Genetically modified pigs lacking CD163 PSTII-domain-coding exon 13 are completely resistant to PRRSV infection.

CD163 expressed on cell surface of porcine alveolar macrophages (PAMs) serves as a cellular entry receptor for porcine reproductive and respiratory syndrome virus (PRRSV). The extracellular portion of CD163 contains nine scavenger receptor cysteine-rich (SRCR) and two proline-serine-threonine (PST) domains. Genomic editing of pigs to remove the entire CD163 or just the SRCR5 domain confers resistance to infection with both PRRSV-1 and PRRSV-2 viruses. By performing a mutational analysis of CD163, previous in vitro infection experiments showed resistance to PRRSV infection following deletion of exon 13 which encodes the first 12 amino acids of the 16 amino acid PSTII domain. These findings predicted that removal of exon 13 can be used as a strategy to produce gene-edited pigs fully resistant to PRRSV infection. In this study, to determine whether the deletion of exon 13 is sufficient to confer resistance of pigs to PRRSV infection, we produced pigs possessing a defined CD163 exon 13 deletion (ΔExon13 pigs) and evaluated their susceptibility to viral infection. Wild type (WT) and CD163 modified pigs, placed in the same room, were infected with PRRSV-2. The modified pigs remained PCR and serologically negative for PRRSV throughout the study; whereas the WT pigs supported PRRSV infection and showed PRRSV related pathology. Importantly, our data also suggested that removal of exon 13 did not affect the main physiological function associated with CD163 in vivo. These results demonstrate that a modification of CD163 through a precise deletion of exon 13 provides a strategy for protection against PRRSV infection.

Twisted fiber microfluidics: a cutting-edge approach to 3D spiral devices.

The development of 3D spiral microfluidics has opened new avenues for leveraging inertial focusing to analyze small fluid volumes, thereby advancing research across chemical, physical, and biological disciplines. While traditional straight microchannels rely solely on inertial lift forces, the novel spiral geometry generates Dean drag forces, eliminating the necessity for external fields in fluid manipulation. Nevertheless, fabricating 3D spiral microfluidics remains a labor-intensive and costly endeavor, hindering its widespread adoption. Moreover, conventional lithographic methods primarily yield 2D planar devices, thereby limiting the selection of materials and geometrical configurations. To address these challenges, this work introduces a streamlined fabrication method for 3D spiral microfluidic devices, employing rotational force within a miniaturized thermal drawing process, termed as mini-rTDP. This innovation allows for rapid prototyping of twisted fiber-based microfluidics featuring versatility in material selection and heightened geometric intricacy. To validate the performance of these devices, we combined computational modeling with microtomographic particle image velocimetry (µTPIV) to comprehensively characterize the 3D flow dynamics. Our results corroborate the presence of a steady secondary flow, underscoring the effectiveness of our approach. Our 3D spiral microfluidics platform paves the way for exploring intricate microflow dynamics, with promising applications in areas such as drug delivery, diagnostics, and lab-on-a-chip systems.

DAZL Knockout Pigs as Recipients for Spermatogonial Stem Cell Transplantation.

Spermatogonial stem cell (SSC) transplantation into the testis of a germ cell (GC)-depleted surrogate allows transmission of donor genotype via donor-derived sperm produced by the recipient. Transplantation of gene-edited SSCs provides an approach to propagate gene-edited large animal models. DAZL is a conserved RNA-binding protein important for GC development, and DAZL knockout (KO) causes defects in GC commitment and differentiation. We characterized DAZL-KO pigs as SSC transplantation recipients. While there were GCs in 1-week-old (wko) KO, complete GC depletion was observed by 10 wko. Donor GCs were transplanted into 18 DAZL-KO recipients at 10-13 wko. At sexual maturity, semen and testes were evaluated for transplantation efficiency and spermatogenesis. Approximately 22% of recipient seminiferous tubules contained GCs, including elongated spermatids and proliferating spermatogonia. The ejaculate of 89% of recipients contained sperm, exclusively from donor origin. However, sperm concentration was lower than the wild-type range. Testicular protein expression and serum hormonal levels were comparable between DAZL-KO and wild-type. Intratesticular testosterone and Leydig cell volume were increased, and Leydig cell number decreased in transplanted DAZL-KO testis compared to wild-type. In summary, DAZL-KO pigs support donor-derived spermatogenesis following SSC transplantation, but low spermatogenic efficiency currently limits their use for the production of offspring.

