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Errors in development occur in all vertebrates. When severe, these anomalies are lethal and frequently escape attention. In rare cases, animals with profound malformations are born and can provide a glimpse into structures and their respective function that would otherwise go unnoticed. A rare abnormality in a hatchling Alligator mississippiensis is described in which duplication of the skull, face, and brain was incomplete. The rostral skull, face, and associated forebrain, including the olfactory apparatus, were duplicated. However, the caudal skull and brainstem were not. These observations were made with advanced imaging using both computed tomography and magnetic resonance coupled with gross brain dissections. These abnormal features emphasize the complex and intertwined relationship between the development of the brain, face, and skull which are influenced by certain signaling molecules, possible gene mutation(s), and potential environmental factors.

Plastic debris is thought to be widespread in freshwater ecosystems globally1. However, a lack of comprehensive and comparable data makes rigorous assessment of its distribution challenging2,3. Here we present a standardized cross-national survey that assesses the abundance and type of plastic debris (>250 μm) in freshwater ecosystems. We sample surface waters of 38 lakes and reservoirs, distributed across gradients of geographical position and limnological attributes, with the aim to identify factors associated with an increased observation of plastics. We find plastic debris in all studied lakes and reservoirs, suggesting that these ecosystems play a key role in the plastic-pollution cycle. Our results indicate that two types of lakes are particularly vulnerable to plastic contamination: lakes and reservoirs in densely populated and urbanized areas and large lakes and reservoirs with elevated deposition areas, long water-retention times and high levels of anthropogenic influence. Plastic concentrations vary widely among lakes; in the most polluted, concentrations reach or even exceed those reported in the subtropical oceanic gyres, marine areas collecting large amounts of debris4. Our findings highlight the importance of including lakes and reservoirs when addressing plastic pollution, in the context of pollution management and for the continued provision of lake ecosystem services.

Laser-to-composite interactions are becoming increasingly common in diverse applications such as diagnostics, fabrication and machining, and directed energy weapon systems. These interactions can induce seemingly imperceptible damage to the material. It is therefore desirable to have a means of sensing laser exposure. Smart or self-sensing materials may be a powerful method of addressing this need. Herein, we present a study on the potential of using changes in the electrical properties of carbon nanofiber (CNF)-modified composites as a way of detecting laser exposure and degradation. To test laser sensing capabilities, CNF composite specimens were exposed to an infra-red laser operating at 1064 nm, 35 kHz, and pulse duration of 8 ns for a total of 20 s. The resistances of the specimens were then measured post-ablation, and it was found that for 1.0 wt.% CNFs, the average resistance increased by approximately 18% thereby demonstrating laser sensing capabilities. In order to expand on this result, electrical impedance tomography (EIT) was employed for spatial localization of laser exposures of 1, 3, 5, 10, and 20 s on a larger, plate-like specimens. EIT was not only successful in detecting and localizing exposures, but it could also find laser damages that were virtually imperceptible to the naked eye. Based on these results, this research could lead to the development of novel carbon-based smart material systems for real-time detection and tracking of laser exposure in the measurement, fabrication, and defense industries.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved variants with substitutions in the spike receptor-binding domain (RBD) that affect its affinity for angiotensin-converting enzyme 2 (ACE2) receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites—a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single–amino acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently Asn 501 →Tyr (N501Y), cause epistatic shifts in the effects of mutations at other sites. These epistatic shifts shape subsequent evolutionary change—for example, enabling many of the antibody-escape substitutions in the Omicron RBD. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution.

The optimal enoxaparin dosing strategy to achieve venous thromboembolism (VTE) prophylaxis in trauma patients remains unclear. Current dosing guidelines often include weight, age, and renal function but still fail to achieve appropriate prophylactic anti-Xa levels in many patients. We hypothesized that additional patient factors influence anti-Xa response to enoxaparin in trauma patients.This is a retrospective review of patients admitted to a Level 1 trauma center for ≥4 days from July 2015 to September 2020, who received enoxaparin VTE prophylaxis per protocol (50-59 kg, 30 mg/dose; 60-99 kg, 40 mg/dose; ≥100 kg, 50 mg/dose; all doses every 12 hours) and had an appropriately timed peak anti-Xa level. Multivariate regression was performed to identify independent predictors of prophylactic anti-Xa levels (0.2-0.4 IU/mL) upon first measurement.The cohort (N = 1,435) was 76.4% male, with a mean ± SD age of 49.9 ± 20.0 years and a mean ± SD weight of 82.5 ± 20.2 kg (males, 85.2 kg; females, 73.7 kg; p0.001). Overall, 68.6% of patients (n = 984) had a prophylactic anti-Xa level on first assessment (69.6% of males, 65.1% of females). Males were more likely to have a subprophylactic level than females (22.1% vs. 8.0%, p0.001), whereas females were more likely to have supraprophylactic levels than males (26.9% vs. 8.3%, p0.001). When controlling for creatinine clearance, anti-Xa level was independently associated with dose-to-weight ratio (odds ratio, 0.191 for 0.5 mg/kg; p0.001; confidence interval, 0.151-0.230) and female sex (odds ratio, 0.060; p0.001; confidence interval, 0.047-0.072). Weight and age were not significant when controlling for the other factors.Male patients have a decreased anti-Xa response to enoxaparin when compared with female patients, leading to a greater incidence of subprophylactic anti-Xa levels in male patients at all dose-to-weight ratios. To improve the accuracy of VTE chemoprophylaxis, sex should be considered as a variable in enoxaparin dosing models.Therapeutic/Care Management; Level III.

