Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening.

Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.

What is the role of the hippocampus and parahippocampal gyrus in the persistence of tinnitus?

The hippocampus and parahippocampal gyrus have been implicated as part of a tinnitus network by a number of studies. These structures are usually considered in the context of a "limbic system," a concept typically invoked to explain the emotional response to tinnitus. Despite this common framing, it is not apparent from current literature that this is necessarily the main functional role of these structures in persistent tinnitus. Here, we highlight a different role that encompasses their most commonly implicated functional position within the brain-that is, as a memory system. We consider tinnitus as an auditory object that is held in memory, which may be made persistent by associated activity from the hippocampus and parahippocampal gyrus. Evidence from animal and human studies implicating these structures in tinnitus is reviewed and used as an anchor for this hypothesis. We highlight the potential for the hippocampus/parahippocampal gyrus to facilitate maintenance of the memory of the tinnitus percept via communication with auditory cortex, rather than (or in addition to) mediating emotional responses to this percept.

Theta oscillations within right dorsolateral prefrontal cortex contribute differently to speech versus limb inhibition.

Evidence suggests that speech and limb movement inhibition are subserved by common neural mechanisms, particularly within the right prefrontal cortex. In a recent study, we found that cathodal stimulation of right dorsolateral prefrontal cortex (rDLPFC) differentially modulated P3 event-related potentials for speech versus limb inhibition. In the present study, we further analyzed these data to examine the effects of cathodal high-definition transcranial direct current stimulation (HD-tDCS) over rDLPFC on frontal theta - an oscillatory marker of cognitive control - in response to speech and limb inhibition, during a Go/No-Go task in 21 neurotypical adults. Electroencephalography data demonstrated that both speech and limb No-Go elicited prominent theta activity over right prefrontal electrodes, with stronger activity for speech compared to limb. Moreover, we found that cathodal stimulation significantly increased theta power over right prefrontal electrodes for speech versus limb No-Go. Source analysis revealed that cathodal, but not sham, stimulation increased theta activity within rDLPFC and bilateral premotor cortex for speech No-Go compared to limb movement inhibition. These findings complement our previous report and suggest (1) right prefrontal theta activity is an amodal oscillatory mechanism supporting speech and limb inhibition, (2) larger theta activity in prefrontal electrodes for speech versus limb following cathodal stimulation may reflect allocation of additional neural resources for a more complex motor task, such as speech compared to limb movement. These findings have translational implications for conditions such as Parkinson's disease, wherein both speech and limb movement are impaired.

Distribution of multiunit pitch responses recorded intracranially from human auditory cortex.

The perception of pitch is a fundamental percept, which is mediated by the auditory system, requiring the abstraction of stimulus properties related to the spectro-temporal structure of sound. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to species differences or differences in the recording measures and choices of stimuli used in previous studies. Moreover, it was unknown whether the human brain contains pitch neurons and how distributed such neurons might be. Here, we present the first study to measure multiunit neural activity in response to pitch stimuli in the auditory cortex of intracranially implanted humans. The stimulus sets were regular-interval noise with a pitch strength that is related to the temporal regularity and a pitch value determined by the repetition rate and harmonic complexes. Specifically, we demonstrate reliable responses to these different pitch-inducing paradigms that are distributed throughout Heschl's gyrus, rather than being localized to a particular region, and this finding was evident regardless of the stimulus presented. These data provide a bridge across animal and human studies and aid our understanding of the processing of a critical percept associated with acoustic stimuli.

Mimicry in misophonia: A large-scale survey of prevalence and relationship with trigger sounds.

