An infection prevention bundle that consisted of the development of a response team, public–academic partnership, daily assessment, regular testing, isolation, and environmental controls was implemented in 26 skilled nursing facilities in Detroit, Michigan (March 2020–April 2021). This intervention was associated with sustained control of severe acute respiratory coronavirus virus 2 infection among residents and staff.

OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.

Older adults’ mental health problems are a growing public health concern, especially because their rate of mental health service use is particularly low. Decades of mental health service utilisation models have been developed, yet key assumptions from these models focus primarily on factors that facilitate or inhibit access into the treatment system without taking into considering the dynamics of how individuals respond to their mental health problems and engage in service utilisation. More recently, dynamic models like the Network Episode Model (NEM-II) have been developed to challenge the underlying, rational choice assumption of traditional utilisation models. Given the multifaceted and complex nature of older adults’ mental health problems, the objective of this study was to examine whether the NEM-II is a helpful and appropriate model for understanding the dynamic process of how older adults navigate the mental health system, including factors that advanced and delayed help-seeking. Our qualitative analyses from 15 interviews with older adults revealed that their backgrounds, social supports and treatment systems influence, and are influenced by, their illness careers. Factors that delayed help-seeking included: a lack of support, ‘inappropriate’ referrals/advice from treatment professionals and poor mental health literacy. This research suggests the NEM-II is a helpful and appropriate theory for understanding older adults’ pathways to treatment, and has implications to enhance older adults’ access to psychological services.

We present a shoreline-based, millennial-scale record of lake-level changes spanning 12.8–2.3 ka for a large closed-basin lake system on the southwestern Tibetan Plateau. Fifty-three radiocarbon and eight U–Th series ages of tufa and beach cement provide age control on paleoshorelines ringing the basin, supplemented by nineteen ages from shell and aquatic plant material from natural exposures generally recording lake regressions. Our results show that paleo-Ngangla Ring Tso exceeded modern lake level (4727 m asl) continuously between ~ 12.8 and 2.3 ka. The lake was at its highstand 135 m (4862 m asl) above the modern lake from 10.3 ka to 8.6 ka. This is similar to other closed-basin lakes in western Tibet, and coincides with peak Northern Hemisphere summer insolation and peak Indian Summer Monsoon intensity. The lake experienced a series of millennial-scale oscillations centered on 11.5, 10.8, 8.3, 5.9 and 3.6 ka, consistent with weak monsoon events in proxy records of the Indian Summer Monsoon. It is unclear whether these events were forced by North Atlantic or Indian Ocean conditions, but based on the abrupt lake-level regressions recorded for Ngangla Ring Tso, they resulted in significant periodic reductions in rainfall over the western Tibetan Plateau throughout the Holocene.

The Asian Monsoon, which brings ~80% of annual precipitation to much of the Tibetan Plateau, provides runoff to major rivers across the Asian continent. Paleoclimate records indicate summer insolation and North Atlantic paleotemperature changes forced variations in monsoon rainfall through the Holocene, resulting in hydrologic and ecologic changes in plateau watersheds. We present a record of Holocene hydrologic variability in the Yarlung Tsangpo (YT) valley of the southern Tibetan Plateau, based on sedimentology and 14C dating of organic-rich black mats’ in paleowetlands deposits, that shows changes in wetlands extent in response to changing monsoon intensity. Four sedimentary units indicate decreasing monsoon intensity since 10.4 ka BP. Wet conditions occurred at ~10.4 ka BP, ~9.6 ka BP and ~7.9–4.8 ka BP, with similar-to-modern conditions from ~4.6–2.0 ka BP, and drier-than-modern conditions from ~2.0 ka BP to present. Wetland changes correlate with monsoon intensity changes identified in nearby records, with weak monsoon intervals corresponding to desiccation and erosion of wetlands. Dating of in situ ceramic and microlithic artifacts within the wetlands indicates Epipaleolithic human occupation of the YT valley after 6.6 ka BP, supporting evidence for widespread colonization of the Tibetan Plateau in the early and mid-Holocene during warm, wet post-glacial conditions.

