Alternative splicing of GluN1 gates glycine site-dependent nonionotropic signaling by NMDAR receptors.

N-methyl-D-aspartate (NMDA) receptors (NMDARs), a principal subtype of excitatory neurotransmitter receptor, are composed as tetrameric assemblies of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits. NMDARs can signal nonionotropically through binding of glycine alone to its cognate site on GluN1. A consequence of this signaling by glycine is that NMDARs are primed such that subsequent gating, produced by glycine and glutamate, drives receptor internalization. The GluN1 subunit contains eight alternatively spliced isoforms produced by including or excluding the N1 and the C1, C2, or C2' polypeptide cassettes. Whether GluN1 alternative splicing affects nonionotropic signaling by NMDARs is a major outstanding question. Here, we discovered that glycine priming of recombinant NMDARs critically depends on GluN1 isoforms lacking the N1 cassette; glycine priming is blocked in splice variants containing N1. On the other hand, the C-terminal cassettes-C1, C2, or C2'-each permit glycine signaling. In wild-type mice, we found glycine-induced nonionotropic signaling at synaptic NMDARs in CA1 hippocampal pyramidal neurons. This nonionotropic signaling by glycine to synaptic NMDARs was prevented in mice we engineered, such that GluN1 obligatorily contained N1. We discovered in wild-type mice that, in contrast to pyramidal neurons, synaptic NMDARs in CA1 inhibitory interneurons were resistant to glycine priming. But we recapitulated glycine priming in inhibitory interneurons in mice engineered such that GluN1 obligatorily lacked the N1 cassette. Our findings reveal a previously unsuspected molecular function for alternative splicing of GluN1 in controlling nonionotropic signaling of NMDARs by activating the glycine site.

ACTing Spiritually: Integrating Spiritual Care and Mental Health Care within a US Department of Veterans Affairs Inpatient Psychiatric Unit.

As a part of the VA's interprofessional fellowship in psychosocial rehabilitation, the authors developed an 8-week spirituality group manual, ACTing Spiritually, which incorporates principles of acceptance and commitment therapy (ACT) into a spirituality group protocol. The group, administered weekly as possible for 28 weeks on an inpatient psychiatric unit at a veterans affairs (VA) medical center in West Haven, CT, aimed to incorporate veterans' spirituality into their mental health treatment through concepts of acceptance, values, mindfulness, and committed action. ACTing Spiritually ran in tandem with a basic ACT group and the two groups had comparable average group sizes, suggesting interest in ACTing Spiritually similarly compares to interest in a basic ACT group in this context. In addition, development of the group yielded several qualitative findings, including a discussion of the similarities and differences between ACT and spiritual care, clinical gains for chaplains conducting the group, and clinical tensions that arose through the process of integration. The study provided preliminary evidence of the potential feasibility and acceptability of ACTing Spiritually. Next steps should include a formal evaluation of its potential efficacy.

Effectiveness of Lay Bystander Hands-Only Cardiopulmonary Resuscitation on a Mattress versus the Floor: A Randomized Cross-Over Trial.

