Herpes simplex virus spreads rapidly in human foreskin, partly driven by chemokine-induced redistribution of Nectin-1 on keratinocytes.

HSV infects keratinocytes in the epidermis of skin via nectin-1. We established a human foreskin explant infection model to investigate HSV entry and spread. HSV1 entry could only be achieved by the topical application of virus via high density microarray projections (HD-MAPs) to the epidermis, which penetrated beyond one third of its thickness, simulating in vivo microtrauma. Rapid lateral spread of HSV1 to a mean of 13 keratinocytes wide occurred after 24 hours and free virus particles were observed between keratinocytes, consistent with an intercellular route of spread. Nectin-1 staining was markedly decreased in foci of infection in the epidermis and in the human keratinocyte HaCaT cell line. Nectin-1 was redistributed, at the protein level, in adjacent uninfected cells surrounding infection, inducible by CCL3, IL-8 (or CXCL8), and possibly CXCL10 and IL-6, thus facilitating spread. These findings provide the first insights into HSV1 entry and spread in human inner foreskin in situ.

Adoption of an Enhanced Recovery After Surgery Protocol Increases Cost of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy and Does not Improve Outcomes.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been shown to reduce length of stay (LOS) and complications. The impact of ERAS protocols on the cost of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has not been studied. PATIENTS AND METHODS: We performed a retrospective cohort analysis of patients undergoing CRS-HIPEC from 2016-2022 at a single quaternary center. Propensity score matching was used to create pre-and post-ERAS cohorts. Cost, overall and serious complications, and intensive care unit (ICU) length of stay (LOS) between the two cohorts were compared using the Mann-Whitney U-test for continuous variables and χ2 test for categorical variables. RESULTS: Our final matched cohort consisted of 100 patients, with 50 patients in both the pre- and post-ERAS groups. After adjusting for patient complexity and inflation, the median total cost [$75,932 ($67,166-102,645) versus $92,992 ($80,720-116,710), p = 0.02] and operating room cost [$26,817 ($23,378-33,121) versus $34,434 ($28,085-$41,379), p < 0.001] were significantly higher in the post-ERAS cohort. Overall morbidity (n = 22, 44% versus n = 17, 34%, p = 0.40) and ICU length of stay [2 days (IQR 1-3) versus 2 days (IQR 1-4), p = 0.70] were similar between the two cohorts. A total cost increase of $22,393 [SE $13,047, 95% CI (-$3178 to $47,965), p = 0.086] was estimated after implementation of ERAS, with operating room cost significantly contributing to this increase [$8419, SE $1628, 95% CI ($5228-11,609), p < 0.001]. CONCLUSIONS: CRS-HIPEC ERAS protocols were associated with higher total costs due to increased operating room costs at a single institution. There was no significant difference in ICU LOS and complications after the implementation of the ERAS protocol.

Examining the Potential of Pharmacies to Expand Pre-Exposure Prophylaxis Access Along Georgia's Fixed-Route Public Transit: A Geospatial Analysis.

BACKGROUND: Despite accounting for more than half of new Human Immunodeficiency Virus diagnoses in the United States, the South has fewer than 30% of all pre-exposure prophylaxis users. Pre-exposure prophylaxis access geospatial analyses have focused on drive time but analyses along public transit routes have not been evaluated. Given the proximity to pharmacists and pharmacies, involvement in pre-exposure prophylaxis services may increase access and uptake of this preventative health need. OBJECTIVE: The objectives were to compare the rate of pre-exposure prophylaxis uptake between Georgia counties with and without public transit, to assess the geospatial accessibility of services along public transit, and to evaluate the potential impact of expanding pre-exposure prophylaxis services to community pharmacies. METHODS: Pre-exposure prophylaxis uptake rates between counties with and without public transit were compared using the Mann-Whitney U test. Geospatial analysis was performed using ArcGIS Pro and Geoda. The Pearson correlation coefficient was used to determine the relationship between pre-exposure prophylaxis uptake rates and population and county characteristics. Spatial analysis was completed to uncover predictors for pre-exposure prophylaxis uptake rates. Increased access to pre-exposure prophylaxis along public transit was calculated by reporting the number of counties that would experience at least a 50% increase in pre-exposure prophylaxis access through community pharmacies. RESULTS: Pre-exposure prophylaxis uptake is significantly higher in Georgia counties with versus without public transit (P < 0.001). Pre-exposure prophylaxis rate is positively correlated with the accessibility of community pharmacies and pre-exposure prophylaxis clinics along fixed-route public transit (R2 = 0.524). Among pre-exposure prophylaxis clinics, 44% are inaccessible by public transit alone. Community pharmacies are significantly more widely distributed and accessible along public transit routes than pre-exposure prophylaxis clinics. CONCLUSION: Transportation remains a barrier to accessing pre-exposure prophylaxis. Georgia community pharmacies along public transit may serve as a solution to pre-exposure prophylaxis care access barriers.