BACKGROUND: Misophonia is often referred to as a disorder that is characterized by excessive negative emotional responses, including anger and anxiety, to "trigger sounds" which are typically day-to-day sounds, such as those generated from people eating, chewing, and breathing. Misophonia (literally "hatred of sounds") has commonly been understood within an auditory processing framework where sounds cause distress due to aberrant processing in the auditory and emotional systems of the brain. However, a recent proposal suggests that it is the perceived action (e.g., mouth movement in eating/chewing sounds as triggers) of the trigger person, and not the sounds per se, that drives the distress in misophonia. Since observation or listening to sounds of actions of others are known to prompt mimicry in perceivers, we hypothesized that mimicking the action of the trigger person may be prevalent in misophonia. Apart from a few case studies and anecdotal information, a relation between mimicking and misophonia has not been systematically evaluated. METHOD: In this work, we addressed this limitation by collecting data on misophonia symptoms and mimicry behavior using online questionnaires from 676 participants. RESULTS: Analysis of these data shows that (i) more than 45% of individuals with misophonia reported mimicry, indicating its wide prevalence, (ii) the tendency to mimic varies in direct proportion to misophonia severity, (iii) compared to other human and environmental sounds, trigger sounds of eating and chewing are more likely to trigger mimicking, and (iv) the act of mimicking provides some degree of relief from distress to people with misophonia. CONCLUSION: This study shows prevalence of mimicry and its relation to misophonia severity and trigger types. The theoretical framework of misophonia needs to incorporate the phenomenon of mimicry and its effect on management of misophonia distress.

High-definition transcranial direct current stimulation over right dorsolateral prefrontal cortex differentially modulates inhibitory mechanisms for speech vs. limb movement.

Evidence suggests that planning and execution of speech and limb movement are subserved by common neural substrates. However, less is known about whether they are supported by a common inhibitory mechanism. P3 event-related potentials (ERPs) is a neural signature of motor inhibition, which are found to be generated by several brain regions including the right dorsolateral prefrontal cortex (rDLPFC). However, the relative contribution of rDLPFC to the P3 response associated with speech versus limb inhibition remains elusive. We investigated the contribution of rDLPFC to the P3 underlying speech versus limb movement inhibition. Twenty-one neurotypical adults received both cathodal and sham high-definition transcranial direct current stimulation (HD-tDCS) over rDLPFC. ERPs were subsequently recorded while subjects were performing speech and limb Go/No-Go tasks. Cathodal HD-tDCS decreased accuracy for speech versus limb No-Go. Both speech and limb No-Go elicited a similar topographical distribution of P3, with significantly larger amplitudes for speech versus limb at a frontocentral location following cathodal HD-tDCS. Moreover, results showed stronger activation in cingulate cortex and rDLPFC for speech versus limb No-Go following cathodal HD-tDCS. These results indicate (1) P3 is an ERP marker of amodal inhibitory mechanisms that support both speech and limb inhibition, (2) larger P3 for speech versus limb No-Go following cathodal HD-tDCS may reflect the recruitment of additional neural resources-particularly within rDLPFC and cingulate cortex-as compensatory mechanisms to counteract the temporary stimulation-induced decline in speech inhibitory process. These findings have translational implications for neurological conditions that concurrently affect speech and limb movement.

Neural Correlates of Individual Differences in Speech-in-Noise Performance in a Large Cohort of Cochlear Implant Users.