STUDY OBJECTIVE: Bystander cardiopulmonary resuscitation increases the likelihood of out-of-hospital cardiac arrest survival by more than two-fold. A common barrier to the prompt initiation of compressions is moving victims to the floor, but compression quality on a "floor" versus a "mattress" has not been tested among lay bystanders. METHODS: We conducted a prospective, randomized, cross-over trial comparing lay bystander compression quality using a manikin on a bed versus the floor. Participants included adults without professional health care training. We randomized participants to the order of manikin placement, either on a mattress or on the floor. For both, participants were instructed to perform 2 minutes of chest compressions on a cardiopulmonary resuscitation Simon manikin Gaumard (Gaumard Scientific, Miami, FL). The primary outcome was mean compression depth (cm) over 2 minutes. We fit a linear regression model adjusted for scenario order, age, sex, and body mass index with robust standard errors to account for repeated measures and reported mean differences with 95% confidence intervals (CIs). RESULTS: Our sample of 80 adults was 66% female with a mean age of 50.5 years (SD 18.2). The mean compression depth on the mattress was 2.9 cm (SD 2.3) and 3.5 cm (SD 2.2) on the floor, a mean difference of 0.58 cm (95% CI 0.18, 0.98). Compression depth fell below the 5 to 6 cm depth recommended by the American Heart Association on both surfaces. In the adjusted model, the mean depth was greater when the manikin was on the floor than the mattress (adjusted mean difference 0.62 cm; 95% CI 0.23 to 1.01), and mean depth was less for females than males (adjusted mean difference -1.42 cm, 95% CI -2.59, -0.25). In addition, the difference in compression depth was larger for female participants (mean difference 0.94 cm; 95% CI 0.54, 1.34) than for male participants (mean difference -0.01 cm; 95% CI -0.80, 0.78), and the interaction was statistically significant (P = .04). CONCLUSION: The mean compression depth was significantly smaller on the mattress and with female bystanders. Further research is needed to understand the benefit of moving out-of-hospital cardiac arrest victims to the floor relative to the detrimental effect of delaying chest compressions.

A multimedia paediatric cardiology assessment tool for medical students and general paediatric trainees: development and validation.

BACKGROUND: Understanding how cardiovascular structure and physiology guide management is critically important in paediatric cardiology. However, few validated educational tools are available to assess trainee knowledge. To address this deficit, paediatric cardiologists and fellows from four institutions collaborated to develop a multimedia assessment tool for use with medical students and paediatric residents. This tool was developed in support of a novel 3-dimensional virtual reality curriculum created by our group. METHODS: Educational domains were identified, and questions were iteratively developed by a group of clinicians from multiple centres to assess understanding of key concepts. To evaluate content validity, content experts completed the assessment and reviewed items, rating item relevance to educational domains using a 4-point Likert scale. An item-level content validity index was calculated for each question, and a scale-level content validity index was calculated for the assessment tool, with scores of ≥0.78 and ≥0.90, respectively, representing excellent content validity. RESULTS: The mean content expert assessment score was 92% (range 88-97%). Two questions yielded ≤50% correct content expert answers. The item-level content validity index for 29 out of 32 questions was ≥0.78, and the scale-level content validity index was 0.92. Qualitative feedback included suggestions for future improvement. Questions with ≤50% content expert agreement and item-level content validity index scores <0.78 were removed, yielding a 27-question assessment tool. CONCLUSIONS: We describe a multi-centre effort to create and validate a multimedia assessment tool which may be implemented within paediatric trainee cardiology curricula. Future efforts may focus on content refinement and expansion to include additional educational domains.

Virtual reality curriculum increases paediatric residents' knowledge of CHDs.

OBJECTIVES: Virtual reality has emerged as a unique educational modality for medical trainees. However, incorporation of virtual reality curricula into formal training programmes has been limited. We describe a multi-centre effort to develop, implement, and evaluate the efficacy of a virtual reality curriculum for residents participating in paediatric cardiology rotations. METHODS: A virtual reality software program ("The Stanford Virtual Heart") was utilised. Users are placed "inside the heart" and explore non-traditional views of cardiac anatomy. Modules for six common congenital heart lesions were developed, including narrative scripts. A prospective case-control study was performed involving three large paediatric residency programmes. From July 2018 to June 2019, trainees participating in an outpatient cardiology rotation completed a 27-question, validated assessment tool. From July 2019 to February 2020, trainees completed the virtual reality curriculum and assessment tool during their cardiology rotation. Qualitative feedback on the virtual reality experience was also gathered. Intervention and control group performances were compared using univariate analyses. RESULTS: There were 80 trainees in the control group and 52 in the intervention group. Trainees in the intervention group achieved higher scores on the assessment (20.4 ± 2.9 versus 18.8 ± 3.8 out of 27 questions answered correctly, p = 0.01). Further analysis showed significant improvement in the intervention group for questions specifically testing visuospatial concepts. In total, 100% of users recommended integration of the programme into the residency curriculum. CONCLUSIONS: Virtual reality is an effective and well-received adjunct to clinical curricula for residents participating in paediatric cardiology rotations. Our results support continued virtual reality use and expansion to include other trainees.