An intersectional examination of the impact of COVID-stress and discrimination on college students' resilience and mental health.

Objective: To investigate the impact of COVID-stress and discrimination on mental health among a group of diverse college students using an intersectional framework. Participants: One thousand six hundred seventy-one undergraduate students (Mage = 20.42, SD = 2.74) were recruited from nine college campuses. Methods: Participants completed an online questionnaire assessing mental health symptoms, COVID-stress, and in-school discrimination. Hierarchical regressions and multi-group SEM path analysis were conducted to examine differences across intersectional identities. Results: Female-identifying students reported higher COVID-stress, anxiety and depressive symptoms, and lower resilience compared to males. COVID-stress and discrimination were highest among certain minoritized student groups. Using an intersectional framework, more COVID-stress and discrimination were associated with increased anxiety for almost all women of color. Unexpectedly, COVID-stress predicted anxiety symptoms for almost all male intersectional groups. Conclusions: Findings reaffirm the intersectional framework and highlight significant disparities in how students experience COVID-stress, discrimination, and mental health outcomes along dimensions of gender and race/ethnicity.

Compact and modular autonomous surface vehicle for water research: The Naval Operating Research Drone Assessing Climate Change (NORDACC).

Research, monitoring, and management of marine and aquatic ecosystems often require surface water samples to measure biogeochemical and optical parameters. Traditional sampling with a boat and several personnel onboard can be labor-intensive and safety requirements limit sampling activities in high-risk environments. This paper describes the Naval Operating Research Drone Assessing Climate Change (NORDACC). NORDACC is an open source, light-weight, and portable autonomous surface vehicle that can acquire surface water samples while also measuring sea surface temperature and salinity for the duration of its deployment. NORDACC is ideal for operations in remote areas where resources and personnel are limited. Two sample bottles, each one liter in volume, can be filled, either at pre-programmed sampling stations or manually, using the remote control. A trimaran design provides buoyancy and stability, with hulls constructed of vacuum-formed acrylonitrile butadiene styrene (ABS) plastic. NORDACC can navigate autonomously between waypoints and features first person view capabilities for enhanced situational awareness. NORDACC's performance was validated in Aarhus Bay, Denmark, collecting multiple surface water samples in winds in excess of 8 ms-1 and steep, choppy waves.

First gene-edited calf with reduced susceptibility to a major viral pathogen.

Bovine viral diarrhea virus (BVDV) is one of the most important viruses affecting the health and well-being of bovine species throughout the world. Here, we used CRISPR-mediated homology-directed repair and somatic cell nuclear transfer to produce a live calf with a six amino acid substitution in the BVDV binding domain of bovine CD46. The result was a gene-edited calf with dramatically reduced susceptibility to infection as measured by reduced clinical signs and the lack of viral infection in white blood cells. The edited calf has no off-target edits and appears normal and healthy at 20 months of age without obvious adverse effects from the on-target edit. This precision bred, proof-of-concept animal provides the first evidence that intentional genome alterations in the CD46 gene may reduce the burden of BVDV-associated diseases in cattle and is consistent with our stepwise, in vitro and ex vivo experiments with cell lines and matched fetal clones.

Correction to: US Parents' Domestic Labor During the First Year of the COVID-19 Pandemic.

[This corrects the article DOI: 10.1007/s11113-022-09735-1.].

Teclistamab-cqyv: The First Bispecific T-Cell Engager Antibody for the Treatment of Patients With Relapsed or Refractory Multiple Myeloma.

