Ice and ocean constraints on early human migrations into North America along the Pacific coast.

Founding populations of the first Americans likely occupied parts of Beringia during the Last Glacial Maximum (LGM). The timing, pathways, and modes of their southward transit remain unknown, but blockage of the interior route by North American ice sheets between ~26 and 14 cal kyr BP (ka) favors a coastal route during this period. Using models and paleoceanographic data from the North Pacific, we identify climatically favorable intervals when humans could have plausibly traversed the Cordilleran coastal corridor during the terminal Pleistocene. Model simulations suggest that northward coastal currents strengthened during the LGM and at times of enhanced freshwater input, making southward transit by boat more difficult. Repeated Cordilleran glacial-calving events would have further challenged coastal transit on land and at sea. Following these events, ice-free coastal areas opened and seasonal sea ice was present along the Alaskan margin until at least 15 ka. Given evidence for humans south of the ice sheets by 16 ka and possibly earlier, we posit that early people may have taken advantage of winter sea ice that connected islands and coastal refugia. Marine ice-edge habitats offer a rich food supply and traversing coastal sea ice could have mitigated the difficulty of traveling southward in watercraft or on land over glaciers. We identify 24.5 to 22 ka and 16.4 to 14.8 ka as environmentally favorable time periods for coastal migration, when climate conditions provided both winter sea ice and ice-free summer conditions that facilitated year-round marine resource diversity and multiple modes of mobility along the North Pacific coast.

Classical creativity: A functional magnetic resonance imaging (fMRI) investigation of pianist and improviser Gabriela Montero.

Improvisation is sometimes described as instant composition and offers a glimpse into real-time musical creativity. Over the last decade, researchers have built up our understanding of the core neural activity patterns associated with musical improvisation by investigating cohorts of professional musicians. However, since creative behavior calls on the unique individuality of an artist, averaging data across musicians may dilute important aspects of the creative process. By performing case study investigations of world-class artists, we may gain insight into their unique creative abilities and achieve a deeper understanding of the biological basis of musical creativity. In this experiment, functional magnetic resonance imaging and functional connectivity were used to study the neural correlates of improvisation in famed Classical music performer and improviser, Gabriela Montero. GM completed two control tasks of varying musical complexity; for the Scale condition she repeatedly played a chromatic scale and for the Memory condition she performed a given composition by memory. For the experimental improvisation condition, she performed improvisations. Thus, we were able to compare the neural activity that underlies a generative musical task like improvisation to 'rote' musical tasks of playing pre-learned and pre-memorized music. In GM, improvisation was largely associated with activation of auditory, frontal/cognitive, motor, parietal, occipital, and limbic areas, suggesting that improvisation is a multimodal activity for her. Functional connectivity analysis suggests that the visual network, default mode network, and subcortical networks are involved in improvisation as well. While these findings should not be generalized to other samples or populations, results here shed insight into the brain activity that underlies GM's unique abilities to perform Classical-style musical improvisations.

Teleneurology service provided via tablet technology: 3-year outcomes and physician satisfaction.

INTRODUCTION: This study aimed to demonstrate that teleneurology consultations conducted via tablet technology are an efficient and cost-effective means of managing acute neurologic emergencies at community-based hospitals and that utilizing such technology yields high community physician satisfaction. METHOD: During a 39-month period, Vanderbilt University Medical Center in Tennessee USA, provided teleneurology services to 10 community-based hospitals that lacked adequate neurology coverage. Hospitalists at one community-based hospital were not comfortable treating any patient with a neurologic symptom, resulting in 100% of those patients being transferred. This facility now retains more than 60% of neurology patients. For less than US$1200, these hospitals were able to meet the only capital expenditure required to launch this service: the purchase of handheld tablet computers. Real-time teleneurology consultations were conducted via tablet using two-way video conferencing, radiologic image sharing, and medical record documentation. Community physicians were regularly surveyed to assess satisfaction. RESULTS: From February 2014 to May 2017, 3626 teleneurology consultations were conducted. Community physicians, in partnership with neurologists, successfully managed 87% of patients at the community-based hospital. Only 13% of patients required transfer to another facility for a higher level of care. The most common diagnoses included stroke (34%), seizure (11%), and headache/migraine (6%). The average time for the neurologist to answer a request for consultation page and connect with the community physician was 10.6 minutes. Ninety-one percent of community physicians were satisfied or somewhat satisfied with the overall service. CONCLUSION: In the assessment of neurology patients, tablets are a more cost-effective alternative to traditional telehealth technologies. The devices promote efficiency in consultations through ease of use and low transfer rates, and survey results indicate community physician satisfaction.