Reprint of: Survey of Georgia community pharmacists' needs to engage in advanced community pharmacy services.

BACKGROUND: Community pharmacists improve health, reduce fragmentation in care, lower health costs, and improve health outcomes. In Georgia, pharmacists are able to enter collaborative drug therapy management protocols, such as hypertension management, with a collaborating physician, which may allow pharmacists to provide advanced community pharmacy services (ACPS), however few Georgia pharmacists have this licensure. No program(s) exist that empower pharmacists to successfully engage in ACPS across the state of Georgia nor trains pharmacists to successfully engage in collaborative practice. OBJECTIVE: The goal of this project was to explore community pharmacists' perception, confidence, and engagement in ACPS and how this can improve access to care in Georgia. METHODS: Six hundred one independent community pharmacists were sent an electronic survey May 13, 2022, with weekly email reminders through June 17, 2022. Results were analyzed with the independent sample t test. Thematic analysis was completed on open response survey questions. RESULTS: Ninety responses were received (15% response rate). In the majority of survey outcomes, no differences were found in needs for success between rural versus urban pharmacists. Pharmacies with a smaller technician-to-pharmacists ≤2 (staffing) ratios identified billing for services as a higher priority need for success for them to confidently engage in ACPS (P = 0.012) while pharmacies with a higher technician-to-pharmacists >2 (staffing) ratio agreed a larger need was in optimization of current workflow to allow for advanced community pharmacy service incorporation (P = 0.034). All community pharmacists agreed they would require expansion in staffing and the qualities desired for additional hires to support ACPS include ambition, proficiency, and communication skills. CONCLUSION: Numerous needs for success exist for community pharmacists to feel comfortable and confident to engage in ACPS. Addressing these needs may increase community pharmacist impact through increasing utilization of these services.

Survey of Georgia community pharmacists' needs to engage in advanced community pharmacy services.

BACKGROUND: Community pharmacists improve health, reduce fragmentation in care, lower health costs, and improve health outcomes. In Georgia, pharmacists are able to enter collaborative drug therapy management protocols, such as hypertension management, with a collaborating physician, which may allow pharmacists to provide advanced community pharmacy services (ACPS), however few Georgia pharmacists have this licensure. No program(s) exist that empower pharmacists to successfully engage in ACPS across the state of Georgia nor trains pharmacists to successfully engage in collaborative practice. OBJECTIVE: The goal of this project was to explore community pharmacists' perception, confidence, and engagement in ACPS and how this can improve access to care in Georgia. METHODS: Six hundred one independent community pharmacists were sent an electronic survey May 13, 2022, with weekly email reminders through June 17, 2022. Results were analyzed with the independent sample t test. Thematic analysis was completed on open response survey questions. RESULTS: Ninety responses were received (15% response rate). In the majority of survey outcomes, no differences were found in needs for success between rural versus urban pharmacists. Pharmacies with a smaller technician-to-pharmacists ≤2 (staffing) ratios identified billing for services as a higher priority need for success for them to confidently engage in ACPS (P = 0.012) while pharmacies with a higher technician-to-pharmacists >2 (staffing) ratio agreed a larger need was in optimization of current workflow to allow for advanced community pharmacy service incorporation (P = 0.034). All community pharmacists agreed they would require expansion in staffing and the qualities desired for additional hires to support ACPS include ambition, proficiency, and communication skills. CONCLUSION: Numerous needs for success exist for community pharmacists to feel comfortable and confident to engage in ACPS. Addressing these needs may increase community pharmacist impact through increasing utilization of these services.

Collaborative drug therapy modification (CDTM): Facilitators, barriers, and perceptions of individual pharmacist participation in Georgia.