Multiple myeloma (MM) remains an incurable malignancy originating from plasma cells. Despite significant advances in treatment, relapses remain inevitable, and novel therapies continue to be needed. Teclistamab-cqyv is a first-in-class, bispecific T-cell engager (BiTE) antibody for the treatment of MM. Teclistamab-cqyv activates the immune system by binding to the cluster of differentiation 3 (CD3) receptor expressed on the surface of T cells and to the B-cell maturation antigen (BCMA) expressed on the surface of MM cells and some healthy B-lineage cells. Teclistamab-cqyv has been shown to be effective in a pivotal trial that demonstrated an overall response rate of more than 60% in heavily pretreated patients. Compared with other BCMA-targeted agents, the side effect profile of teclistamab-cqyv suggests a more tolerable option for elderly patients. Teclistamab-cqyv is now approved by the US Food and Drug Administration (FDA) as monotherapy for the treatment of adult patients with relapsed or refractory MM.

Macroalgal habitats support a sustained flux of floating biomass but limited carbon export beyond a Greenland fjord.

Despite growing attention on the contribution of macroalgae to carbon cycling and sequestration (blue carbon), more observational data is needed to constrain current estimates. In this study, we estimate the floating macroalgal carbon flux within and beyond a large sub-Arctic fjord system, Nuup Kangerlua, Greenland, which could potentially reach carbon sinks. Our study estimates 1) the fjord-scale area with macroalgal coverage and barrens caused by sea urchin grazing, 2) the floating macroalgal biomass in the fjord, and 3) the annual export flux of floating macroalgae out of the fjord system. ROV surveys documented that macroalgal habitats cover 32 % of the seafloor within the photic zone (0-30 m) with an average coverage of 39.6, 22, and 7.2 % in the depth intervals 0-10, 10-20, and 20-30 m, respectively. 15 % of the area suitable for macroalgae was denuded by sea urchin grazing. Floating macroalgae were common with an average biomass of 55 kg wet weight km-2. Densities and species composition varied seasonally with the highest levels after storms. The floating biomass was composed of intertidal macroalgal species (58 %) (Fucus vesiculosus, Fucus distichus, and Ascophyllum nodosum) and kelps (42 %) (Saccharina longicruris, S. latissima, and Alaria esculenta). We deployed surface GPS drifters to simulate floating macroalgal trajectories and velocity. Data indicated that 80 % of the floating biomass is retained in the fjord where its fate in relation to long-term sequestration is unknown. Export beyond the fjord was limited and indicated an annual floating macroalgal export beyond the fjord of only 6.92 t C yr-1, which is equal to ~0.02 % of the annual net primary production. Our findings suggest that floating macroalgae support a limited blue carbon potential beyond this fjord and that future research should focus on the fate of retained floating macroalgae and subsurface export to resolve the connectivity between macroalgal habitats and long-term carbon sinks.

Mapping intertidal macrophytes in fjords in Southwest Greenland using Sentinel-2 imagery.

Changes in the distribution of coastal macrophytes in Greenland, and elsewhere in the Arctic are difficult to quantify as the region remains challenging to access and monitor. Satellite imagery, in particular Sentinel-2 (S2), may enable large-scale monitoring of coastal areas in Greenland but its use is impacted by the optically complex environments and the scarcity of supporting data in the region. Additionally, the canopies of the dominant macrophyte species in Greenland do not extend to the sea surface, limiting the use of indices that exploit the reflection of near-infrared radiation by vegetation due to its absorption by seawater. Three hypotheses are tested: I) 10-m S2 imagery and commonly used detection methods can identify intertidal macrophytes that are exposed at low tide in an optically complex fjord system in Greenland impacted by marine and land terminating glaciers; II) detached and floating macrophytes accumulate in patches that are sufficiently large to be detected by 10-m S2 images; III) iceberg scour and/or turbid meltwater runoff shape the spatial distribution of intertidal macroalgae in fjord systems with marine-terminating glaciers. The NDVI produced the best results in optically complex fjord systems in Greenland. 12 km2 of exposed intertidal macrophytes were identified in the study area at low tide. Floating mats of macrophytes ranged in area from 400 m2 to 326,800 m2 and were most common at the mouth of the fjord. Icebergs and turbidity appear to play a role in structuring the distribution of intertidal macrophytes and the retreat of marine terminating glaciers could allow macrophytes cover to expand. The challenges and solutions presented here apply to most fjords in Greenland and, therefore, the methodology may be extended to produce a Greenland-wide estimate of intertidal macrophytes.