OBJECTIVES: Understanding speech-in-noise (SiN) is a complex task that recruits multiple cortical subsystems. Individuals vary in their ability to understand SiN. This cannot be explained by simple peripheral hearing profiles, but recent work by our group ( Kim et al. 2021 , Neuroimage ) highlighted central neural factors underlying the variance in SiN ability in normal hearing (NH) subjects. The present study examined neural predictors of SiN ability in a large cohort of cochlear-implant (CI) users. DESIGN: We recorded electroencephalography in 114 postlingually deafened CI users while they completed the California consonant test: a word-in-noise task. In many subjects, data were also collected on two other commonly used clinical measures of speech perception: a word-in-quiet task (consonant-nucleus-consonant) word and a sentence-in-noise task (AzBio sentences). Neural activity was assessed at a vertex electrode (Cz), which could help maximize eventual generalizability to clinical situations. The N1-P2 complex of event-related potentials (ERPs) at this location were included in multiple linear regression analyses, along with several other demographic and hearing factors as predictors of SiN performance. RESULTS: In general, there was a good agreement between the scores on the three speech perception tasks. ERP amplitudes did not predict AzBio performance, which was predicted by the duration of device use, low-frequency hearing thresholds, and age. However, ERP amplitudes were strong predictors for performance for both word recognition tasks: the California consonant test (which was conducted simultaneously with electroencephalography recording) and the consonant-nucleus-consonant (conducted offline). These correlations held even after accounting for known predictors of performance including residual low-frequency hearing thresholds. In CI-users, better performance was predicted by an increased cortical response to the target word, in contrast to previous reports in normal-hearing subjects in whom speech perception ability was accounted for by the ability to suppress noise. CONCLUSIONS: These data indicate a neurophysiological correlate of SiN performance, thereby revealing a richer profile of an individual's hearing performance than shown by psychoacoustic measures alone. These results also highlight important differences between sentence and word recognition measures of performance and suggest that individual differences in these measures may be underwritten by different mechanisms. Finally, the contrast with prior reports of NH listeners in the same task suggests CI-users performance may be explained by a different weighting of neural processes than NH listeners.

Novelty-induced frontal-STN networks in Parkinson's disease.

Novelty detection is a primitive subcomponent of cognitive control that can be deficient in Parkinson's disease (PD) patients. Here, we studied the corticostriatal mechanisms underlying novelty-response deficits. In participants with PD, we recorded from cortical circuits with scalp-based electroencephalography (EEG) and from subcortical circuits using intraoperative neurophysiology during surgeries for implantation of deep brain stimulation (DBS) electrodes. We report three major results. First, novel auditory stimuli triggered midfrontal low-frequency rhythms; of these, 1-4 Hz "delta" rhythms were linked to novelty-associated slowing, whereas 4-7 Hz "theta" rhythms were specifically attenuated in PD. Second, 32% of subthalamic nucleus (STN) neurons were response-modulated; nearly all (94%) of these were also modulated by novel stimuli. Third, response-modulated STN neurons were coherent with midfrontal 1-4 Hz activity. These findings link scalp-based measurements of neural activity with neuronal activity in the STN. Our results provide insight into midfrontal cognitive control mechanisms and how purported hyperdirect frontobasal ganglia circuits evaluate new information.

Speech artifact is also present in spike data.

Bush et al. (2022) highlight that brain recordings examining speech production can be significantly affected by microphonic artifact, which would change the interpretation of these kinds of data. While these findings are vital in determining whether data are artifactual or physiological in origin, frequencies were only examined up to 250 Hz (i.e., local field potentials), which would imply that spike-related data (single or multi-neuron recordings) are unaffected. We highlight here that this type of contamination may also be present in unit recordings, with the same aim to understand genuine neural mechanisms rather than mis-interpreting artifactual data.

Indirect effects of African megaherbivore conservation on bat diversity in the world's oldest desert.

In extreme environments, temperature and precipitation are often the main forces responsible for structuring ecological communities and species distributions. The role of biotic interactions is typically thought to be minimal. By clustering around rare and isolated features, like surface water, however, effects of herbivory by desert-dwelling wildlife can be amplified. Understanding how species interact in these environments is critical to safeguarding vulnerable or data-deficient species. We examined whether African elephants (Loxodonta africana), black rhinoceros (Diceros bicornis), and southern giraffe (Giraffa giraffa) modulate insectivorous bat communities around permanent waterholes in the Namib Desert. We estimated megaherbivore use of sites based on dung transects, summarized vegetation productivity from satellite measurements of the normalized difference vegetation index, and surveyed local bat communities acoustically. We used structural equation models to identify relationships among megaherbivores and bat species richness and dry- (November 2016-January 2017) and wet- (February-May 2017) season bat activity. Site-level megaherbivore use in the dry season was positively associated with bat activity-particularly that of open-air foragers-and species richness through indirect pathways. When resources were more abundant (wet season), however, these relationships were weakened. Our results indicate that biotic interactions contribute to species distributions in desert areas and suggest the conservation of megaherbivores in this ecosystem may indirectly benefit insectivorous bat abundance and diversity. Given that how misunderstood and understudied most bats are relative to other mammals, such findings suggest that managers pursue short-term solutions (e.g., community game guard programs, water-point protection near human settlements, and ecotourism) to indirectly promote bat conservation and that research includes megaherbivores' effects on biodiversity at other trophic levels.

