship with the probability of pCR. In this subtype, NLR could bea useful biomarker to predict tumor response to NAC. Further studies including other clinical parameters for systemicinflammation such as platelet counts, intratumoral NLR or body mass index could help identify patients that wouldget the most benefit from NAC.     

A novel fMRI paradigm to dissociate the behavioral and neural components of mixed‐strategy decision making from non‐strategic decisions in humans

During competitive interactions, such as predator–prey or team sports, the outcome of one's actions is dependent on both their own choices and those of their opponents. Success in these rivalries requires that individuals choose dynamically and unpredictably, often adopting a mixed strategy. Understanding the neural basis of strategic decision making is complicated by the fact that it recruits various cognitive processes that are often shared with non‐strategic forms of decision making, such as value estimation, working memory, response inhibition, response selection, and reward processes. Although researchers have explored neural activity within key brain regions during mixed‐strategy games, how brain activity differs in the context of strategic interactions versus non‐strategic choices is not well understood. We developed a novel behavioral paradigm to dissociate choice behavior during mixed‐strategy interactions from non‐strategic choices, and we used task‐based functional magnetic resonance imaging (fMRI) to contrast brain activation. In a block design, participants competed in the classic mixed‐strategy game, “matching pennies,” against a dynamic computer opponent designed to exploit predictability in players’ response patterns. Results were contrasted with a non‐strategic task that had comparable sensory input, motor output, and reward rate; thus, differences in behavior and brain activation reflect strategic processes. The mixed‐strategy game was associated with activation of a distributed cortico‐striatal network compared to the non‐strategic task. We propose that choosing in mixed‐strategy contexts requires additional cognitive demands present to a lesser degree during the control task, illustrating the strength of this design in probing function of cognitive systems beyond core sensory, motor, and reward processes.     

Cholinergic modulation of striatal microcircuits

The purpose of this review is to bridge the gap between earlier literature on striatal cholinergic interneurons and mechanisms of microcircuit interaction demonstrated with the use of newly available tools. It is well known that the main source of the high level of acetylcholine in the striatum, compared to other brain regions, is the cholinergic interneurons. These interneurons provide an extensive local innervation that suggests they may be a key modulator of striatal microcircuits. Supporting this idea requires the consideration of functional properties of these interneurons, their influence on medium spiny neurons, other interneurons, and interactions with other synaptic regulators. Here, we underline the effects of intrastriatal and extrastriatal afferents onto cholinergic interneurons and discuss the activation of pre‐ and postsynaptic muscarinic and nicotinic receptors that participate in the modulation of intrastriatal neuronal interactions. We further address recent findings about corelease of other transmitters in cholinergic interneurons and actions of these interneurons in striosome and matrix compartments. In addition, we summarize recent evidence on acetylcholine‐mediated striatal synaptic plasticity and propose roles for cholinergic interneurons in normal striatal physiology. A short examination of their role in neurological disorders such as Parkinson's, Huntington's, and Tourette's pathologies and dystonia is also included.     

Conserved residues in yeast initiator tRNA calibrate initiation accuracy by regulating preinitiation complex stability at the start codon

Eukaryotic initiator tRNA (tRNA_i) contains several highly conserved unique sequence features, but their importance in accurate start codon selection was unknown. Here we show that conserved bases throughout tRNA_i, from the anticodon stem to acceptor stem, play key roles in ensuring the fidelity of start codon recognition in yeast cells. Substituting the conserved G31:C39 base pair in the anticodon stem with different pairs reduces accuracy (the Sui⁻ [suppressor of initiation codon] phenotype), whereas eliminating base pairing increases accuracy (the Ssu⁻ [suppressor of Sui⁻] phenotype). The latter defect is fully suppressed by a Sui⁻ substitution of T-loop residue A54. These genetic data are paralleled by opposing effects of Sui⁻ and Ssu⁻ substitutions on the stability of methionylated tRNA_i (Met-tRNA_i) binding (in the ternary complex [TC] with eIF2-GTP) to reconstituted preinitiation complexes (PICs). Disrupting the C3:G70 base pair in the acceptor stem produces a Sui⁻ phenotype and also reduces the rate of TC binding to 40S subunits in vitro and in vivo. Both defects are suppressed by an Ssu⁻ substitution in eIF1A that stabilizes the open/P_OUT conformation of the PIC that exists prior to start codon recognition. Our data indicate that these signature sequences of tRNA_i regulate accuracy by distinct mechanisms, promoting the open/P_OUT conformation of the PIC (for C3:G70) or destabilizing the closed/P_IN state (for G31:C39 and A54) that is critical for start codon recognition.     

Acute surgical unit safely reduces unnecessary after-hours cholecystectomy

Introduction

The acute surgical model has been trialled in several institutions with mixed results. The aim of this study was to determine whether the acute surgical model provides better outcomes for patients with acute biliary presentation, compared with the traditional emergency surgery model of care.

Methods

A retrospective review was carried out of patients who were admitted for management of acute biliary presentation, before and after the establishment of an acute surgical unit (ASU). Outcomes measured were time to operation, operating time, after-hours operation (6pm – 8am), length of stay and surgical complications.

Results

A total of 342 patients presented with acute biliary symptoms and were managed operatively. The median time to operation was significantly reduced in the ASU group (32.4 vs 25.4 hours, p=0.047), as were the proportion of operations performed after hours (19.5% vs 2.5%, p<0.001) and the median length of stay (4 vs 3 days, p<0.001). The median operating time, rate of conversion to open cholecystectomy and wound infection rates remained similar.

Conclusions

Implementation of an ASU can lead to objective differences in outcomes for patients who present with acute cholecystitis. In our study, the ASU significantly reduced time to operation, the number of operations performed after hours and length of stay.