The Body, the Mind, and the Spirit: Including the Spiritual Domain in Mental Health Care.

This article supports the expansion of Engel's (Science (AAAS) 196(4286):129-136, 1977) biopsychosocial model into a biopsychosocial-spiritual model, as Sulmasy (The Gerontologist 42(5):24-33, 2002) and others have suggested. It utilizes case studies to describe five areas of clinical work within mental health (religious grandiosity, depression and grief, demoralization and suicidality, moral injury, and opioid use disorder) with emerging evidence for the inclusion of the spiritual domain in addition to the biological, psychological, and social. For each clinical area, an underutilization of the spiritual domain is compared with a more developed and integrated use. An argument is made for continuing to develop, understand, and utilize a biopsychosocial-spiritual model in mental health.

What Is Consciousness? Integrated Information vs. Inference.

Any successful naturalistic account of consciousness must state what consciousness is, in terms that are compatible with the rest of our naturalistic descriptions of the world. Integrated Information Theory represents a pioneering attempt to do just this. This theory accounts for the core features of consciousness by holding that there is an equivalence between the phenomenal experience associated with a system and its intrinsic causal power. The proposal, however, fails to provide insight into the qualitative character of consciousness and, as a result of its proposed equivalence between consciousness and purely internal dynamics, into the intentional character of conscious perception. In recent years, an alternate group of theories has been proposed that claims consciousness to be equivalent to certain forms of inference. One such theory is the Living Mirror theory, which holds consciousness to be a form of inference performed by all living systems. The proposal of consciousness as inference overcomes the shortcomings of Integrated Information Theory, particularly in the case of conscious perception. A synthesis of these two perspectives can be reached by appreciating that conscious living systems are self-organising in nature. This mode of organization requires them to have a high level of integration. From this perspective, we can understand consciousness as being dependent on a system possessing non-trivial amounts of integrated information while holding that the process of inference performed by the system is the fact of consciousness itself.

Contrast gain control occurs independently of both parvalbumin-positive interneuron activity and shunting inhibition in auditory cortex.

Contrast gain control is the systematic adjustment of neuronal gain in response to the contrast of sensory input. It is widely observed in sensory cortical areas and has been proposed to be a canonical neuronal computation. Here, we investigated whether shunting inhibition from parvalbumin-positive interneurons-a mechanism involved in gain control in visual cortex-also underlies contrast gain control in auditory cortex. First, we performed extracellular recordings in the auditory cortex of anesthetized male mice and optogenetically manipulated the activity of parvalbumin-positive interneurons while varying the contrast of the sensory input. We found that both activation and suppression of parvalbumin interneuron activity altered the overall gain of cortical neurons. However, despite these changes in overall gain, we found that manipulating parvalbumin interneuron activity did not alter the strength of contrast gain control in auditory cortex. Furthermore, parvalbumin-positive interneurons did not show increases in activity in response to high-contrast stimulation, which would be expected if they drive contrast gain control. Finally, we performed in vivo whole-cell recordings in auditory cortical neurons during high- and low-contrast stimulation and found that no increase in membrane conductance was observed during high-contrast stimulation. Taken together, these findings indicate that while parvalbumin-positive interneuron activity modulates the overall gain of auditory cortical responses, other mechanisms are primarily responsible for contrast gain control in this cortical area.NEW & NOTEWORTHY We investigated whether contrast gain control is mediated by shunting inhibition from parvalbumin-positive interneurons in auditory cortex. We performed extracellular and intracellular recordings in mouse auditory cortex while presenting sensory stimuli with varying contrasts and manipulated parvalbumin-positive interneuron activity using optogenetics. We show that while parvalbumin-positive interneuron activity modulates the gain of cortical responses, this activity is not the primary mechanism for contrast gain control in auditory cortex.

Learning from errors: students' and instructors' practices, attitudes, and beliefs.