BACKGROUND: Georgia Board of Pharmacy (BOP) regulations permit pharmacists to engage in collaborative drug therapy modification (CDTM) with physicians, allowing them to perform patient assessments, adjust pharmacotherapy, and order laboratory tests. Pharmacist-led CDTM can positively affect health outcomes leading to reduced healthcare expenditures. CDTM is underutilized, with < 1% of Georgia pharmacists holding an active license to practice CDTM. OBJECTIVE(S): The objective of this study was to examine CDTM licensed pharmacists' perceptions of facilitators and barriers in providing CDTM. METHODS: Georgia-licensed CDTM pharmacists were invited to participate in a 60-minute qualitative interview. Interview questions were developed from electronic survey responses. The interview was designed to elicit information regarding perceived benefits and barriers to CDTM implementation. Guided by the Consolidated Framework for Implementation Research, thematic analysis was applied to identify themes using ATLAS.ti software to code. Themes were described qualitatively and prevalence of each was reported. RESULTS: Nine interviews were conducted, and data saturation was achieved at interview 6. After resolution of discrepancies, 100% coding agreement was reached among 2 independent researchers. Nine themes were identified, and each was categorized as a facilitator or barrier to establishing pharmacist-led CDTM in Georgia. Themes associated with facilitating were (prevalence %) (1) practice autonomy (100), (2) personal attributes (100), (3) having support (100), and (4) institutional logistics (88). Barrier themes included issues concerning (5) the Georgia BOP (100), (6) pharmacist autonomy (88), (7) lack of provider status (88), (8) institutional restrictions (75), and (9) personal development (e.g., confidence) (22). CONCLUSION: Facilitators to the establishment of pharmacist-led CDTM exist and pharmacists can capitalize on these to create successful CDTM programs. Barriers are varied, and it may be difficult to systematically address individual barriers such as pharmacist autonomy and personal development. Barriers associated with institutional restrictions, the Georgia BOP, and lack of provider status can likely be removed or addressed by policy.

Plasmacytoid dendritic cells have divergent effects on HIV infection of initial target cells and induce a pro-retention phenotype.

Although HIV infection inhibits interferon responses in its target cells in vitro, interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, pDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.

Georgia community pharmacies and clinics: An evaluation of health outcomes and care access.

BACKGROUND: Care access remains a major social determinant of health. Safety net clinics may not be numerically sufficient to meet the health care demand for vulnerable populations. Community pharmacists remain a trusted health care provider and serve as first-line care access points. To date, Georgia care access points by safety net clinics and community pharmacies have not been compared. OBJECTIVES: This study sought to evaluate care access across Georgia. County health outcomes and health factor rankings were compared with mortality prevalence of respiratory disease, diabetes mellitus, kidney disease, and a composite of ambulatory care sensitive conditions emergency department (ER) utilization and hospital discharge. In addition, this study sought to determine whether care access points improve if community pharmacies were to provide primary care services. DESIGN AND OUTCOME MEASURES: Geographic information systems mapping was used to locate safety net clinics and community pharmacies. Care access difference was analyzed using a 2-sample t test and health outcomes and rankings were evaluated using ordinary least square regression analysis. RESULTS: A significant difference in care access points was found between safety net clinics and community pharmacies across the state of Georgia (P < 0.05). Mortality prevalence for respiratory disease (P < 0.01), diabetes mellitus (P < 0.1), kidney disease (P < 0.05), ER utilization (P < 0.01), and hospital discharge (P < 0.01) was lower in counties in the top 50% than the bottom 50% health outcome ranking and health factor ranking. Approximately 95% of counties (n = 151) would experience more than a 50% increase in primary care access points by way of community pharmacies. CONCLUSION: Community pharmacies are well positioned to address primary care disease states, reduce health care resource strain, and decrease preventable health care resource utilization. Leveraging pharmacists to provide primary care services can address care access issues and may improve care quality and reduce preventable hospitalizations and ER utilization in Georgia.

A Scoping Review Evaluating the Effect of SGLT-2 Inhibitors on Insulin Dose Requirements in Insulin-Dependent Patients With Type 2 Diabetes.