Between a Rock and a Hard Place: COVID Concerns and Partnered U.S. Mothers' Employment during the COVID-19 Pandemic.

Shutdowns of in-person school and childcare in spring 2020 in response to the coronavirus disease 2019 (COVID-19) pandemic were associated with substantial reductions in mothers' labor force participation (LFP). By fall 2020, in-person school and daycare were more widely available, but mothers' LFP remained as low as it was in spring. Coincidently, by fall 2020, daily COVID deaths had also began to peak. Using unique panel survey data from partnered U.S. mothers (n = 263), the authors use structural equation modeling to analyze how mothers' concerns over COVID shaped their LFP in fall 2020. Findings show that mothers' COVID concerns were associated with reduced LFP via children's time at home, perceived stress, and remote work. Concerned mothers were more likely to keep children home, but this resulted in less paid work likely vis-à-vis work-family conflicts. The findings illuminate one reason mothers' LFP failed to rebound in fall 2020 despite increased access to in-person school and daycare.

Tebentafusp-tebn: A Novel Bispecific T-Cell Engager for Metastatic Uveal Melanoma.

Uveal melanoma is the most common intraocular cancer in adults. Metastatic uveal melanoma has a poor prognosis. Tebentafusp-tebn is the first drug in the new immune mobilizing monoclonal T-cell receptors against cancer (ImmTAC) class of T cell-directed therapy. Tebentafusp-tebn has been shown in a randomized phase III clinical trial to lead to improved overall survival and progression-free survival when compared with single-agent pembrolizumab, ipilimumab, or dacarbazine in previously untreated human leukocyte antigen (HLA)-A*02:01-positive metastatic uveal melanoma patients. Tebentafusp-tebn is now approved by the US Food and Drug Administration in HLA-A*02:01-positive uveal melanoma patients as first-line therapy in the metastatic setting.

US Parents' Domestic Labor During the First Year of the COVID-19 Pandemic.

It is important to assess the long-term consequences of the COVID-19 pandemic for gender equality, but we know little about US parents' domestic arrangements beyond the early days of the pandemic or how simultaneous changes in employment, earnings, telework, gender ideologies, and care supports may have altered domestic arrangements. This study assesses changes in parents' domestic labor during the first year of the pandemic using fixed-effects regression on data from a longitudinal panel of 700 different-sex partnered US parents collected at three time points: March, April, and November 2020. Parents' divisions of housework and childcare became more equal early in the pandemic, but divisions of housework reverted toward pre-pandemic levels by Fall 2020 whereas fathers' shares of childcare remained elevated. Changes in parents' divisions of domestic labor were largely driven by changes in parents' labor force conditions, but shifts in gender ideology also mattered. Decreases in fathers' labor force participation and increases in telecommuting in April portended increases in fathers' shares of domestic tasks. As fathers increased their time in paid work and returned to in-person work by fall, their shares of domestic labor fell. Shifts toward more traditional gender ideologies were also associated with decreases in fathers' shares of childcare in Fall 2020. Overall, results point to remote work as a possible means for achieving greater gender equality in domestic labor among couples, but shifts toward traditional gender ideologies may suppress any gains stemming from supportive work-family policies. Supplementary Information: The online version contains supplementary material available at 10.1007/s11113-022-09735-1.

Targeted Gene Editing in Porcine Germ Cells.

As the genetic mutations driving human disease are identified, there is an increasing need for a biomedical model that can accurately represent the disease of interest and provide a platform for potential therapeutic testing. Pigs are a better model for human disease than rodents because of their genetic and physiological similarities to humans. However, current methods to generate porcine models are both technically challenging and expensive. Germline genetic modification through gene edited spermatogonia provides an effective alternative to how these models are developed. Here, we report an improved technique of gene editing in spermatogonia of pigs using CRISPR-Cas9 to generate different edits that reflect the genotypes of human diseases.

Evaporation driven smart patterning of microparticles on a rigid-soft composite substrate.

