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The timing of the last deglaciation of the Laurentide Ice Sheet in western New York is poorly constrained. The lack of direct chronology in the region has led to a hypothesis that the Laurentide Ice Sheet re-advanced to near its Last Glacial Maximum terminal position in western New York at ∼ 13 ka, which challenges long-standing datasets. To address this hypothesis, we obtained new chronology from the Kent (terminal) and Lake Escarpment (first major recessional) moraines using radiocarbon ages in sediment cores from moraine kettles supplemented with two optically stimulated luminescence ages from topset beds in an ice-contact delta. The two optically stimulated luminescence ages date the Kent (terminal) position to 19.8 ± 2.6 and 20.6 ± 2.9 ka. Within the sediment cores, there is sedimentological evidence of an unstable landscape during basin formation; radiocarbon ages from the lowest sediments in our cores are not in stratigraphic order and date from 19 350–19 600 to 14 050–14 850 cal BP. We interpret these ages as loosely minimum-limiting constraints on ice sheet retreat. Our oldest radiocarbon age of 19 350–19 600 cal BP – from a rip-up clast – suggests ice-free conditions at that time. Above the lowest sediments there is organic-rich silt and radiocarbon ages in stratigraphic order. We interpret the lowest ages in these organic-rich sediments as minimum-limiting constraints on kettle basin formation. The lowest radiocarbon ages from organic-rich sediments from sites on both Kent and Lake Escarpment moraines range from 15 000–15 400 to 13 600–14 000 cal BP. We interpret the 5 kyr lag between the optically stimulated luminescence ages and kettle basin formation as the result of persistent buried ice in ice-cored moraines until ∼ 15 to 14 ka. The cold conditions associated with Heinrich Stadial 1 may have enabled the survival of ice-cored moraines until after 15 ka, and, in turn, climate amelioration during the Bølling period (14.7–14.1 ka) may have initiated landscape stabilization. This model potentially reconciles the sedimentological and chronological evidence underpinning the re-advance hypothesis, which instead could be the result of moraine instability and sediment mobilization during the Bølling–Allerød periods (14.7–13 ka). Age control for future work should focus on features that are not dependent on local climate.

The lack of continental ice sheets in Alaska during the Last Glacial Maximum (LGM; 26–19 ka) has long been attributed to extensive aridity in the western Arctic. More recently, climate model outputs, a few isolated paleoclimate studies, and global paleoclimate synthesis products show mild summer temperature depressions in Alaska compared to much of the high northern latitudes. This suggests the importance of limited summer temperature depressions in controlling the relatively limited glacier growth during the LGM. To explore this further, we present a new statewide map of LGM alpine glacier equilibrium line altitudes (ELAs), LGM ΔELAs (LGM ELA anomalies relative to the Little Ice Age, LIA), and ΔELA-based estimates of temperature depressions across Alaska to assess paleoclimate conditions. We reconstructed paleoglacier surfaces in ArcGIS to calculate ELAs using an accumulation area ratio (AAR) of 0.58 and an area–altitude balance ratio (AABR) of 1.56. We calculated LGM ELAs (n= 480) in glaciated massifs in the state, excluding areas in southern Alaska that were covered by the Cordilleran Ice Sheet. The data show a trend of increasing ELAs from the southwest to the northeast during both the LGM and the LIA, indicating a consistent southern Bering Sea and northernmost Pacific Ocean precipitation source. Our LGM–LIA ΔELAs from the Alaska Range, supported with limited LGM–LIA ΔELAs from the Brooks Range and the Kigluaik Mountains, average to −355 ± 176 m. This value is much greater than the global LGM average of ca. −1000 m. Using a range of atmospheric lapse rates, LGM–LIA ΔELAs in Alaska translate to summer cooling of < 2–5 ∘C. Our results are consistent with a growing number of local climate proxy reconstructions and global data assimilation syntheses that indicate mild summer temperature across Beringia during the LGM. Limited LGM summer temperature depressions could be explained by the influence of Northern Hemisphere ice sheets on atmospheric circulation.

