Maternal fluoxetine exposure alters cortical hemodynamic and calcium response of offspring to somatosensory stimuli

Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model. While resting-state homotopic contralateral functional connectivity was unperturbed, the evoked cortical response to forepaw stimulation was altered in FLX mice. The stimulated cortex showed decreased activity for FLX versus controls, by both hemodynamic responses [oxyhemoglobin (Hb

Regulated RNA Editing and Functional Epistasis in Shaker Potassium Channels

Regulated point modification by an RNA editing enzyme occurs at four conserved sites in the Drosophila Shaker potassium channel. Single mRNA molecules can potentially represent any of 24 = 16 permutations (isoforms) of these natural variants. We generated isoform expression profiles to assess sexually dimorphic, spatial, and temporal differences. Striking tissue-specific expression was seen for particular isoforms. Moreover, isoform distributions showed evidence for coupling (linkage) of editing sites. Genetic manipulations of editing enzyme activity demonstrated that a chief determinant of Shaker editing site choice resides not in the editing enzyme, but rather, in unknown factors intrinsic to cells. Characterizing the biophysical properties of currents in nine isoforms revealed an unprecedented feature, functional epistasis; biophysical phenotypes of isoforms cannot be explained simply by the consequences of individual editing effects at the four sites. Our results unmask allosteric communication across disparate regions of the channel protein and between evolved and regulated amino acid changes introduced by RNA editing

Carpenters Gap 1: A 47,000 year old record of indigenous adaption and innovation

Here we present the first detailed analysis of the archaeological finds from Carpenters Gap 1 rockshelter, one of the oldest radiocarbon dated sites in Australia and one of the few sites in the Sahul region to preserve both plant and animal remains down to the lowest Pleistocene aged deposits. Occupation at the site began between 51,000 and 45,000 cal BP and continued into the Last Glacial Maximum, and throughout the Holocene. While CG1 has featured in several studies, the full complement of 100 radiocarbon dates is presented here for the first time in stratigraphic context, and a Bayesian model is used to evaluate the age sequence. We present analyses of the stone artefact and faunal assemblages from Square A2, the oldest and deepest square excavated. These data depict a remarkable record of adaptation in technology, mobility, and diet breadth spanning 47,000 years. We discuss the dating and settlement record from CG1 and other northern Australian sites within the context of the new dates for occupation of Madjedbebe in Arnhem Land at 65,000 years (±5700), and implications for colonisation and dispersal within Sahul.We thank the Bunuba Aboriginal Corporation for their assistance in this work. Radiocarbon dates obtained in 2013 and 2014 and micromorphological research by Vannieuwenhuyse were funded by the Australian Research Council grant LP100200415 ‘Lifeways of the first Australians’ with contributions from the Kimberley Foundation Australia and the Department of Sustainability, Water, Populations and Communities, awarded to O'Connor and Balme, as well as support from the Centre of Excellence for Australian Biodiversity and Heritage as well as support from the Australian Research Council Centre of Excellence for Australian Biodiversity and Heritage (CE170100015)

Integration of a Retrograde Signal during Synapse Formation by Glia-Secreted TGF-β Ligand

SummaryGlial cells are crucial regulators of synapse formation, elimination, and plasticity [1, 2]. In vitro studies have begun to identify glial-derived synaptogenic factors [1], but neuron-glia signaling events during synapse formation in vivo remain poorly defined. The coordinated development of pre- and postsynaptic compartments at the Drosophila neuromuscular junction (NMJ) depends on a muscle-secreted retrograde signal, the TGF-β/BMP Glass bottom boat (Gbb) [3, 4]. Muscle-derived Gbb activates the TGF-β receptors Wishful thinking (Wit) and either Saxophone (Sax) or Thick veins (Tkv) in motor neurons [3, 4]. This induces phosphorylation of Mad (P-Mad) in motor neurons, its translocation into the nucleus with a co-Smad, and activation of transcriptional programs controlling presynaptic bouton growth [5]. Here we show that NMJ glia release the TGF-β ligand Maverick (Mav), which likely activates the muscle activin-type receptor Punt to potently modulate Gbb-dependent retrograde signaling and synaptic growth. Loss of glial Mav results in strikingly reduced P-Mad at NMJs, decreased Gbb transcription in muscle, and in turn reduced muscle-to-motor neuron retrograde TGF-β/BMP signaling. We propose that by controlling Gbb release from muscle, glial cells fine tune the ability of motor neurons to extend new synaptic boutons in correlation to muscle growth. Our work identifies a novel glia-derived synaptogenic factor by which glia modulate synapse formation in vivo

Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

BACKGROUND: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. METHODS: We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1 RESULTS: Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1 CONCLUSIONS: These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics

MyChart Messaging: Patient Preferences about Timing of Provider Responses to Medical Advice Requests

Background: Patients frequently utilize portal messaging to reach their healthcare provider.1 This mode of communication allows for greater patient engagement in health concerns.2 MyChart messaging has grown recently, increasing physician workload.3,4 Understanding patient preferences for MyChart messaging may improve patient communication, potentially decreasing the response burden on physicians. Methods: A 12-question REDCap survey was sent via MyChart message to 31,502 patients in 8 UVM Health Network (UVMHN) affiliated adult primary care and family medicine practices. Survey data were analyzed in excel. Key Results: The survey was completed by 2011 (6.4%) patients, with 77% of respondents having used MyChart to ask their provider a question. MyChart messaging is always or often (69.1%) the first method patients use to contact their healthcare provider with 22% submitting urgent concerns. There is a significant association between when a patient prefers to receive a message and the time it takes providers to respond to their message (p \u3c 0.001). On average, patients would prefer to not restrict MyChart messaging to business hours. Discussion: Patients prefer prompt message responses from their providers and providers are meeting this preference. Future work could better observe the relationship between provider response time and patient preferences for physician response time. Data from Epic should be analyzed to determine if patient perceptions align with MyChart message records. Other efforts should include educating patients about appropriate messages to send via MyChart, or if a phone call is warranted. 1 North F, Luhman KE, Mallmann EA, Mallmann TJ, Tulledge-Scheitel SM, North EJ, Pecina JL. A Retrospective Analysis of Provider-to-Patient Secure Messages: How Much Are They Increasing, Who Is Doing the Work, and Is the Work Happening After Hours? JMIR Med Inform. 2020 Jul 8;8(7):e16521. doi: 10.2196/16521. 2 Avdagovska M, Ballermann M, Olson K, Graham T, Menon D, Stafinski T. Patient Portal Implementation and Uptake: Qualitative Comparative Case Study. J Med Internet Res. 2020;22(7):e18973. 3 Arndt BG, Beasley JW, Watkinson MD, et al. Tethered to the EHR: Primary Care Physician Workload Assessment Using EHR Event Log Data and Time-Motion Observations. Ann Fam Med. 2017;15(5):419-426. 4 Laccetti AL, Chen B, Cai J, et al. Increase in Cancer Center Staff Effort Related to Electronic Patient Portal Use. J Oncol Pract. 2016 (12):e981- e990

Provider Perspectives on Language Barriers in MyChart Enrollment for Patients with Limited English Proficiency