In some educational contexts, such as during assessments, it is essential to avoid errors. In other contexts, however, generating an error can foster valuable learning opportunities. For instance, generating errors can improve memory for correct answers. In two surveys conducted at three large public universities in North America, we investigated undergraduate students' and instructors' awareness of the pedagogical benefits of generating errors, as well as related practices, attitudes, and beliefs. Surveyed topics included the incorporation of errors into learning activities, opinions about the consequences of studying errors, and approaches to feedback. Many students had an aversion towards making errors during learning and did not use opportunities to engage in errorful generation, yet studied or analysed errors when they occurred. Many instructors had a welcoming attitude towards errors that occur during learning, yet varied in providing students with resources that facilitate errorful generation. Overall, these findings reveal the prevalence of an ambivalent approach to errors: Students and instructors avoid generating errors but prioritise learning from them when they occur. These results have important implications for the implementation of pretesting, productive failure, and other error-focused learning techniques in educational contexts.

Causal inference for spatial constancy across whole body motion.

The brain uses self-motion information to internally update egocentric representations of locations of remembered world-fixed visual objects. If a discrepancy is observed between this internal update and reafferent visual feedback, this could be either due to an inaccurate update or because the object has moved during the motion. To optimally infer the object's location it is therefore critical for the brain to estimate the probabilities of these two causal structures and accordingly integrate and/or segregate the internal and sensory estimates. To test this hypothesis, we designed a spatial updating task involving passive whole body translation. Participants, seated on a vestibular sled, had to remember the world-fixed position of a visual target. Immediately after the translation, the reafferent visual feedback was provided by flashing a second target around the estimated "updated" target location, and participants had to report the initial target location. We found that the participants' responses were systematically biased toward the position of the second target position for relatively small but not for large differences between the "updated" and the second target location. This pattern was better captured by a Bayesian causal inference model than by alternative models that would always either integrate or segregate the internally updated target location and the visual feedback. Our results suggest that the brain implicitly represents the posterior probability that the internally updated estimate and the visual feedback come from a common cause and uses this probability to weigh the two sources of information in mediating spatial constancy across whole body motion. NEW & NOTEWORTHY When we move, egocentric representations of object locations require internal updating to keep them in register with their true world-fixed locations. How does this mechanism interact with reafferent visual input, given that objects typically do not disappear from view? Here we show that the brain implicitly represents the probability that both types of information derive from the same object and uses this probability to weigh their contribution for achieving spatial constancy across whole body motion.

Beyond the 12 steps: Integrating chaplaincy services into Veteran Affairs substance use specialty care.

Background: Interprofessional training is increasing in focus within medical education. Although substance use treatment has long been interprofessional in nature, chaplaincy has been relatively absent in outpatient settings. Since 2013, the Veterans Health Administration has supported an Interprofessional Advanced Fellowship in Addiction Treatment (IAFAT), with 7 sites nationally recruiting across multiple health care disciplines. In the fall of 2017, Veteran Affairs Connecticut Healthcare System (VACHS) became the first such fellowship to expand its recruitment to include chaplain fellows. We seek to share rationale for recruiting chaplains, current curriculum and curricular needs, and the potential roles of chaplains in outpatient addiction treatment. Methods: Collaborating with the office of chaplaincy education, we describe the process of chaplain recruitment, incorporation into a new treatment setting, and supervision, and we report on the feasibility of this innovative training initiative. Results: During the first year, the chaplain fellow has developed and maintained a new clinical service in an outpatient substance use disorder (SUD) specialty care setting, delivering over 150 hours of group and individual treatment to veterans. He has provided 12 presentations to staff on the role of a chaplain and other related topics, as well as written an article on the topic of addiction for a clergy audience. Anecdotally, staff satisfaction has been high, and the current chaplain is helping to recruit for his replacement. Limitations: As a feasibility pilot project, there is no outcome and very limited quantitative data. Conclusions: Chaplain fellows can be successfully incorporated into outpatient SUD clinics with a noticeable degree of fellow, staff, and patient satisfaction.

Contrast gain control in mouse auditory cortex.