Configurational and Conformational Equilibria of N6-(2-Deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5- N-methylformamidopyrimidine (MeFapy-dG) Lesion in DNA.

The most common lesion in DNA occurring due to clinical treatment with Temozolomide or cellular exposures to other methylating agents is 7-methylguanine (N7-Me-dG). It can undergo a secondary reaction to form N6-(2-deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5- N-methylformamidopyrimidine (MeFapy-dG). MeFapy-dG undergoes epimerization in DNA to produce either α or ß deoxyribose anomers. Additionally, conformational rotation around the formyl bond, C5- N5 bond, and glycosidic bond may occur. To characterize and quantitate the mixture of these isomers in DNA, a 13C-MeFapy-dG lesion, in which the CH3 group of the MeFapy-dG was isotopically labeled, was incorporated into the trimer 5'-TXT-3' and the dodecamer 5'-CATXATGACGCT-3' (X = 13C-MeFapy-dG). NMR spectroscopy of both the trimer and dodecamer revealed that the MeFapy-dG lesion exists in single strand DNA as ten configurationally and conformationally discrete species, eight of which may be unequivocally assigned. In the duplex dodecamer, the MeFapy-dG lesion exists as six configurationally and conformationally discrete species. Analyses of NMR data in the single strand trimer confirm that for each deoxyribose anomer, atropisomerism occurs around the C5- N5 bond to produce R a and S a atropisomers. Each atropisomer exhibits geometrical isomerism about the formyl bond yielding E and Z conformations. 1H NMR experiments allow the relative abundances of the species to be determined. For the single strand trimer, the α and ß anomers exist in a 3:7 ratio, favoring the ß anomer. For the ß anomer, with respect to the C5- N5 bond, the R a and S a atropisomers are equally populated. However, the Z geometrical isomer of the formyl moiety is preferred. For the α anomer, the E- S a isomer is present at 12%, whereas all other isomers are present at 5-7%. DNA processing enzymes may differentially recognize different isomers of the MeFapy-dG lesion. Moreover, DNA sequence-specific differences in the populations of configurational and conformational species may modulate biological responses to the MeFapy-dG lesion.

Fractal structure enables temporal prediction in music.

1/f serial correlations and statistical self-similarity (fractal structure) have been measured in various dimensions of musical compositions. Musical performances also display 1/f properties in expressive tempo fluctuations, and listeners predict tempo changes when synchronizing. Here the authors show that the 1/f structure is sufficient for listeners to predict the onset times of upcoming musical events. These results reveal what information listeners use to anticipate events in complex, non-isochronous acoustic rhythms, and this will entail innovative models of temporal synchronization. This finding could improve therapies for Parkinson's and related disorders and inform deeper understanding of how endogenous neural rhythms anticipate events in complex, temporally structured communication signals.

Examining Cash Expenditures and Associated HIV-Related Behaviors Using Financial Diaries in Women Employed by Sex Work in Rural Uganda: Findings from the Kyaterekera Study.

