The neurobiology of Etruscan shrew active touch

The Etruscan shrew, Suncus etruscus, is not only the smallest terrestrial mammal, but also one of the fastest and most tactile hunters described to date. The shrew's skeletal muscle consists entirely of fast-twitch types and lacks slow fibres. Etruscan shrews detect, overwhelm, and kill insect prey in large numbers in darkness. The cricket prey is exquisitely mechanosensitive and fast-moving, and is as big as the shrew itself. Experiments with prey replica show that shape cues are both necessary and sufficient for evoking attacks. Shrew attacks are whisker guided by motion- and size-invariant Gestalt-like prey representations. Shrews often attack their prey prior to any signs of evasive manoeuvres. Shrews whisk at frequencies of approximately 14 Hz and can react with latencies as short as 25–30 ms to prey movement. The speed of attacks suggests that shrews identify and classify prey with a single touch. Large parts of the shrew's brain respond to vibrissal touch, which is represented in at least four cortical areas comprising collectively about a third of the cortical volume. Etruscan shrews can enter a torpid state and reduce their body temperature; we observed that cortical response latencies become two to three times longer when body temperature drops from 36°C to 24°C, suggesting that endothermy contributes to the animal's high-speed sensorimotor performance. We argue that small size, high-speed behaviour and extreme dependence on touch are not coincidental, but reflect an evolutionary strategy, in which the metabolic costs of small body size are outweighed by the advantages of being a short-range high-speed touch and kill predator

Treatment of established status epilepticus in the elderly - a study protocol for a prospective multicenter double-blind comparative effectiveness trial (ToSEE)

Background!#!Status epilepticus (SE) is a common neurological emergency condition that especially affects the elderly and old population. Older people with SE frequently have non-convulsive SE (NCSE) and are also at special risk of suffering a poor outcome. The application of benzodiazepines fails to control SE in about one third of the cases. For benzodiazepine refractory SE (BRSE) in elderly, there is little evidence that would justify the choice of one of the commonly used antiepileptic drugs. The present study aims to generate evidence for the treatment of BRSE in this age group.!##!Methods!#!We will conduct a prospective, randomized, double-blind comparative effectiveness study in more than twenty hospitals in Germany over a four-year period. Four hundred and seventy-seven elderly patients (≥ 65 years old) diagnosed with BRSE will be allocated by 1:1 randomization to receive either levetiracetam or valproate. All types of SE will be considered. For the diagnosis NCSE a verification by EEG is required. Levetiracetam or valproate will be administered in one single infusion. The primary endpoint is the stable cessation of ictal activity 15 min after the start of infusion persisting for the following 45 min of observation. EEG recording is maintained over the whole observation period, clinical examinations are conducted in predefined intervals. In case of treatment success patients and study staff remain blinded until 60 min after the start of the infusion. Adverse events will be recorded until the end of the study. EEG data will be reviewed by two external independent experts. To obtain data about the further treatment of SE, intrahospital complications and the functional outcome in the short term the study participants will be observed until the day of discharge or day 30 whichever is earliest.!##!Discussion!#!ToSEE is the first study which shall deliver evidence for the SE-therapy in the elderly and old population in a controlled prospective comparator study. By design it also shall collect information about therapy regimes and outcome aspects of this disease.!##!Trial registration!#!The trial has been registered at the German Clinical Trials Register on 3 July, 2020 ( DRKS00022308 ,  https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022308 )

Association of drug transporter expression with mortality and progression-free survival in stage IV head and neck squamous cell carcinoma.

Drug transporters such as P-glycoprotein (ABCB1) have been associated with chemotherapy resistance and are considered unfavorable prognostic factors for survival of cancer patients. Analyzing mRNA expression levels of a subset of drug transporters by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or protein expression by tissue microarray (TMA) in tumor samples of therapy naïve stage IV head and neck squamous cell carcinoma (HNSCC) (qRT-PCR, n = 40; TMA, n = 61), this in situ study re-examined the significance of transporter expression for progression-free survival (PFS) and overall survival (OS). Data from The Cancer Genome Atlas database was used to externally validate the respective findings (n = 317). In general, HNSCC tended to lower expression of drug transporters compared to normal epithelium. High ABCB1 mRNA tumor expression was associated with both favorable progression-free survival (PFS, p = 0.0357) and overall survival (OS, p = 0.0535). Similar results were obtained for the mRNA of ABCC1 (MRP1, multidrug resistance-associated protein 1; PFS, p = 0.0183; OS, p = 0.038). In contrast, protein expression of ATP7b (copper transporter ATP7b), mRNA expression of ABCG2 (BCRP, breast cancer resistance protein), ABCC2 (MRP2), and SLC31A1 (hCTR1, human copper transporter 1) did not correlate with survival. Cluster analysis however revealed that simultaneous high expression of SLC31A1, ABCC2, and ABCG2 indicates poor survival of HNSCC patients. In conclusion, this study militates against the intuitive dogma where high expression of drug efflux transporters indicates poor survival, but demonstrates that expression of single drug transporters might indicate even improved survival. Prospectively, combined analysis of the 'transportome' should rather be performed as it likely unravels meaningful data on the impact of drug transporters on survival of patients with HNSCC