OBJECTIVE: Assess evidence describing the effect of Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors on total daily insulin (TDI) requirements in insulin-dependent patients with type 2 diabetes. DATA SOURCES: A scoping review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Protocols and Scoping Reviews (PRISMA-ScR) guidelines. The search was conducted in PubMed; citation mapping was completed in Web of Science. Filters for human studies, English language, and a publication date, from January 1, 2005 to April 12, 2021, were applied. STUDY SELECTION AND DATA EXTRACTION: Studies assessing insulin dose requirements with concurrent use of an SGLT2 inhibitor for patients with type 2 diabetes were included. DATA SYNTHESIS: Sixteen studies were included and demonstrated that addition of an SGLT2 inhibitor typically reduced TDI requirements. Insulin reductions were often statistically significant, occurring in studies evaluating (1) within subjects who received SGLT2 inhibitors, and (2) between subjects receiving SGLT2 inhibitors versus placebo. Compared with placebo, insulin dose reduction ranged from -0.72 to -19.2 units. However, studies were relatively small, not designed to assess TDI change, and some utilized fixed dose insulin protocols or empiric insulin dose reductions. CONCLUSIONS: Lowering insulin requirements may have benefits, such as decreased hypoglycemia risk, insulin resistance, and cost. Addition of an SGLT2 inhibitor may modestly reduce TDI requirements for patients with type 2 diabetes. Evidence indicating SGLT2 inhibitor use reduces TDI may lead to additional implementation in practice and inform future research. Further research is needed to clarify insulin type (i.e., basal or prandial) and degree of TDI reduction expected with addition of an SGLT2 inhibitor.

Lateralized Cerebral Processing of Abstract Linguistic Structure in Clear and Degraded Speech.

Human cortical activity measured with magnetoencephalography (MEG) has been shown to track the temporal regularity of linguistic information in connected speech. In the current study, we investigate the underlying neural sources of these responses and test the hypothesis that they can be directly modulated by changes in speech intelligibility. MEG responses were measured to natural and spectrally degraded (noise-vocoded) speech in 19 normal hearing participants. Results showed that cortical coherence to "abstract" linguistic units with no accompanying acoustic cues (phrases and sentences) were lateralized to the left hemisphere and changed parametrically with intelligibility of speech. In contrast, responses coherent to words/syllables accompanied by acoustic onsets were bilateral and insensitive to intelligibility changes. This dissociation suggests that cerebral responses to linguistic information are directly affected by intelligibility but also powerfully shaped by physical cues in speech. This explains why previous studies have reported widely inconsistent effects of speech intelligibility on cortical entrainment and, within a single experiment, provided clear support for conclusions about language lateralization derived from a large number of separately conducted neuroimaging studies. Since noise-vocoded speech resembles the signals provided by a cochlear implant device, the current methodology has potential clinical utility for assessment of cochlear implant performance.

An efficient and adaptive test of auditory mental imagery.

The ability to silently hear music in the mind has been argued to be fundamental to musicality. Objective measurements of this subjective imagery experience are needed if this link between imagery ability and musicality is to be investigated. However, previous tests of musical imagery either rely on self-report, rely on melodic memory, or do not cater in range of abilities. The Pitch Imagery Arrow Task (PIAT) was designed to address these shortcomings; however, it is impractically long. In this paper, we shorten the PIAT using adaptive testing and automatic item generation. We interrogate the cognitive processes underlying the PIAT through item response modelling. The result is an efficient online test of auditory mental imagery ability (adaptive Pitch Imagery Arrow Task: aPIAT) that takes 8 min to complete, is adaptive to participant's individual ability, and so can be used to test participants with a range of musical backgrounds. Performance on the aPIAT showed positive moderate-to-strong correlations with measures of non-musical and musical working memory, self-reported musical training, and general musical sophistication. Ability on the task was best predicted by the ability to maintain and manipulate tones in mental imagery, as well as to resist perceptual biases that can lead to incorrect responses. As such, the aPIAT is the ideal tool in which to investigate the relationship between pitch imagery ability and musicality.

Macrophage Activation in the Dorsal Root Ganglion in Rats Developing Autotomy after Peripheral Nerve Injury.

Autotomy, self-mutilation of a denervated limb, is common in animals after peripheral nerve injury (PNI) and is a reliable proxy for neuropathic pain in humans. Understanding the occurrence and treatment of autotomy remains challenging. The objective of this study was to investigate the occurrence of autotomy in nude and Wistar rats and evaluate the differences in macrophage activation and fiber sensitization contributing to the understanding of autotomy behavior. Autotomy in nude and Wistar rats was observed and evaluated 6 and 12 weeks after sciatic nerve repair surgery. The numbers of macrophages and the types of neurons in the dorsal root ganglion (DRG) between the two groups were compared by immunofluorescence studies. Immunostaining of T cells in the DRG was also assessed. Nude rats engaged in autotomy with less frequency than Wistar rats. Autotomy symptoms were also relatively less severe in nude rats. Immunofluorescence studies revealed increased macrophage accumulation and activation in the DRG of Wistar rats. The percentage of NF200+ neurons was higher at 6 and 12 weeks in Wistar rats compared to nude rats, but the percentage of CGRP+ neurons did not differ between two groups. Additionally, macrophages were concentrated around NF200-labeled A fibers. At 6 and 12 weeks following PNI, CD4+ T cells were not found in the DRG of the two groups. The accumulation and activation of macrophages in the DRG may account for the increased frequency and severity of autotomy in Wistar rats. Our results also suggest that A fiber neurons in the DRG play an important role in autotomy.