HYPOTHESIS: A liquid droplet on a rigid polydimethylsiloxane (PDMS) substrate exhibits a higher receding contact angle (θr), therefore, recedes earlier than its softer counterpart. The three-phase contact line of a suspension droplet on a composite rigid-soft PDMS substrate can be selectively tuned wherein the contact line recedes on the rigid substrate sooner and approaches toward the softer side, with microparticles eventually being deposited in the softer substrate region. EXPERIMENTS: A composite PDMS substrate containing soft cores of various shapes (circular and non-circular) surrounded by rigid matrices was fabricated by employing 3D printing and soft lithography. A sessile suspension droplet containing spherical microparticles was deposited on the composite substrate and evaporated under ambient conditions. The evaporation dynamics was recorded and analyzed. FINDINGS: Evaporation-induced patterning (in circular, triangular, and rectangular areas) with sizes ranging from microns to millimetres were obtained. For the first time, by varying the ratio of the rigid-soft regions in the PDMS substrate, we were able to obtain different deposition sizes and shapes from an identical droplet. Instead of using lithographically patterned substrate, our simple methodology by using 3D printing and soft lithography opened up a new avenue for patterning microparticles based on a rigid-soft composite substrate.

Outcomes After Operative Reconstruction of Symptomatic Rib Nonunions.

OBJECTIVE: To assess the outcomes of patients after rib nonunion reconstruction. DESIGN: Retrospective case series. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Between January 2007 and August 2019, 25 consecutive patients with 51 nonunions with disabling pain or chronic instability were treated for nonunited rib fractures. INTERVENTION: Rib nonunion reconstructions performed using plate and screw fixation, recannalizing the medullary canal and augmented with autogenous iliac crest bone graft. MAIN OUTCOME MEASUREMENTS: Patient demographics, mechanism of injury, number of rib nonunions, and postoperative radiographs were assessed. Satisfaction, patient-reported complications, return to occupation and activity, and general health measures were captured using patient questionnaires. RESULTS: In 25 patients, 51 painful rib nonunions were surgically treated. The average length from injury to surgical rib reconstruction was 25.1 months (range = 3-118 months; median = 12 months). Follow-up was obtained in 18 of 25 patients (72%) with a mean of 46.1 months (range = 13-139 months). All ribs achieved radiographic union at an average of 12.3 weeks (range = 8-24 weeks) after surgery. Sixteen of 18 patients (89%) reported satisfaction with surgery and 15 patients (83%) reported mild to no pain at final follow-up. Five patients had complications that all resolved after subsequent treatment. CONCLUSIONS: Successful treatment of symptomatic rib nonunion is possible using rib plates in conjunction with bone grafting and has high union rates, satisfactory results, and limited complications. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Optimization and Fabrication of Multi-Level Microchannels for Long-Term Imaging of Bacterial Growth and Expansion.

Bacteria are unicellular organisms whose length is usually around a few micrometers. Advances in microfabrication techniques have enabled the design and implementation of microdevices to confine and observe bacterial colony growth. Microstructures hosting the bacteria and microchannels for nutrient perfusion usually require separate microfabrication procedures due to different feature size requirements. This fact increases the complexity of device integration and assembly process. Furthermore, long-term imaging of bacterial dynamics over tens of hours requires stability in the microscope focusing mechanism to ensure less than one-micron drift in the focal axis. In this work, we design and fabricate an integrated multi-level, hydrodynamically-optimized microfluidic chip to study long-term Escherichia coli population dynamics in confined microchannels. Reliable long-term microscopy imaging and analysis has been limited by focus drifting and ghost effect, probably caused by the shear viscosity changes of aging microscopy immersion oil. By selecting a microscopy immersion oil with the most stable viscosity, we demonstrate successful captures of focally stable time-lapse bacterial images for ≥72 h. Our fabrication and imaging methodology should be applicable to other single-cell studies requiring long-term imaging.

Duration-Weighted Exposure to Neighborhood Disadvantage and Racial-Ethnic Differences in Adolescent Sexual Behavior.