Mapping Social Behavior-Induced Brain Activation at Cellular Resolution in the Mouse

Summary Understanding how brain activation mediates behaviors is a central goal of systems neuroscience. Here, we apply an automated method for mapping brain activation in the mouse in order to probe how sex-specific social behaviors are represented in the male brain. Our method uses the immediate-early-gene c-fos, a marker of neuronal activation, visualized by serial two-photon tomography: the c-fos-GFP+ neurons are computationally detected, their distribution is registered to a reference brain and a brain atlas, and their numbers are analyzed by statistical tests. Our results reveal distinct and shared female and male interaction-evoked patterns of male brain activation representing sex discrimination and social recognition. We also identify brain regions whose degree of activity correlates to specific features of social behaviors and estimate the total numbers and the densities of activated neurons per brain areas. Our study opens the door to automated screening of behavior-evoked brain activation in the mouse

Mapping Social Behavior-Induced Brain Activation at Cellular Resolution in the Mouse

Understanding how brain activation mediates behaviors is a central goal of systems neuroscience. Here, we apply an automated method for mapping brain activation in the mouse in order to probe how sex-specific social behaviors are represented in the male brain. Our method uses the immediate-early-gene c-fos, a marker of neuronal activation, visualized by serial two-photon tomography: the c-fos-GFP+ neurons are computationally detected, their distribution is registered to a reference brain and a brain atlas, and their numbers are analyzed by statistical tests. Our results reveal distinct and shared female and male interaction-evoked patterns of male brain activation representing sex discrimination and social recognition. We also identify brain regions whose degree of activity correlates to specific features of social behaviors and estimate the total numbers and the densities of activated neurons per brain areas. Our study opens the door to automated screening of behavior-evoked brain activation in the mouse.Howard Hughes Medical InstituteGatsby Charitable Foundatio

mRNA expression of drug transporters in HNSCC.

<p>(A) Determination of mRNA expression levels of drug transporters by qRT-PCR in a study sample of therapy naïve stage IVa HNSCC tumors (n = 40, grey boxes) and normal control samples (n = 14, white boxes) (relative mRNA expression normalized to the lowest value). (B) External validation by HNSCC RNAseq mRNA expression data derived from the ‘The Cancer Genome Atlas’ (TCGA) consortium. Comparison of normalized counts of paired tumor (n = 37, grey boxes) and adjacent noncancerous normal tissue (n = 37, white boxes). Whisker indicates 5–95 percentile; Mann-Whitney U test; **, p<0.01; ***, p<0.001.</p

Hierarchical clustering of mRNA expression and survival of HNSCC patients.

<p>(A) Heatmap of the median normalized log2 transformed mRNA expressions hierarchically clustered with Euclidean distance matrix and complete linkage. Three distinct groups were uncovered: First group (n = 14) low expression of all drug transporters evaluated (#1, red framed), second group (n = 19) high <i>ABCB1</i> and high <i>ABCC1</i> expression (#2, yellow framed) and a third group (n = 7) showing low <i>ABCB1</i>/<i>ABCC1</i> expression but high levels of either <i>ABCG2</i>, <i>SLC31A1</i>, or <i>ABCC2</i> (#3, green framed). (B) Survival analysis by Kaplan-Meier curves and log rank test revealed that patients of group #3 (n = 7) tended to survive shorter than those of group #2 (n = 19). Best survival was seen for patients of group #1 (n = 14) who show a lower expression of drug transporters.</p

Correlation of high mRNA expression and shortened survival of HNSCC patients.

<p>Classification of HNSCC patients according to the expression level of the respective gene in high (n = 20) or low (n = 20) expression group. Survival analysis by Kaplan-Meier curves and log rank test revealed that patients with high gene expression tended to accompany a shorter progression-free and overall survival.</p