BACKGROUND: Women employed by sex work (WESW) have a high risk of human immunodeficiency virus (HIV) infection and experience economic barriers in accessing care. However, few studies have described their financial lives and the relationship between expenditures and HIV-related behaviors. METHODS: This exploratory study used financial diaries to collect expenditure and income data from WESW in Uganda over 6 months. Data were collected as part of a larger trial that tested the efficacy of an HIV prevention intervention method. Descriptive statistics were used to quantify women's income, relative expenditures, and negative cash balances. Bivariate and multivariate logistic regressions were used to examine the odds of sexual risk behavior or use of HIV medications for several cash scenarios. RESULTS: A total of 163 WESW were enrolled; the participants mean age was 32 years old. Sex work was the sole source of employment for most WESW (99%); their average monthly income was $62.32. Food accounted for the highest proportion of spending (44%) followed by sex work (20%) and housing expenditures (11%). WESW spent the least on health care (5%). Expenditures accounted for a large but variable proportion of these women's income (56% to 101%). Most WESW (74%) experienced a negative cash balance. Some also reported high sex work (28%), health care (24%), and education (28%) costs. The prevalence of condomless sex (77%) and sex with drugs/alcohol (70%) was high compared to use of ART/PrEP (Antiretroviral therapy/Pre-exposure prophylaxis) medications (45%). Women's cash expenditures were not statistically significantly associated with HIV-related behaviors. However, the exploratory study observed a consistent null trend of lower odds of condomless sex (adjusted odds ratio (AOR) = 0.70, 95% confidence interval (CI): 0.28-1.70), sex with drugs/alcohol (AOR = 0.93, 95% CI: 0.42-2.05), and use of ART/PrEP (AOR = 0.80, 95% CI: 0.39-1.67) among women who experienced a negative cash balance versus those who did not. Similar trends were observed for other cash scenarios. CONCLUSION: Financial diaries are a feasible tool to assess the economic lives of vulnerable women. Despite having paid work, most WESW encountered a myriad of financial challenges with limited spending on HIV prevention. Financial protections and additional income-generating activities may improve their status. More robust research is needed to understand the potentially complex relationship between income, expenditures, and HIV risk among vulnerable sex workers.

Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy for Depression: A Systematic Review of Cognitive Outcomes.

Objectives: Summarize existing literature on cognitive outcomes of MBSR and MBCT for individuals with depression. Methods: Following PRISMA (2021) guidance, we conducted a systematic review. We searched databases for studies published from 2000 to 2020 which examined cognitive outcomes of MBSR and MBCT in individuals with at least mild depressive symptoms. The search result in 10 studies (11 articles) meeting inclusion criteria. Results: We identified five single armed trials and five randomized controlled trials. Results indicated that three studies did not show any improvements on cognitive outcomes, and seven studies showed at least one improvement in cognitive outcomes. Conclusions: Overall, the review highlighted several inconsistencies in the literature including inconsistent use of terminology, disparate samples, and inconsistent use of methodology. These inconsistencies may help to explain the mixed results of MBSR and MBCT on cognitive outcomes. Recommendations include a more streamlined approach to studying cognitive outcomes in depressed individuals in the context of MBSR and MBCT.

Use of Diagnosis Codes to Find Blood Transfusion Adverse Events in Electronic Health Records.

OBJECTIVE: Electronic health records (EHRs) and big data tools offer the opportunity for surveillance of adverse events (patient harm associated with medical care). We used International Classification of Diseases, Ninth Revision, codes in electronic records to identify known, and potentially novel, adverse reactions to blood transfusion. METHODS: We used 49,331 adult admissions involving critical care at a major teaching hospital, 2001-2012, in the Medical Information Mart for Intensive Care III EHRs database. We formed a T (defined as packed red blood cells, platelets, or plasma) group of 21,443 admissions versus 25,468 comparison (C) admissions. The International Classification of Diseases, Ninth Revision, Clinical Modification , diagnosis codes were compared for T versus C, described, and tested with statistical tools. RESULTS: Transfusion adverse events (TAEs) such as transfusion-associated circulatory overload (TACO; 12 T cases; rate ratio [RR], 15.61; 95% confidence interval [CI], 2.49-98) were found. There were also potential TAEs similar to TAEs, such as fluid overload disorder (361 T admissions; RR, 2.24; 95% CI, 1.88-2.65), similar to TACO. Some diagnoses could have been sequelae of TAEs, including nontraumatic compartment syndrome of abdomen (52 T cases; RR, 6.76; 95% CI, 3.40-14.9) possibly being a consequence of TACO. CONCLUSIONS: Surveillance for diagnosis codes that could be TAE sequelae or unrecognized TAE might be useful supplements to existing medical product adverse event programs.