Theta oscillations support the interface between language and memory.

Recent evidence shows that hippocampal theta oscillations, usually linked to memory and navigation, are also observed during online language processing, suggesting a shared neurophysiological mechanism between language and memory. However, it remains to be established what specific roles hippocampal theta oscillations may play in language, and whether and how theta mediates the communication between the hippocampus and the perisylvian cortical areas, generally thought to support language processing. With whole-head magnetoencephalographic (MEG) recordings, the present study investigated these questions with two experiments. Using a violation paradigm, extensively used for studying neural underpinnings of different aspects of linguistic processing, we found increased theta power (4-8 â€‹Hz) in the hippocampal formation, when participants read a semantically incorrect vs. correct sentence ending. Such a pattern of results was replicated using different sentence stimuli in another cohort of participants. Importantly, no significant hippocampal theta power increase was found when participants read a semantically correct but syntactically incorrect sentence ending vs. a correct sentence ending. These findings may suggest that hippocampal theta oscillations are specifically linked to lexical-semantic related processing, and not general information processing in sentence reading. Furthermore, we found significantly transient theta phase coupling between the hippocampus and the left superior temporal gyrus, a hub area of the cortical network for language comprehension. This transient theta phase coupling may provide an important channel that links the memory and language systems for the generation of sentence meaning. Overall, these findings help specify the role of hippocampal theta in language, and provide a novel neurophysiological mechanism at the network level that may support the interface between memory and language.

Ordered Hydrogen-Bonded Alcohol Networks Confined in Lewis Acid Zeolites Accelerate Transfer Hydrogenation Turnover Rates.

The disruption of ordered water molecules confined within hydrophobic reaction pockets alters the energetics of adsorption and catalysis, but a mechanistic understanding of how nonaqueous solvents influence catalysis in microporous voids remains unclear. Here, we use kinetic analyses coupled with IR spectroscopy to study how alkanol hydrogen-bonding networks confined within hydrophobic and hydrophilic zeolite catalysts modify reaction free energy landscapes. Hydrophobic Beta zeolites containing framework Sn atoms catalyze the transfer hydrogenation reaction of cyclohexanone in a 2-butanol solvent 10× faster than their hydrophilic analogues. This rate enhancement stems from the ability of hydrophobic Sn-Beta to inhibit the formation of extended liquid-like 2-butanol oligomers and promote dimeric H-bonded 2-butanol networks. These different intraporous 2-butanol solvent structures manifest as differences in the activation and adsorption enthalpies and entropies that comprise the free energy landscape of transfer hydrogenation catalysis. The ordered H-bonding solvent network present in hydrophobic Sn-Beta stabilizes the transfer hydrogenation transition state to a greater extent than the liquid-like 2-butanol solvent present in hydrophilic Sn-Beta, giving rise to higher turnover rates on hydrophobic Sn-Beta. Additionally, reactant adsorption within hydrophobic Sn-Beta is driven by the breakup of intraporous solvent-solvent interactions, resulting in positive enthalpies of adsorption that are partially compensated by an increase in the solvent reorganization entropy. Collectively, these results emphasize the ability of the zeolite pore to regulate the structure of confined nonaqueous H-bonding solvent networks, which offers an additional dimension to modulate adsorption and reactivity.

Individual differences in motor development during early childhood: An MEG study.