Efectos Indirectos de la Conservación de Mega Herbívoros Africanos sobre la Diversidad de Murciélagos en el Desierto Más Antiguo del Mundo Resumen Es común que en los ambientes extremos la temperatura y la precipitación sean las principales responsables de la estructura en las comunidades ecológicas y en la distribución de las especies. Con frecuencia se cree que el papel de las interacciones bióticas en estas características es mínimo. Sin embargo, si nos enfocamos en características raras y aisladas, como el agua superficial, los efectos de la herbivoría ocasionada por la fauna del desierto puede ser amplificada. El entendimiento de cómo las especies interactúan en estos ambientes es importante para salvaguardar a las especies vulnerables o con datos insuficientes. Examinamos si los elefantes africanos (Loxodonta africana), los rinocerontes negros (Diceros bicornis) y la jirafa sureña (Giraffa giraffa) modulan las comunidades de murciélagos insectívoros alrededor de los abrevaderos permanentes en el Desierto del Namib. Estimamos el uso que le dan los mega herbívoros a ciertos sitios con base en transectos, en la productividad de la vegetación resumida a partir de las medidas satelitales del índice normalizado de diferencias en la vegetación (INDV) y en censos acústicos de las comunidades locales de murciélagos. Usamos modelos de ecuaciones estructurales para identificar las relaciones entre los mega herbívoros y la riqueza de especies de murciélagos con la actividad de los quirópteros durante la temporada seca (noviembre 2016 - enero 2017) y la lluviosa (febrero - mayo 2017). El uso a nivel de sitio dado por los mega herbívoros durante la temporada seca estuvo asociado positivamente con la actividad de los murciélagos-particularmente para aquellos que forrajean a cielo abierto-y la riqueza de especies por vías indirectas. Sin embargo, cuando los recursos fueron más abundantes (temporada de lluvias), estas relaciones fueron débiles. Nuestros resultados indican que las interacciones bióticas contribuyen a la distribución de las especies en áreas desérticas y sugieren que la conservación de los mega herbívoros en este ecosistema puede beneficiar indirectamente a la abundancia y la diversidad de los murciélagos insectívoros. Ya que los murciélagos suelen ser poco valorados y poco estudiados en comparación con otros mamíferos, nuestros descubrimientos sugieren que los gestores buscan soluciones a corto plazo (p. ej.: programas de guardias comunitarias de las presas de caza, protección de puntos de abastecimiento de agua cercanos a establecimientos humanos, ecoturismo) para promover indirectamente la conservación de murciélagos y que la investigación incluye los efectos de los mega herbívoros sobre la biodiversidad en otros niveles tróficos.

Validation of the Iowa Test of Consonant Perception.