Peripheral artery disease (PAD) is an atherosclerotic disease that impairs blood flow and muscle function in the lower limbs. A skeletal muscle myopathy characterized by mitochondrial dysfunction and oxidative damage is present in PAD; however, the underlying mechanisms are not well established. We investigated the impact of chronic ischemia on skeletal muscle microcirculatory function and its association with leg skeletal muscle mitochondrial function and oxygen delivery and utilization capacity in PAD. Gastrocnemius samples and arterioles were harvested from patients with PAD (n = 10) and age-matched controls (Con, n = 11). Endothelium-dependent and independent vasodilation was assessed in response to flow (30 μL·min(−1)), acetylcholine, and sodium nitroprusside (SNP). Skeletal muscle mitochondrial respiration was quantified by high-resolution respirometry, microvascular oxygen delivery, and utilization capacity (tissue oxygenation index, TOI) were assessed by near-infrared spectroscopy. Vasodilation was attenuated in PAD (P < 0.05) in response to acetylcholine (Con: 71.1 ± 11.1%, PAD: 45.7 ± 18.1%) and flow (Con: 46.6 ± 20.1%, PAD: 29.3 ± 10.5%) but not SNP (P = 0.30). Complex I + II state 3 respiration (P < 0.01) and TOI recovery rate were impaired in PAD (P < 0.05). Both flow and acetylcholine-mediated vasodilation were positively associated with complex I + II state 3 respiration (r = 0.5 and r = 0.5, respectively, P < 0.05). Flow-mediated vasodilation and complex I + II state 3 respiration were positively associated with TOI recovery rate (r = 0.8 and r = 0.7, respectively, P < 0.05). These findings suggest that chronic ischemia attenuates skeletal muscle arteriole endothelial function, which may be a key mediator for mitochondrial and microcirculatory dysfunction in the PAD leg skeletal muscle. Targeting microvascular dysfunction may be an effective strategy to prevent and/or reverse disease progression in PAD. NEW & NOTEWORTHY Ex vivo skeletal muscle arteriole endothelial function is impaired in claudicating patients with PAD, and this is associated with attenuated skeletal muscle mitochondrial respiration. In vivo skeletal muscle oxygen delivery and utilization capacity is compromised in PAD, and this may be due to microcirculatory and mitochondrial dysfunction. These results suggest that targeting skeletal muscle arteriole function may lead to improvements in skeletal muscle mitochondrial respiration and oxygen delivery and utilization capacity in claudicating patients with PAD.

Active processes drive and guide biological dynamics across scales -- from subcellular cytoskeletal remodelling, through tissue development in embryogenesis, to population-level bacterial colonies expansion. In each of these, biological functionality requires collective flows to occur while self-organized structures are protected; however, the mechanisms by which active flows can spontaneously constrain their dynamics to preserve structure have not previously been explained. By studying collective flows and defect dynamics in active nematic films, we demonstrate the existence of a self-constraint -- a two-way, spontaneously arising relationship between activity-driven isosurfaces of flow boundaries and mesoscale nematic structures. Our results show that self-motile defects are tightly constrained to viscometric surfaces -- contours along which vorticity and strain-rate balance. This in turn reveals that self-motile defects break mirror symmetry when they move along a single viscometric surface, in contrast with expectations. This is explained by an interdependence between viscometric surfaces and bend walls -- elongated narrow kinks in the orientation field. Although we focus on extensile nematic films, numerical results show the constraint holds whenever activity leads to motile half-charge defects. This mesoscale cross-field self-constraint offers a new framework for tackling complex 3D active turbulence, designing dynamic control into biomimetic materials, and understanding how biological systems can employ active stress for dynamic self-organization., 10 pages, 4 figures

Acute respiratory distress syndrome is characterized by non-cardiogenic pulmonary edema, decreased pulmonary compliance, and abnormalities in gas exchange, especially hypoxemia. Patients with acute respiratory distress syndrome (ARDS) who receive support with venovenous (V-V) extracorporeal membrane oxygenation (ECMO) usually have severe lung disease. Many patients with ARDS have associated pulmonary vascular injury which can result in elevated pulmonary vascular resistance and right heart dysfunction. Since V-V ECMO relies upon preserved cardiac function, right heart failure has important implications for patient evaluation, management, and outcomes. Worsening right heart function complicates ARDS and disease processes. Given the increasing use of ECMO to support patients with ARDS, an understanding of right ventricular-ECMO and cardiopulmonary interactions is essential for the clinician. A narrative review of the manifestations of right heart dysfunction, as well as diagnosis and management strategies for the patient with ARDS on ECMO, is provided.