Background: There are 25 million people in the United States with limited English proficiency (LEP). Patients with LEP are a vulnerable population who may have worse health outcomes compared to English-proficient patients, as they face barriers to safe, effective, and high-quality care. Previous studies show this population is likely to benefit from utilization of patient portals, which allow users to access personal health information and communicate with healthcare providers. Current literature reports that patients with LEP and their families have a strong interest in using the patient portal as it can help them understand their providers and health, remember their care plan, and have more control over their health. However, there is less portal access and utilization among patients with LEP. This study was conducted to obtain provider perspectives surrounding MyChart engagement of patients with LEP to identify potential barriers to MyChart enrollment at the University of Vermont Health Network (UVMHN). Methods: EPIC’s Slicer Dicer tool was utilized to obtain UVMHN patient counts organized by reported language and MyChart activation. Data was collected from an anonymous REDCap survey sent to 211 providers within UVMHN Departments of General Internal Medicine, Family Medicine, and Pediatrics, and analyzed utilizing Excel. Results: 67.9% of UVMHN Primary Care English speakers have MyChart activated compared to 46.9% of patients with LEP. Providers strongly believe that MyChart is beneficial to patients and families with 72.1% of providers agreeing that it improves the patient-provider relationship. When asked specifically about patients with LEP, 36% of providers agree that MyChart access is beneficial to care. 49% report they are likely to encourage MyChart enrollment to their patients with LEP; however, only 14% know how to assist in enrollment. Differences in knowledge of language services are seen in different visit modalities: 78.1% of providers report ability to provide language services during in-person visits compared to 48.8% for video visits and 46.3% for telephone visits. Once made aware of the differences in MyChart activation status between English proficient patients and patients with LEP, providers frequently requested more education around language assistance, MyChart activation instructions to provide patients in their dominant language, translation tools within EPIC, and training for support staff to also encourage patients with LEP to enroll in MyChart. Conclusions: While providers overwhelmingly believe MyChart is useful to patient care and are likely to recommend it to their patients with LEP, they lack the tools and education necessary to aid in equitable enrollment. Educational materials and translated resources should be created for providers to utilize in assisting their patients with LEP. A follow-up study with patients would provide an opportunity to compare patient and provider responses and gain additional perspectives on MyChart access and utilization

Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p= 4.89 x 10 - 57) , high mitotic index (p= 5.25 x 10 - 28), pleomorphism (p= 6.31 x 10-19), ER negative (p= 9.02 x 10-35 ), PR negative (p= 9.24 x 10-24 ), triple negative phenotype (p= 6.67 x 10-21) , PAM50.Her2 (p=5.19 x 10-13 ), PAM50.Basal (p=2.7 x 10-41), PAM50.LumB (p=1.56 x 10-26), integrative molecular cluster 1 (intClust.1) ( p=7.47 x 10-12), intClust.5 (p=4.05 x 10-12) and intClust. 10 (p=7.59 x 10-38 ) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p=4.4 x 10-16) and multivariate analysis (p=9.19 x 10-7). At the protein level, in ER positive tumours , FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps< 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps<0.05). In ER positive as well as in ER negative tumours, FEN1 protein over expression is associated with poor survival in univariate and multivariate analysis (ps<0.01). In ovarian epithelial cancers , similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps<0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer

Assignment of epidemiological lineages in an emerging pandemic using the pangolin tool.

Funder: Oxford Martin School, University of OxfordThe response of the global virus genomics community to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been unprecedented, with significant advances made towards the 'real-time' generation and sharing of SARS-CoV-2 genomic data. The rapid growth in virus genome data production has necessitated the development of new analytical methods that can deal with orders of magnitude of more genomes than previously available. Here, we present and describe Phylogenetic Assignment of Named Global Outbreak Lineages (pangolin), a computational tool that has been developed to assign the most likely lineage to a given SARS-CoV-2 genome sequence according to the Pango dynamic lineage nomenclature scheme. To date, nearly two million virus genomes have been submitted to the web-application implementation of pangolin, which has facilitated the SARS-CoV-2 genomic epidemiology and provided researchers with access to actionable information about the pandemic's transmission lineages

Body Temperature Monitoring and SARS Fever Hotline, Taiwan

In Taiwan, a temperature-monitoring campaign and hotline for severe acute respiratory syndrome (SARS) fever were implemented in June 2003. Among 1,966 calls, fever was recorded in 19% (n = 378); 18 persons at high risk for SARS were identified. In a cross-sectional telephone survey, 95% (n = 1,060) of households knew about the campaign and 7 households reported fever