Speech perception (especially in background noise) is a critical problem for hearing-impaired listeners and an important issue for cognitive hearing science. Despite a plethora of standardized measures, few single-word closed-set tests uniformly sample the most frequently used phonemes and use response choices that equally sample phonetic features like place and voicing. The Iowa Test of Consonant Perception (ITCP) attempts to solve this. It is a proportionally balanced phonemic word recognition task designed to assess perception of the initial consonant of monosyllabic consonant-vowel-consonant (CVC) words. The ITCP consists of 120 sampled CVC words. Words were recorded from four different talkers (two female) and uniformly sampled from all four quadrants of the vowel space to control for coarticulation. Response choices on each trial are balanced to equate difficulty and sample a single phonetic feature. This study evaluated the psychometric properties of ITCP by examining reliability (test-retest) and validity in a sample of online normal-hearing participants. Ninety-eight participants completed two sessions of the ITCP along with standardized tests of words and sentence in noise (CNC words and AzBio sentences). The ITCP showed good test-retest reliability and convergent validity with two popular tests presented in noise. All the materials to use the ITCP or to construct your own version of the ITCP are freely available [Geller, McMurray, Holmes, and Choi (2020). https://osf.io/hycdu/].

Exposing Pathological Sensory Predictions in Tinnitus Using Auditory Intensity Deviant Evoked Responses.

We tested the popular, unproven theory that tinnitus is caused by resetting of auditory predictions toward a persistent low-intensity sound. Electroencephalographic mismatch negativity responses, which quantify the violation of sensory predictions, to unattended tinnitus-like sounds were greater in response to upward than downward intensity deviants in 26 unselected chronic tinnitus subjects with normal to severely impaired hearing, and in 15 acute tinnitus subjects, but not in 26 hearing and age-matched controls (p < 0.001, receiver operator characteristic, area under the curve, 0.77), or in 20 healthy and hearing-impaired controls presented with simulated tinnitus. The findings support a prediction resetting model of tinnitus generation, and may form the basis of a convenient tinnitus biomarker, which we name Intensity Mismatch Asymmetry, which is usable across species, is quick and tolerable, and requires no training.SIGNIFICANCE STATEMENT In current models, perception is based around the generation of internal predictions of the environment, which are tested and updated using evidence from the senses. Here, we test the theory that auditory phantom perception (tinnitus) occurs when a default auditory prediction is formed to explain spontaneous activity in the subcortical pathway, rather than ignoring it as noise. We find that chronic tinnitus patients show an abnormal pattern of evoked responses to unexpectedly loud and quiet sounds that both supports this hypothesis and provides fairly accurate classification of tinnitus status at the individual subject level. This approach to objectively demonstrating the predictions underlying pathological perceptual states may also have a much wider utility, for instance, in chronic pain.

Nitric oxide increases gain in the ventral cochlear nucleus of guinea pigs with tinnitus.

Previous work has led to the hypothesis that, during the production of noise-induced tinnitus, higher levels of nitric oxide (NO), in the ventral cochlear nucleus (VCN), increase the gain applied to a reduced input from the cochlea. To test this hypothesis, we noise-exposed 26 guinea pigs, identified evidence of tinnitus in 12 of them and then compared the effects of an iontophoretically applied NO donor or production inhibitor on VCN single unit activity. We confirmed that the mean driven firing rate for the tinnitus and control groups was the same while it had fallen in the non-tinnitus group. By contrast, the mean spontaneous rate had increased for the tinnitus group relative to the control group, while it remained the same for the non-tinnitus group. A greater proportion of units responded to exogenously applied NO in the tinnitus (56%) and non-tinnitus groups (71%) than a control population (24%). In the tinnitus group, endogenous NO facilitated the driven firing rate in 37% (7/19) of neurons and appeared to bring the mean driven rate back up to control levels by a mechanism involving N-methyl-D-aspartic acid (NMDA) receptors. By contrast, in the non-tinnitus group, endogenous NO only facilitated the driven firing rate in 5% (1/22) of neurons and there was no facilitation of driven rate in the control group. The effects of endogenous NO on spontaneous activity were unclear. These results suggest that NO is involved in increasing the gain applied to driven activity, but other factors are also involved in the increase in spontaneous activity.

Nitric oxide regulates the firing rate of neuronal subtypes in the guinea pig ventral cochlear nucleus.