Direct observations of the size of the Greenland Ice Sheet during Quaternary interglaciations are sparse yet valuable for testing numerical models of ice-sheet history and sea level contribution. Recent measurements of cosmogenic nuclides in bedrock from beneath the Greenland Ice Sheet collected during past deep-drilling campaigns reveal that the ice sheet was significantly smaller, and perhaps largely absent, sometime during the past 1.1 million years. These discoveries from decades-old basal samples motivate new, targeted sampling for cosmogenic-nuclide analysis beneath the ice sheet. Current drills available for retrieving bed material from the US Ice Drilling Program require < 700 m ice thickness and a frozen bed, while quartz-bearing bedrock lithologies are required for measuring a large suite of cosmogenic nuclides. We find that these and other requirements yield only ∼ 3.4 % of the Greenland Ice Sheet bed as a suitable drilling target using presently available technology. Additional factors related to scientific questions of interest are the following: which areas of the present ice sheet are the most sensitive to warming, where would a retreating ice sheet expose bare ground rather than leave a remnant ice cap, and which areas are most likely to remain frozen bedded throughout glacial cycles and thus best preserve cosmogenic nuclides? Here we identify locations beneath the Greenland Ice Sheet that are best suited for potential future drilling and analysis. These include sites bordering Inglefield Land in northwestern Greenland, near Victoria Fjord and Mylius-Erichsen Land in northern Greenland, and inland from the alpine topography along the ice margin in eastern and northeastern Greenland. Results from cosmogenic-nuclide analysis in new sub-ice bedrock cores from these areas would help to constrain dimensions of the Greenland Ice Sheet in the past.

The late-Pleistocene history of the coastal Cordilleran Ice Sheet remains relatively unstudied compared to chronologies of the Laurentide Ice Sheet. Yet accurate reconstructions of Cordilleran Ice Sheet extent and the timing of ice retreat along the Pacific Coast are essential for paleoclimate modeling, assessing meltwater contribution to the North Pacific, and determining the availability of ice-free land along the coastal Cordilleran Ice Sheet margin for human migration from Beringia into the rest of the Americas. To improve the chronology of Cordilleran Ice Sheet history in the Alexander Archipelago, Alaska, we applied 10Be and 36Cl dating to boulders and glacially sculpted bedrock in areas previously hypothesized to have remained ice-free throughout the local Last Glacial Maximum (LLGM; 20–17 ka). Results indicate that these sites, and more generally the coastal northern Alexander Archipelago, became ice-free by 15.1 ± 0.9 ka (n = 12 boulders; 1 SD). We also provide further age constraints on deglaciation along the southern Alexander Archipelago and combine our new ages with data from two previous studies. We determine that ice retreated from the outer coast of the southern Alexander Archipelago at 16.3 ± 0.8 ka (n = 14 boulders; 1 SD). These results collectively indicate that areas above modern sea level that were previously mapped as glacial refugia were covered by ice during the LLGM until between ∼ 16.3 and 15.1 ka. As no evidence was found for ice-free land during the LLGM, our results suggest that previous ice-sheet reconstructions underestimate the regional maximum Cordilleran Ice Sheet extent, and that all ice likely terminated on the continental shelf. Future work should investigate whether presently submerged areas of the continental shelf were ice-free.

We applied luminescence dating to a suite of shorelines constructed by pluvial Lake Clover in northeastern Nevada, USA during the last glacial cycle. At its maximum extent, the lake covered 740 km2 with a mean depth of 16 m and a water volume of 13 km3. In the north-central sector of the lake basin, 10 obvious beach ridges extend from the highstand to the lowest shoreline over a horizontal distance of ~1.5 km, representing a lake area decrease of 35%. These ridges are primarily composed of sandy gravel and rise ~1.0 m above the alluvial fan surface on which they are superposed. Single grain luminescence dating of K-feldspar using the pIRIR SAR (post-infrared infrared single-aliquot regenerative dose) protocol, corroborated by SAR dating of quartz, indicates that the highstand shoreline was constructed ca. 16–17 ka during Heinrich Stadial I (Greenland Stadial 2, GS-2), matching 14C age control for this shoreline elsewhere in the basin. The lake regressed rapidly during the Bølling/Allerød (GI-1), before the rate of regression slowed during the Younger Dryas interval (GS-1). The lowest shoreline was constructed ca. 10 ka. Persistence of Lake Clover into the early Holocene may reflect enhanced monsoonal precipitation driven by the summer insolation maximum.