Microbial mats are common in polar streams and often dominate benthic biomass. Climate change may be enhancing the variability of stream flows in the Antarctic, but so far studies investigating mat responses to disturbance have been limited in this region. Mat regrowth was evaluated following disturbance by experimentally scouring rocks from an ephemeral McMurdo Dry Valley stream over two summers (2001–02 and 2012–13). Mats were sampled at the beginning and resampled at the end of the flow season. In 2012–13, mats were additionally resampled mid-season along with previously undisturbed controls. In 2001–02 rocks regained 47% of chlorophyll a and 40% of ash-free dry mass by the end of the summer, while in 2012–13 rocks regrew 18% and 27%, respectively. Mat stoichiometry differed between summers, and reflected differences in biomass and discharge. Oscillatoria spp. were greatest on scoured rocks and Phormidium spp. on undisturbed rocks. Small diatoms Humidophila and Fistulifera spp. increased throughout the summer in all mats, with the latter more abundant in scoured communities. Collectively, these data suggest that mats are variable intra-annually, responsive to hydrology and require multiple summers to regrow initial biomass once lost. These results will aid the interpretation of long-term data, as well as inform Antarctic Specially Managed Area protocols.

The timely ingestion and absorption of colostral immunoglobulin is a critical determinant of neonatal calf health. Calves are born without appreciable concentrations of the serum immunoglobulins needed to protect against pathogenic bacteria, viruses and protozoa (Tyler & Parish, 1995). The beneficial effect of passive transfer of colostral immunoglobulin also extends beyond the neonatal period and persists into juvenile and adult life (Robison et al. 1988; Tyler et al. 1998; DeNise et al. 1989). Calves with failure of passive transfer, defined as serum protein < 50 g/l or serum IgG < 10 g/l, have increased mortality risks that persist until 10 weeks of age (Tyler et al. 1998).

Several diseases are potentially spread by the ingestion of colostrum, including bovine leukosis and Johne's disease (Perrin & Polack, 1988; Streeter et al. 1995). In one study 22% of latently infected cows were demonstrated to shed Mycobacterium paratuberculosis in their colostrum (Streeter et al. 1995). Optimal programmes to prevent and eradicate these diseases generally include the provision that calves are given colostrum derived from cows of known negative disease status. Pasteurization or heat treatment of colostrum may provide a mechanism whereby calves are provided with protection against neonatal disease without creating undue potential for infection by chronic, economically relevant diseases.

Attempts to heat disinfect colostrum are common in goat herds (MacKenzie et al. 1987). Pasteurization has been demonstrated to be effective against the caprine arthritis–encephalomyelitis virus (Adams et al. 1983; MacKenzie et al. 1987). Although Myco. paratuberculosis appears to resist pasteurization, this form of processing has been demonstrated to decrease the likelihood of positive colostral cultures for Myco. paratuberculosis under experimental conditions (Meylan et al. 1996). Sterilizing the milk and colostrum given to calves is a logical and reasonable strategy to prevent transmission of infectious microorganisms. The potential disadvantage of heat treating colostrum is that the immunoglobulins in colostrum may become denatured (Smith & Sherman, 1994). Pasteurization causes only a slight decrease in the colostral concentration of IgG in cattle (Meylan et al. 1996); however, the biological behaviour of these pasteurized immunoglobulins has not been critically examined. Therefore, we cannot be completely confident that immunoglobulin absorption, persistence in serum and biological activity are unchanged by this processing.

The goal of this study was to determine the effect of pasteurization at 76 and 63 °C on the absorption of IgG from colostrum. Should these procedures decrease immunoglobulin absorption, the use of pasteurization in disease eradication programmes would require increased efforts to optimize the passive transfer of immunoglobulin.