Complete Genome Sequence of Microbacterium foliorum Bacteriophage Librie.

Bacteriophage Librie was isolated from a soil sample from Clarksville, TN, using the bacterium Microbacterium foliorum. Librie has a 39,941 bp genome with 62 predicted protein-coding genes and 1 predicted gene for tRNA. Based on its gene content similarity to actinobacteriophages, Librie is grouped with phages in cluster EA5.

Finding Potential Adverse Events in the Unstructured Text of Electronic Health Care Records: Development of the Shakespeare Method.

BACKGROUND: Big data tools provide opportunities to monitor adverse events (patient harm associated with medical care) (AEs) in the unstructured text of electronic health care records (EHRs). Writers may explicitly state an apparent association between treatment and adverse outcome ("attributed") or state the simple treatment and outcome without an association ("unattributed"). Many methods for finding AEs in text rely on predefining possible AEs before searching for prespecified words and phrases or manual labeling (standardization) by investigators. We developed a method to identify possible AEs, even if unknown or unattributed, without any prespecifications or standardization of notes. Our method was inspired by word-frequency analysis methods used to uncover the true authorship of disputed works credited to William Shakespeare. We chose two use cases, "transfusion" and "time-based." Transfusion was chosen because new transfusion AE types were becoming recognized during the study data period; therefore, we anticipated an opportunity to find unattributed potential AEs (PAEs) in the notes. With the time-based case, we wanted to simulate near real-time surveillance. We chose time periods in the hope of detecting PAEs due to contaminated heparin from mid-2007 to mid-2008 that were announced in early 2008. We hypothesized that the prevalence of contaminated heparin may have been widespread enough to manifest in EHRs through symptoms related to heparin AEs, independent of clinicians' documentation of attributed AEs. OBJECTIVE: We aimed to develop a new method to identify attributed and unattributed PAEs using the unstructured text of EHRs. METHODS: We used EHRs for adult critical care admissions at a major teaching hospital (2001-2012). For each case, we formed a group of interest and a comparison group. We concatenated the text notes for each admission into one document sorted by date, and deleted replicate sentences and lists. We identified statistically significant words in the group of interest versus the comparison group. Documents in the group of interest were filtered to those words, followed by topic modeling on the filtered documents to produce topics. For each topic, the three documents with the maximum topic scores were manually reviewed to identify PAEs. RESULTS: Topics centered around medical conditions that were unique to or more common in the group of interest, including PAEs. In each use case, most PAEs were unattributed in the notes. Among the transfusion PAEs was unattributed evidence of transfusion-associated cardiac overload and transfusion-related acute lung injury. Some of the PAEs from mid-2007 to mid-2008 were increased unattributed events consistent with AEs related to heparin contamination. CONCLUSIONS: The Shakespeare method could be a useful supplement to AE reporting and surveillance of structured EHR data. Future improvements should include automation of the manual review process.

The role of Northeast Pacific meltwater events in deglacial climate change.