The gaseous free radical, nitric oxide (NO) acts as a ubiquitous neuromodulator, contributing to synaptic plasticity in a complex way that can involve either long term potentiation or depression. It is produced by neuronal nitric oxide synthase (nNOS) which is presynaptically expressed and also located postsynaptically in the membrane and cytoplasm of a subpopulation of each major neuronal type in the ventral cochlear nucleus (VCN). We have used iontophoresis in vivo to study the effect of the NOS inhibitor L-NAME (L-NG-Nitroarginine methyl ester) and the NO donors SIN-1 (3-Morpholinosydnonimine hydrochloride) and SNOG (S-Nitrosoglutathione) on VCN units under urethane anaesthesia. Collectively, both donors produced increases and decreases in driven and spontaneous firing rates of some neurones. Inhibition of endogenous NO production with L-NAME evoked a consistent increase in driven firing rates in 18% of units without much effect on spontaneous rate. This reduction of gain produced by endogenous NO was mirrored when studying the effect of L-NAME on NMDA(N-Methyl-D-aspartic acid)-evoked excitation, with 30% of units showing enhanced NMDA-evoked excitation during L-NAME application (reduced NO levels). Approximately 25% of neurones contain nNOS and the NO produced can modulate the firing rate of the main principal cells: medium stellates (choppers), large stellates (onset responses) and bushy cells (primary-like responses). The main endogenous role of NO seems to be to partly suppress driven firing rates associated with NMDA channel activity but there is scope for it to increase neural gain if there were a pathological increase in its production following hearing loss.

Endothelial Cell-Targeted Deletion of PPARγ Blocks Rosiglitazone-Induced Plasma Volume Expansion and Vascular Remodeling in Adipose Tissue.

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that represent an effective class of insulin-sensitizing agents; however, clinical use is associated with weight gain and peripheral edema. To elucidate the role of PPARγ expression in endothelial cells (ECs) in these side effects, EC-targeted PPARγ knockout (Pparg ΔEC) mice were placed on a high-fat diet to promote PPARγ agonist-induced plasma volume expansion, and then treated with the TZD rosiglitazone. Compared with Pparg-floxed wild-type control (Pparg f/f) mice, Pparg ΔEC treated with rosiglitazone are resistant to an increase in extracellular fluid, water content in epididymal and inguinal white adipose tissue, and plasma volume expansion. Interestingly, histologic assessment confirmed significant rosiglitazone-mediated capillary dilation within white adipose tissue of Pparg f/f mice, but not Pparg ΔEC mice. Analysis of ECs isolated from untreated mice in both strains suggested the involvement of changes in endothelial junction formation. Specifically, compared with cells from Pparg f/f mice, Pparg ΔEC cells had a 15-fold increase in focal adhesion kinase, critically important in EC focal adhesions, and >3-fold significant increase in vascular endothelial cadherin, the main component of focal adhesions. Together, these results indicate that rosiglitazone has direct effects on the endothelium via PPARγ activation and point toward a critical role for PPARγ in ECs during rosiglitazone-mediated plasma volume expansion.

A Retrospective Assessment of a Failed Collaborative Process in Conservation.

Collaboration provides one tool for managing the complicated and often the contentious natural resource issues. Successful collaborative arrangements involve a mix of actors bringing key attributes to the table: power, capacity, motivation, mandate, and synergy. These attributes, if missing or if one overshadows the rest, can derail the collaborative process and/or the conservation outcomes. We offer a case study of natural gas field development impacts on America's only endemic ungulate-pronghorn (Antilocapra americana)-winter range in the Upper Green River Basin (UGRB), Wyoming, USA. We illustrate how a collaborative process can go awry, given asymmetries between the relative strengths and the associated attributes of actors, and the subsequent extent to which this imbalance created an unfavorable situation for continued collaboration. The case study reveals disagreements on technical data and potential insight on agency capture operating at a local scale. Despite these process challenges, some conservation outcomes resulted from work generated by the collaboration. Our experience underscores the importance of defining a clear purpose for collaborative processes at the outset, articulating specific roles, ensuring transparency among actors, and flexibility for long-term management as possible ways, in which the groups involved in collaborations to manage natural resources can complement each other's strengths and strive for better conservation outcomes.