The neocortex is thought to employ a number of canonical computations, but little is known about whether these computations rely on shared mechanisms across different neural populations. In recent years, the mouse has emerged as a powerful model organism for the dissection of the circuits and mechanisms underlying various aspects of neural processing and therefore provides an important avenue for research into putative canonical computations. One such computation is contrast gain control, the systematic adjustment of neural gain in accordance with the contrast of sensory input, which helps to construct neural representations that are robust to the presence of background stimuli. Here, we characterized contrast gain control in the mouse auditory cortex. We performed laminar extracellular recordings in the auditory cortex of the anesthetized mouse while varying the contrast of the sensory input. We observed that an increase in stimulus contrast resulted in a compensatory reduction in the gain of neural responses, leading to representations in the mouse auditory cortex that are largely contrast invariant. Contrast gain control was present in all cortical layers but was found to be strongest in deep layers, indicating that intracortical mechanisms may contribute to these gain changes. These results lay a foundation for investigations into the mechanisms underlying contrast adaptation in the mouse auditory cortex. NEW & NOTEWORTHY We investigated whether contrast gain control, the systematic reduction in neural gain in response to an increase in sensory contrast, exists in the mouse auditory cortex. We performed extracellular recordings in the mouse auditory cortex while presenting sensory stimuli with varying contrasts and found this form of processing was widespread. This finding provides evidence that contrast gain control may represent a canonical cortical computation and lays a foundation for investigations into the underlying mechanisms.

Effect of depth information on multiple-object tracking in three dimensions: A probabilistic perspective.

Many daily situations require us to track multiple objects and people. This ability has traditionally been investigated in observers tracking objects in a plane. This simplification of reality does not address how observers track objects when targets move in three dimensions. Here, we study how observers track multiple objects in 2D and 3D while manipulating the average speed of the objects and the average distance between them. We show that performance declines as speed increases and distance decreases and that overall tracking accuracy is always higher in 3D than in 2D. The effects of distance and dimensionality interact to produce a more than additive improvement in performance during tracking in 3D compared to 2D. We propose an ideal observer model that uses the object dynamics and noisy observations to track the objects. This model provides a good fit to the data and explains the key findings of our experiment as originating from improved inference of object identity by adding the depth dimension.

Bayesian adaptive stimulus selection for dissociating models of psychophysical data.

Comparing models facilitates testing different hypotheses regarding the computational basis of perception and action. Effective model comparison requires stimuli for which models make different predictions. Typically, experiments use a predetermined set of stimuli or sample stimuli randomly. Both methods have limitations; a predetermined set may not contain stimuli that dissociate the models, whereas random sampling may be inefficient. To overcome these limitations, we expanded the psi-algorithm (Kontsevich & Tyler, 1999) from estimating the parameters of a psychometric curve to distinguishing models. To test our algorithm, we applied it to two distinct problems. First, we investigated dissociating sensory noise models. We simulated ideal observers with different noise models performing a two-alternative forced-choice task. Stimuli were selected randomly or using our algorithm. We found using our algorithm improved the accuracy of model comparison. We also validated the algorithm in subjects by inferring which noise model underlies speed perception. Our algorithm converged quickly to the model previously proposed (Stocker & Simoncelli, 2006), whereas if stimuli were selected randomly, model probabilities separated slower and sometimes supported alternative models. Second, we applied our algorithm to a different problem-comparing models of target selection under body acceleration. Previous work found target choice preference is modulated by whole body acceleration (Rincon-Gonzalez et al., 2016). However, the effect is subtle, making model comparison difficult. We show that selecting stimuli adaptively could have led to stronger conclusions in model comparison. We conclude that our technique is more efficient and more reliable than current methods of stimulus selection for dissociating models.

Best practices in active and student-centered learning in physiology classes.

This review article includes our analysis of the literature and our own experiences in using various types of active learning as best practices for evidence-based teaching in physiology. We have evaluated what physiology students should be expected to learn and what are specific challenges to enhancing their learning of physiology principles. We also consider how the instructor should design his or her teaching to improve buy-in from both students and other faculty members. We include a discussion of how the readers can evaluate their teaching approaches for their successes in enhancing student learning of physiology. Thus we have addressed pedagogical improvements specific to student learning of physiology, with additional suggestions from cognitive psychology approaches that can improve physiology teaching and learning.