Columbia River megafloods occurred repeatedly during the last deglaciation, but the impacts of this fresh water on Pacific hydrography are largely unknown. To reconstruct changes in ocean circulation during this period, we used a numerical model to simulate the flow trajectory of Columbia River megafloods and compiled records of sea surface temperature, paleo-salinity, and deep-water radiocarbon from marine sediment cores in the Northeast Pacific. The North Pacific sea surface cooled and freshened during the early deglacial (19.0-16.5 ka) and Younger Dryas (12.9-11.7 ka) intervals, coincident with the appearance of subsurface water masses depleted in radiocarbon relative to the sea surface. We infer that Pacific meltwater fluxes contributed to net Northern Hemisphere cooling prior to North Atlantic Heinrich Events, and again during the Younger Dryas stadial. Abrupt warming in the Northeast Pacific similarly contributed to hemispheric warming during the Bølling and Holocene transitions. These findings underscore the importance of changes in North Pacific freshwater fluxes and circulation in deglacial climate events.

Phasing of millennial-scale climate variability in the Pacific and Atlantic Oceans.

New radiocarbon and sedimentological results from the Gulf of Alaska document recurrent millennial-scale episodes of reorganized Pacific Ocean ventilation synchronous with rapid Cordilleran Ice Sheet discharge, indicating close coupling of ice-ocean dynamics spanning the past 42,000 years. Ventilation of the intermediate-depth North Pacific tracks strength of the Asian monsoon, supporting a role for moisture and heat transport from low latitudes in North Pacific paleoclimate. Changes in carbon-14 age of intermediate waters are in phase with peaks in Cordilleran ice-rafted debris delivery, and both consistently precede ice discharge events from the Laurentide Ice Sheet, known as Heinrich events. This timing precludes an Atlantic trigger for Cordilleran Ice Sheet retreat and instead implicates the Pacific as an early part of a cascade of dynamic climate events with global impact.

Fractal Tempo Fluctuation and Pulse Prediction.

WE INVESTIGATED PEOPLES' ABILITY TO ADAPT TO THE fluctuating tempi of music performance. In Experiment 1, four pieces from different musical styles were chosen, and performances were recorded from a skilled pianist who was instructed to play with natural expression. Spectral and rescaled range analyses on interbeat interval time-series revealed long-range (1/f type) serial correlations and fractal scaling in each piece. Stimuli for Experiment 2 included two of the performances from Experiment 1, with mechanical versions serving as controls. Participants tapped the beat at »- and ⅛-note metrical levels, successfully adapting to large tempo fluctuations in both performances. Participants predicted the structured tempo fluctuations, with superior performance at the »-note level. Thus, listeners may exploit long-range correlations and fractal scaling to predict tempo changes in music.

The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression.

Many viruses shut off host gene expression to inhibit antiviral responses. Viral proteins and host proteins required for viral replication are typically spared in this process, but the mechanisms of target selectivity during host shutoff remain poorly understood. Using transcriptome-wide and targeted reporter experiments, we demonstrate that the influenza A virus endoribonuclease PA-X usurps RNA splicing to selectively target host RNAs for destruction. Proximity-labeling proteomics reveals that PA-X interacts with cellular RNA processing proteins, some of which are partially required for host shutoff. Thus, PA-X taps into host nuclear pre-mRNA processing mechanisms to destroy nascent mRNAs shortly after their synthesis. This mechanism sets PA-X apart from other viral host shutoff proteins that target actively translating mRNAs in the cytoplasm. Our study reveals a unique mechanism of host shutoff that helps us understand how influenza viruses suppress host gene expression.

Shutoff of Host Gene Expression in Influenza A Virus and Herpesviruses: Similar Mechanisms and Common Themes.

The ability to shut off host gene expression is a shared feature of many viral infections, and it is thought to promote viral replication by freeing host cell machinery and blocking immune responses. Despite the molecular differences between viruses, an emerging theme in the study of host shutoff is that divergent viruses use similar mechanisms to enact host shutoff. Moreover, even viruses that encode few proteins often have multiple mechanisms to affect host gene expression, and we are only starting to understand how these mechanisms are integrated. In this review we discuss the multiplicity of host shutoff mechanisms used by the orthomyxovirus influenza A virus and members of the alpha- and gamma-herpesvirus subfamilies. We highlight the surprising similarities in their mechanisms of host shutoff and discuss how the different mechanisms they use may play a coordinated role in gene regulation.