Racial-ethnic disparities in adolescent sexual risk behavior are associated with health disparities during adulthood and are therefore important to understand. Some scholars argue that neighborhood disadvantage induces disparities, yet prior research is mixed. We extend neighborhood-effects research by addressing long-term exposure to neighborhood disadvantage and estimation bias resulting from inclusion of time-varying covariates. Drawing from the Fragile Families and Child Well-Being Study, we compare a point-in-time proximal measure of neighborhood disadvantage with a duration-weighted measure using marginal structural models with inverse probability of treatment weights. Findings indicate that multiracial, non-Hispanic black, and Hispanic youth exhibit significantly higher sexual risk and duration-weighted exposure to neighborhood disadvantage than non-Hispanic white adolescents. Duration-weighted exposure is a better predictor of sexual initiation and number of partners by age 15 than a point-in-time proximal measure of neighborhood disadvantage and accounts for a substantial portion of the race-ethnic differences in sexual risk.

Does a Rising Median Income Lift All Birth Weights? County Median Income Changes and Low Birth Weight Rates Among Births to Black and White Mothers.

Policy Points Policies that increase county income levels, particularly for middle-income households, may reduce low birth weight rates and shrink disparities between Black and White infants. Given the role of aggregate maternal characteristics in predicting low birth weight rates, policies that increase human capital investments (e.g., funding for higher education, job training) could lead to higher income levels while improving population birth outcomes. The association between county income levels and racial disparities in low birth weight is independent of disparities in maternal risks, and thus a broad set of policies aimed at increasing income levels (e.g., income supplements, labor protections) may be warranted. CONTEXT: Low birth weight (LBW; <2,500 grams) and infant mortality rates vary among place and racial group in the United States, with economic resources being a likely fundamental contributor to these disparities. The goals of this study were to examine time-varying county median income as a predictor of LBW rates and Black-White LBW disparities and to test county prevalence and racial disparities in maternal sociodemographic and health risk factors as mediators. METHODS: Using national birth records for 1992-2014 from the National Center for Health Statistics, a total of approximately 27.4 million singleton births to non-Hispanic Black and White mothers were included. Data were aggregated in three-year county-period observations for 868 US counties meeting eligibility requirements (n = 3,723 observations). Sociodemographic factors included rates of low maternal education, nonmarital childbearing, teenage pregnancy, and advanced-age pregnancy; and health factors included rates of smoking during pregnancy and inadequate prenatal care. Among other covariates, linear models included county and period fixed effects and unemployment, poverty, and income inequality. FINDINGS: An increase of $10,000 in county median income was associated with 0.34 fewer LBW cases per 100 live births and smaller Black-White LBW disparities of 0.58 per 100 births. Time-varying county rates of maternal sociodemographic and health risks mediated the association between median income and LBW, accounting for 65% and 25% of this estimate, respectively, but racial disparities in risk factors did not mediate the income association with Black-White LBW disparities. Similarly, county median income was associated with very low birth weight rates and related Black-White disparities. CONCLUSIONS: Efforts to increase income levels-for example, through investing in human capital, enacting labor union protections, or attracting well-paying employment-have broad potential to influence population reproductive health. Higher income levels may reduce LBW rates and lead to more equitable outcomes between Black and White mothers.

Changes in US Parents' Domestic Labor During the Early Days of the COVID-19 Pandemic.

Stay-at-home orders and the removal of care and domestic supports during the early days of the COVID-19 pandemic substantially disrupted US parents' work and family lives. Although much is known about changes in US parents' paid labor arrangements, the evidence regarding changes in unpaid domestic labor has been largely anecdotal. This study uses novel data from 1,025 US parents in different-sex partnerships to provide a descriptive overview of changes in mothers' and fathers' participation in, and division of, housework and childcare from March 2020 to the early days of the pandemic (late April 2020). Findings show an overall increase in domestic responsibilities for mothers who were already doing most of the household labor. Still, both mothers and fathers report a general shift toward more egalitarian divisions of household labor, driven by increases in fathers' contributions. The shift toward more egalitarian sharing of domestic labor is observed across demographic groups and across types of domestic tasks. Consistent with findings from other countries, egalitarian divisions of domestic labor increased among U.S. parents during the early days of the COVID-19 pandemic. Mothers, nonetheless, report retaining primary responsibility for domestic labor in the majority of families.