The concerted movement of the switch region of Troponin I in cardiac muscle thin filaments as tracked by conventional and pulsed (DEER) EPR.

The absence of a crystal structure of the calcium free state of the cardiac isoform of the troponin complex has hindered our understanding of how the simple binding of Ca2+ triggers conformational changes in troponin which are then propagated to enable muscle contraction. Here we have used continuous wave (CW) and Double Electron-Electron Resonance (DEER) pulsed EPR spectroscopy to measure distances between TnI and TnC to track the movement of the functionally important regulatory 'switch' region of cardiac Tn. Spin labels were placed on the switch region of Troponin I and distances measured to Troponin C. Under conditions of high Ca2+, the interspin distances for one set (TnI151/TnC84) were 'short' (9-10Å) with narrow distance distribution widths (3-8Å) indicating the close interaction of the switch region with the N-lobe of TnC. Additional spin populations representative of longer interspin distances were detected by DEER. These longer distance populations, which were ∼16-19Å longer than the short distance populations, possessed notably broader distance distribution widths (14-29Å). Upon Ca2+ removal, the interspin population shifted toward the longer distances, indicating the release of the switch region from TnC and an overall increase in disorder for this region. Together, our results suggest that under conditions of low Ca2+, the close proximity of the TnI switch region to TnC in the cardiac isoform is necessary for promoting the interaction between the regulatory switch helix with the N-lobe of cardiac Troponin C, which, unlike the skeletal isoform, is largely in a closed conformation.

Institution-Specific Factors Associated With Family Medicine Residency Match Rates.

UNLABELLED: Phenomenon: Existing research provides little specific evidence regarding the association between public and private medical school curricular settings and the proportion of medical students matching into family medicine careers. Institutional differences have been inadequately investigated, as students who match into family medicine are often consolidated into the umbrella of primary care along with those matching in internal medicine and pediatrics. However, understanding medical school contexts in relation to career choice is critical toward designing targeted strategies to address the projected shortage of family physicians. This study examines factors associated with family medicine residency match rates and the extent to which such factors differ across medical school settings. APPROACH: We combined data from a survey of 123 departments of family medicine with graduate placement rates reported to the American Academy of Family Physicians over a 2-year period. Chi-square/Fisher's Exact texts, t tests, and linear regression analyses were used to identify factors significantly associated with average match rate percentages. FINDINGS: The resulting data set included 85% of the U.S. medical schools with Departments of Family Medicine that reported 2011 and 2012 residency match rates in family medicine. Match rates in family medicine were higher among graduates of public than private medical schools-11% versus 7%, respectively, t(92) = 4.00, p < .001. Using a linear regression model and controlling for institutional type, the results indicated 2% higher match rates among schools with smaller annual clerkship enrollments (p  = .03), 3% higher match rates among schools with clerkships lasting more than 3 to 4 weeks (p  = .003), 3% higher match rates at schools with at least 1 family medicine faculty member in a senior leadership role (p  = .04), and 8% lower match rates at private medical schools offering community medicine electives (p < .001, R(2) = .48), F(6, 64) = 9.95, p < .001. Three additional factors were less strongly related and varied by institutional type-informal mentoring, ambulatory primary care learning experiences, and institutional research focus. Insights: Educational opportunities associated with higher match rates in family medicine differ across private and public medical schools. Future research is needed to identify the qualitative aspects of educational programming that contribute to differences in match rates across institutional contexts. Results of this study should prove useful in mitigating physician shortages, particularly in primary care fields such as family medicine.

Human papillomavirus mediated inhibition of DNA damage sensing and repair drives skin carcinogenesis.