Cochlear implant users rely on tempo rather than on pitch information during perception of musical emotion.

OBJECTIVES: The purpose of this study was to investigate the extent to which cochlear implant (CI) users rely on tempo and mode in perception of musical emotion when compared with normal hearing (NH) individuals. METHODS: A test battery of novel four-bar melodies was created and adapted to four permutations with alterations of tonality (major vs. minor) and tempo (presto vs. largo), resulting in non-ambiguous (major key/fast tempo and minor key/slow tempo) and ambiguous (major key/slow tempo, and minor key/fast tempo) musical stimuli. Both CI and NH participants listened to each clip and provided emotional ratings on a Likert scale of +5 (happy) to -5 (sad). RESULTS: A three-way ANOVA demonstrated an overall effect for tempo in both groups, and an overall effect for mode in the NH group. The CI group rated stimuli of the same tempo similarly, regardless of changes in mode, whereas the NH group did not. A subgroup analysis indicated the same effects in both musician and non-musician CI users and NH listeners. DISCUSSION: The results suggest that the CI group relied more heavily on tempo than mode in making musical emotion decisions. The subgroup analysis further suggests that level of musical training did not significantly impact this finding. CONCLUSION: CI users weigh temporal cues more heavily than pitch cues in inferring musical emotion. These findings highlight the significant disadvantage of CI users in comparison with NH listeners for music perception, particularly during recognition of musical emotion, a critically important feature of music.

2,3,7,8, tetrachlorodibenzo-p-dioxin induces oxygen activation associated with cell respiration.

We have investigated the influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on bioenergetic functions of isolated heart-mitochondria. Electron transfer and energy conservation activities were found to be decreased in the presence of very low amounts of the polychlorinated biphenyl compound (1.5 nmol/mg mitochondrial protein). The effect was greatest when substrates for complex I were used. In this case coupling of oxidative phosphorylation to respiration was drastically diminished, essentially at the expense of state 3 respiration, and P/O values were found around 2 instead of 3. Succinate-related energy conservation remained practically unaffected in the presence of TCDD, suggesting an interference of the toxic compound at coupling site I. SOD plus catalase were found to protect energy-linked respiration from the effect of dioxin indicating the involvement of superoxide radicals and H2O2 in the development of the observed phenomena. The present contribution provides experimental evidence on the formation of these oxygen species in the presence of TCDD. Furthermore, the site of action of TCDD is demonstrated and discussed in relation to the oxygen radical formation observed.

Physiologic function of the Wilson disease gene product, ATP7B.

The genes responsible for Wilson disease and Menkes syndrome have been cloned and identified as copper ATPases. These enzymes form part of a large family of transporters, the P-type ATPases. Although copper ATPases share strong structural similarities with these other pumps, comparatively little is known about their physiologic function. In this review, we examine data relating to the Wilson disease protein, ATP7B, in the liver. We present evidence suggesting that ATP7B is located intracellularly, together with data suggesting that, at least in part, ATP7B may also be found on the canalicular membrane. We also examine the form of copper that the transporter recognizes. We then review data on the Long-Evans Cinnamon rat, a model for Wilson disease, and discuss what effect the Wilson disease mutation has on copper transport. Finally, we conclude that, although we have made major advances in our understanding of copper metabolism in the liver, there are still many questions awaiting answers.

Stiff-man syndrome with abnormalities in CSF and computerized tomography findings. Report of a case.

We report a case of stiff-man syndrome with abnormal spinal fluid. Serum protein values were normal, but the spinal fluid levels of immunogammaglobulin G and acute-phase proteins were elevated. We discuss the possibility of an inflammatory process of the nervous system as a cause for these findings. Another interesting observation in our patient was that of local atrophies seen on computerized tomography, indicating hemispheral and especially brainstem lesions. Furthermore, as a new therapeutic possibility, we demonstrated the improvement of spasms and rigidity under the influence of heat.