Next generation sequencing has unlocked a wealth of genotype information for microbial populations, but phenotyping remains a bottleneck for exploiting this information, particularly for pathogens that are difficult to manipulate. Here, we establish a method for high-throughput phenotyping of mixed cultures, in which the pattern of naturally occurring single-nucleotide polymorphisms in each isolate is used as intrinsic barcodes which can be read out by sequencing. We demonstrate that our method can correctly deconvolute strain proportions in simulated mixed-strain pools. As an experimental test of our method, we perform whole genome sequencing of 66 natural isolates of the thermally dimorphic pathogenic fungus Coccidioides posadasii and infer the strain compositions for large mixed pools of these strains after competition at 37°C and room temperature. We validate the results of these selection experiments by recapitulating the temperature-specific enrichment results in smaller pools. Additionally, we demonstrate that strain fitness estimated by our method can be used as a quantitative trait for genome-wide association studies. We anticipate that our method will be broadly applicable to natural populations of microbes and allow high-throughput phenotyping to match the rate of genomic data acquisition.

As SARS-CoV-2 continues to spread worldwide, tractable primary airway cell models that recapitulate the cell-intrinsic response to arising viral variants are needed. Here we describe an adult stem cell-derived human airway organoid model overexpressing the ACE2 receptor (ACE2-OE) that supports robust viral replication while maintaining 3D architecture and cellular diversity of the airway epithelium. ACE2-OE organoids were infected with SARS-CoV-2 variants and subjected to single-cell RNA-sequencing. Interferon-lambda was upregulated in cells with low-level infection while the NF-kB inhibitor alpha gene (encoding IkBa) was consistently upregulated in infected cells, and its expression positively correlated with infection levels. Confocal microscopy showed more IkBa expression in infected than bystander cells, but found concurrent nuclear translocation of NF-kB that IkBa usually prevents. Overexpressing a nondegradable IkBa mutant reduced NF-kB translocation and increased viral infection. These data demonstrate the functionality of ACE2-OE organoids in SARS-CoV-2 research and underscore that the strength of the NF-kB feedback loop in infected cells controls viral replication., (© 2024. The Author(s).)

Importance: Histoplasma is a primary fungal pathogen with the ability to infect otherwise healthy mammalian hosts, causing systemic and sometimes life-threatening disease. Thus far, molecular genetic manipulation of this organism has utilized RNA interference, random insertional mutagenesis, and a homologous recombination protocol that is highly variable and often inefficient. Targeted gene manipulations have been challenging due to poor rates of homologous recombination events in Histoplasma . Interrogation of the virulence strategies of this organism would be highly accelerated by a means of efficiently generating targeted mutations. We have developed a recyclable CRISPR/Cas9 system that can be used to introduce gene disruptions in Histoplasma with high efficiency, thereby allowing disruption of multiple genes., Competing Interests: The authors declare no conflict of interest.

Background: Lack of transgender health education among health professional education programs is a limitation to providing gender-affirming care. Educational interventions have advanced in the past decade using a variety of pedagogical approaches. Although evidence supports that educational interventions can significantly improve student knowledge, comfort levels, preparedness, and clinical skills, few studies have addressed student perceptions of or receptiveness towards transgender health education. The study purpose was to explore student perceptions of transgender health education using a qualitative approach., Methods: We utilized a basic qualitative design to explore student perceptions of transgender health education at a Catholic, Jesuit institution. Participants were medical students (n = 182), medical family therapy students (n = 8), speech, language and hearing sciences students (n = 44), and dietetic interns (n = 30) who participated in an Interprofessional Transgender Health Education Day (ITHED) in partnership with transgender educators and activists. Participants completed an online discussion assignment using eight discussion prompts specific to the ITHED sessions. Data were analyzed using the constant comparative method and triangulated across four medical and allied health programs., Results: A total of 263 participants provided 362 responses across eight discussion prompts. Three major themes resulted: (1) The Power to Help or Harm, (2) The Responsibility to Provide Health Care, and (3) A Posture of Humility: Listen and Learn. Each theme was supported by three to four subthemes., Conclusions: Health professional students were highly receptive towards transgender health education delivered by transgender community members. First-person accounts from session facilitators of both positive and negative experiences in healthcare were particularly effective at illustrating the power of providers to help or harm transgender patients. Reflection and constructive dialogue offers students an opportunity to better understand the lived experiences of transgender patients and explore their identities as healthcare providers at the intersection of their religious and cultural beliefs., (© 2023. The Author(s).)

Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (~30 kb). Here, we present a plasmid-based viral genome assembly and rescue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation., (© 2023. The Author(s).)

The current study involved an investigation of the construct validity of the Emotion Word Fluency Test (EWFT) via conceptual replication and extension of Abeare, Freund, Kaploun, McAuley, and Dumitrescu (2017). Participants were 143 undergraduates ( X age = 19.57, SD = 2.31). Correlations among the EWFT, Delis-Kaplan Executive Function System-Verbal Fluency (letter and category conditions), and the Depression Anxiety and Stress Scales-21: Total and Stress scores were similar to previous research. Prior research with the EWFT did not include an assessment of Theory of Mind. Thus, two Theory of Mind tasks, the Reading the Mind in the Eyes Test and the Unexpected Outcomes Test, were also investigated. A confirmatory factor analysis with verbal fluency and Theory of Mind as latent variables had good model fit and suggested that the EWFT is both a verbal fluency task as well as a Theory of Mind task. EWFT score was not significantly correlated with the Reading the Mind in the Eyes Test score. However, multiple regression analyses indicated that scores on the Unexpected Outcomes Test, which requires understanding and interpreting others' emotions and intentions, accounted for significant variance in EWFT total score beyond the shared variance among verbal fluency tasks. These findings provide initial evidence that the EWFT captures a specific emotion-related component vis-à-vis letter and (nonemotion) category fluency tasks. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The December 2019 outbreak of a novel respiratory virus, SARS-CoV-2, has become an ongoing global pandemic due in part to the challenge of identifying symptomatic, asymptomatic, and pre-symptomatic carriers of the virus. CRISPR diagnostics can augment gold-standard PCR-based testing if they can be made rapid, portable, and accurate. Here, we report the development of an amplification-free CRISPR-Cas13a assay for direct detection of SARS-CoV-2 from nasal swab RNA that can be read with a mobile phone microscope. The assay achieved ∼100 copies/μL sensitivity in under 30 min of measurement time and accurately detected pre-extracted RNA from a set of positive clinical samples in under 5 min. We combined crRNAs targeting SARS-CoV-2 RNA to improve sensitivity and specificity and directly quantified viral load using enzyme kinetics. Integrated with a reader device based on a mobile phone, this assay has the potential to enable rapid, low-cost, point-of-care screening for SARS-CoV-2., Competing Interests: Declaration of interests P.F., S.S., G.J.K., J.A.D., D.A.F., and M.O. have filed patent applications related to this work. The Regents of the University of California have patents issued and pending for CRISPR technologies on which J.A.D. is an inventor. J.A.D. is a cofounder of Caribou Biosciences, Editas Medicine, Scribe Therapeutics, Intellia Therapeutics, and Mammoth Biosciences. J.A.D. is a scientific advisory board member of Caribou Biosciences, Intellia Therapeutics, eFFECTOR Therapeutics, Scribe Therapeutics, Mammoth Biosciences, Synthego, Algen Biotechnologies, Felix Biosciences, and Inari. J.A.D. is a director at Johnson & Johnson and has research projects sponsored by Biogen, Pfizer, AppleTree Partners, and Roche., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E), and glycosaminoglycans (for OC43). Additionally, we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies., Competing Interests: Declaration of Interests J.C.-S., J.O., and K.H. are employees of Synthego Corporation. All authors declare no other competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)