BACKGROUND: The failure to mount an effective DNA damage response to repair UV induced cyclobutane pyrimidine dimers (CPDs) results in an increased propensity to develop cutaneous squamous cell carcinoma (cSCC). High-risk patient groups, such as organ transplant recipients (OTRs) frequently exhibit field cancerization at UV exposed body sites from which multiple human papillomavirus (HPV)-associated cSCCs develop rapidly, leading to profound morbidity and increased mortality. In vitro molecular evidence indicates that HPV of genus beta-papillomavirus (ß-PV) play an important role in accelerating the early stages of skin tumorigenesis. METHODS: We investigated the effects of UV induced DNA damage in murine models of ß-PV E6 oncoprotein driven skin tumorigenesis by crossing K14-HPV8-E6wt mice (developing skin tumors after UV treatment) with K14-CPD-photolyase animals and by generating the K14-HPV8-E6-K136N mutant mouse strain. Thymine dimers (marker for CPDs) and γH2AX (a marker for DNA double strand breaks) levels were determined in the murine skin and organotypic skin cultures of E6 expressing primary human keratinocytes after UV-irradiation by immunohistochemistry and in cell lines by In Cell Western blotting. Phosphorylation of ATR/Chk1 and ATM were assessed in cell lines and organotypic skin cultures by Western blots and immunohistochemistry. RESULTS: Skin tumor development after UV-irradiation in K14-HPV8-E6wt mice could completely be blocked through expression of CPD-photolyase. Through quantification of thymine dimers after UV irradiation in cells expressing E6 proteins with point mutations at conserved residues we identified a critical lysine in the C-terminal part of the protein for prevention of DNA damage repair and p300 binding. Whereas all K14-HPV8-E6wt animals develop skin tumors after UV expression of the HPV8-E6-K136N mutant significantly blocked skin tumor development after UV treatment. The persistence of CPDs in hyperproliferative epidermis K14-HPV8-E6wt skin resulted in the accumulation of γH2AX foci. DNA damage sensing was impaired in E6 positive cells grown as monolayer culture and in organotypic cultures, due to lack of phosphorylation of ATM, ATR and Chk1. CONCLUSION: We showed that cells expressing E6 fail to sense and mount an effective response to repair UV-induced DNA lesions and demonstrated a physiological relevance of E6-mediated inhibition of DNA damage repair for tumor initiation. These are the first mechanistical in vivo data on the tumorigenicity of HPV8 and demonstrate that the impairment of DNA damage repair pathways by the viral E6 protein is a critical factor in HPV-driven skin carcinogenesis.

Hearing in noisy environments: noise invariance and contrast gain control.

Contrast gain control has recently been identified as a fundamental property of the auditory system. Electrophysiological recordings in ferrets have shown that neurons continuously adjust their gain (their sensitivity to change in sound level) in response to the contrast of sounds that are heard. At the level of the auditory cortex, these gain changes partly compensate for changes in sound contrast. This means that sounds which are structurally similar, but have different contrasts, have similar neuronal representations in the auditory cortex. As a result, the cortical representation is relatively invariant to stimulus contrast and robust to the presence of noise in the stimulus. In the inferior colliculus (an important subcortical auditory structure), gain changes are less reliably compensatory, suggesting that contrast- and noise-invariant representations are constructed gradually as one ascends the auditory pathway. In addition to noise invariance, contrast gain control provides a variety of computational advantages over static neuronal representations; it makes efficient use of neuronal dynamic range, may contribute to redundancy-reducing, sparse codes for sound and allows for simpler decoding of population responses. The circuits underlying auditory contrast gain control are still under investigation. As in the visual system, these circuits may be modulated by factors other than stimulus contrast, forming a potential neural substrate for mediating the effects of attention as well as interactions between the senses.

Temporal predictability enhances auditory detection.

Periodic stimuli are common in natural environments and are ecologically relevant, for example, footsteps and vocalizations. This study reports a detectability enhancement for temporally cued, periodic sequences. Target noise bursts (embedded in background noise) arriving at the time points which followed on from an introductory, periodic "cue" sequence were more easily detected (by ∼1.5 dB SNR) than identical noise bursts which randomly deviated from the cued temporal pattern. Temporal predictability and corresponding neuronal "entrainment" have been widely theorized to underlie important processes in auditory scene analysis and to confer perceptual advantage. This is the first study in the auditory domain to clearly demonstrate a perceptual enhancement of temporally predictable, near-threshold stimuli.