Reductions in cortical alpha activity, enhancements in neural responses and impaired gap detection caused by sodium salicylate in awake guinea pigs.

Tinnitus chronically affects between 10-15% of the population but, despite its prevalence, the underlying mechanisms are still not properly understood. One experimental model involves administration of high doses of sodium salicylate, as this is known to reliably induce tinnitus in both humans and animals. Guinea pigs were implanted with chronic electrocorticography (ECoG) electrode arrays, with silver-ball electrodes placed on the dura over left and right auditory cortex. Two more electrodes were positioned over the cerebellum to monitor auditory brainstem responses (ABRs). We recorded resting-state and auditory evoked neural activity from awake animals before and 2 h following salicylate administration (350 mg/kg; i.p.). Large increases in click-evoked responses (> 100%) were evident across the whole auditory cortex, despite significant reductions in wave I ABR amplitudes (in response to 20 kHz tones), which are indicative of auditory nerve activity. In the same animals, significant decreases in 6-10 Hz spontaneous oscillations (alpha waves) were evident over dorsocaudal auditory cortex. We were also able to demonstrate for the first time that cortical evoked potentials can be inhibited by a preceding gap in background noise [gap-induced pre-pulse inhibition (PPI)], in a similar fashion to the gap-induced inhibition of the acoustic startle reflex that is used as a behavioural test for tinnitus. Furthermore, 2 h following salicylate administration, we observed significant deficits in PPI of cortical responses that were closely aligned with significant deficits in behavioural responses to the same stimuli. Together, these data are suggestive of neural correlates of tinnitus and oversensitivity to sound (hyperacusis).

Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus.

Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic ß-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.

Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus.

Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic ß-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.

Desert pastoralists' negative and positive effects on rare wildlife in the Gobi.

In arid regions of the developing world, pastoralists and livestock commonly inhabit protected areas, resulting in human-wildlife conflict. Conflict is inextricably linked to the ecological processes shaping relationships between pastoralists and native herbivores and carnivores. To elucidate relationships underpinning human-wildlife conflict, we synthesized 15 years of ecological and ethnographic data from Ikh Nart Nature Reserve in Mongolia's Gobi steppe. The density of argali (Ovis ammon), the world's largest wild sheep, at Ikh Nart was among the highest in Mongolia, yet livestock were >90% of ungulate biomass and dogs >90% of large-carnivore biomass. For argali, pastoral activities decreased food availability, increased mortality from dog predation, and potentially increased disease risk. Isotope analyses indicated that livestock accounted for >50% of the diet of the majority of gray wolves (Canis lupus) and up to 90% of diet in 25% of sampled wolves (n = 8). Livestock composed at least 96% of ungulate prey in the single wolf pack for which we collected species-specific prey data. Interviews with pastoralists indicated that wolves annually killed 1-4% of Ikh Nart's livestock, and pastoralists killed wolves in retribution. Pastoralists reduced wolf survival by killing them, but their livestock were an abundant food source for wolves. Consequently, wolf density appeared to be largely decoupled from argali density, and pastoralists had indirect effects on argali that could be negative if pastoralists increased wolf density (apparent competition) or positive if pastoralists decreased wolf predation (apparent facilitation). Ikh Nart's argali population was stable despite these threats, but livestock are increasingly dominant numerically and functionally relative to argali. To support both native wildlife and pastoral livelihoods, we suggest training dogs to not kill argali, community insurance against livestock losses to wolves, reintroducing key native prey species to hotspots of human-wolf conflict, and developing incentives for pastoralists to reduce livestock density.