In a previous study, we reported the first measurements of pre-movement and sensorimotor cortex activity in preschool age children (ages 3-5 years) using a customized pediatric magnetoencephalographic system. Movement-related activity in the sensorimotor cortex differed from that typically observed in adults, suggesting that maturation of cortical motor networks was still incomplete by late preschool age. Here we compare these earlier results to a group of school age children (ages 6-8 years) including seven children from the original study measured again two years later, and a group of adults (mean age 31.1 years) performing the same task. Differences in movement-related brain activity were observed both longitudinally within children in which repeated measurements were made, and cross-sectionally between preschool age children, school age children, and adults. Movement-related mu (8-12 Hz) and beta (15-30 Hz) oscillations demonstrated linear increases in amplitude and mean frequency with age. In contrast, movement-evoked gamma synchronization demonstrated a step-like transition from low (30-50 Hz) to high (70-90 Hz) narrow-band oscillations, and this occurred at different ages in different children. Notably, pre-movement activity ('readiness fields') observed in adults was absent in even the oldest children. These are the first direct observations of brain activity accompanying motor responses throughout early childhood, confirming that maturation of this activity is still incomplete by mid-childhood. In addition, individual children demonstrated markedly different developmental trajectories in movement-related brain activity, suggesting that individual differences need to be taken into account when studying motor development across age groups.

The glycosyltransferase GnT-III activates Notch signaling and drives stem cell expansion to promote the growth and invasion of ovarian cancer.

Glycosylation changes associated with cellular transformation can facilitate the growth and progression of tumors. Previously we discovered that the gene Mgat3 encoding the glycosyltransferase GnT-III is elevated in epithelial ovarian carcinomas (EOCs) and leads to the production of abnormal truncated N-linked glycan structures instead of the typical bisected forms. In this study, we are interested in discovering how these abnormal glycans impact the growth and progression of ovarian cancer. We have discovered using stable shRNA gene suppression that GnT-III expression controls the expansion of side-population cells, also known as cancer stem cells. More specifically, we found that GnT-III expression regulates the levels and activation of the heavily glycosylated Notch receptor involved in normal and malignant development. Suppression of GnT-III in EOC cell lines and primary tumor-derived cells resulted in an inhibition of Notch signaling that was more potent than pharmacologic blockage of Notch activation via γ-secretase inhibition. The inhibition resulted from the redirection of the Notch receptor to the lysosome, a novel mechanism. These findings demonstrate a new role for bisecting glycosylation in the control of Notch transport and demonstrate the therapeutic potential of inhibiting GnT-III as a treatment for controlling EOC growth and recurrence.

High-gamma activity in the human hippocampus and parahippocampus during inter-trial rest periods of a virtual navigation task.

In rodents, hippocampal cell assemblies formed during learning of a navigation task are observed to re-emerge during resting (offline) periods, accompanied by high-frequency oscillations (HFOs). This phenomenon is believed to reflect mechanisms for strengthening newly-formed memory traces. Using magnetoencephalography recordings and a beamforming source location algorithm (synthetic aperture magnetometry), we investigated high-gamma (80-140 Hz) oscillations in the hippocampal region in 18 human participants during inter-trial rest periods in a virtual navigation task. We found right hippocampal gamma oscillations mirrored the pattern of theta power in the same region during navigation, varying as a function of environmental novelty. Gamma power during inter-trial rest periods was positively correlated with theta power during navigation in the first task set when the environment was new and predicted greater performance improvement in the subsequent task set two where the environment became familiar. These findings provide evidence for human hippocampal reactivation accompanied by high-gamma activities immediately after learning and establish a link between hippocampal high-gamma activities and subsequent memory performance.

Atypical brain responses to auditory spatial cues in adults with autism spectrum disorder.

The auditory processing atypicalities experienced by many individuals on the autism spectrum disorder might be understood in terms of difficulties parsing the sound energy arriving at the ears into discrete auditory 'objects'. Here, we asked whether autistic adults are able to make use of two important spatial cues to auditory object formation - the relative timing and amplitude of sound energy at the left and right ears. Using electroencephalography, we measured the brain responses of 15 autistic adults and 15 age- and verbal-IQ-matched control participants as they listened to dichotic pitch stimuli - white noise stimuli in which interaural timing or amplitude differences applied to a narrow frequency band of noise typically lead to the perception of a pitch sound that is spatially segregated from the noise. Responses were contrasted with those to stimuli in which timing and amplitude cues were removed. Consistent with our previous studies, autistic adults failed to show a significant object-related negativity (ORN) for timing-based pitch, although their ORN was not significantly smaller than that of the control group. Autistic participants did show an ORN to amplitude cues, indicating that they do not experience a general impairment in auditory object formation. However, their P400 response - thought to indicate the later attention-dependent aspects of auditory object formation - was missing. These findings provide further evidence of atypical auditory object processing in autism with potential implications for understanding the perceptual and communication difficulties associated with the condition.