Background The widespread nature of plastic pollution has given rise to wide scientific and social concern regarding the capacity of these materials to serve as vectors for pathogenic bacteria and reservoirs for Antimicrobial Resistance Genes (ARG). In- and ex-situ were used to characterise the riverine plastisphere taxonomically and functionally in order to determine whether antibiotics within the water influenced the ARG profiles in these microbiomes and how these compared to those on natural surfaces such as wood and their planktonic counterparts. Results We show that plastics support a taxonomically distinct microbiome containing potential pathogens and ARGs. While the plastisphere was similar to those biofilms that grew on wood, they were distinct from the surrounding water microbiome. Hence, whilst potential opportunistic pathogens (i.e. Pseudomonas aeruginosa, Acinetobacter and Aeromonas) and ARG subtypes (i.e. those that confer resistance to macrolides/lincosamides, rifamycin, sulfonamides, disinfecting agents and glycopeptides) were predominant in all surface-related microbiomes, especially on weathered plastics, a completely different set of potential pathogens (i.e. Escherichia, Salmonella, Klebsiella and Streptococcus) and ARGs (i.e. aminoglycosides, tetracycline, aminocoumarin, fluoroquinolones, nitroimidazole, oxazolidinone and fosfomycin) dominated in the planktonic compartment. Our genome-centric analysis allowed the assembly of 215 Metagenome Assembled Genomes (MAGs), linking ARGs and other virulence-related genes to their host. Interestingly, a MAG belonging to Escherichia –that clearly predominated in water– harboured more ARGs and virulence factors than any other MAG, emphasising the potential virulent nature of these pathogenic-related groups. Finally, ex-situ incubations using environmentally-relevant concentrations of antibiotics increased the prevalence of their corresponding ARGs, but different riverine compartments –including plastispheres– were affected differently by each antibiotic. Conclusions Our results provide insights into the capacity of the riverine plastisphere to harbour a distinct set of potentially pathogenic bacteria and function as a reservoir of ARGs. The environmental impact that plastics pose if they act as a reservoir for either pathogenic bacteria or ARGs is aggravated by the persistence of plastics in the environment due to their recalcitrance and buoyancy. Nevertheless, the high similarities with microbiomes growing on natural co-occurring materials and even more worrisome microbiome observed in the surrounding water highlights the urgent need to integrate the analysis of all environmental compartments when assessing risks and exposure to pathogens and ARGs in anthropogenically-impacted ecosystems.

Run-and-tumble processes successfully model several living systems. While studies have typically focused on particles with isotropic tumbles, recent examples exhibit "tumble-turns", in which particles undergo 90{\deg} tumbles and so possess explicitly anisotropic dynamics. We study the consequences of such tumble-turn anisotropicity at both short and long-time scales. We model run-and-tumble-turn particles as self-propelled particles subjected to an angular potential. Using agent-based simulations, we study the interplay of noise and potential on the particles' trajectories, demonstrating that the long-time effect is to alter the tumble-turn time, which governs the long-time dynamics. In particular, when normalized by this timescale, trajectories become independent of the underlying details of the potential. As such, we develop a simplified continuum theory, which quantitatively agrees with agent simulations. The hydrodynamic limit reveals that the transition to diffusive dynamics precedes the transition to isotropic dynamics as the hydrodynamic limit, while purely diffusive, can drive anisotropicity at intermediate times., Comment: 14 pages, 11 figures

Plague, caused by the bacterium Yersinia pestis, is a zoonotic disease of mammalian hosts and flea vectors. Fipronil baits have been used to suppress adult fleas for plague mitigation. The degree and duration of flea control may increase if fipronil also kills other stages in the flea life cycle. We fed grain treated with 0.005% fipronil by weight, or regular nontreated grain, to black-tailed prairie dogs (Cynomys ludovicianus), which excrete fipronil and metabolites in their feces after consuming fipronil in their diet. We presented prairie dog feces to 331 larval Oropsylla montana (Siphonaptera: Ceratophyllidae). When exposed to feces lacking fipronil or metabolites, 84% of larvae survived for 24 h. In contrast, survival declined to 42% for larvae contacting feces from fipronil-treated prairie dogs. Just 7% of larvae consuming feces from fipronil-treated prairie dogs survived. Fipronil and metabolites may persist in host feces for several months or longer in prairie dog burrows where flea larvae dwell and forage. The lethal effects of fipronil on adult and larval fleas (and perhaps other life stages) may help to explain why fipronil baits are capable of suppressing prairie dog fleas for ≥12 mo.

A protein’s genetic architecture – the set of causal rules by which its sequence determines its specific functions – also determines the functional impacts of mutations and the protein’s evolutionary potential. Prior research has proposed that proteins’ genetic architecture is very complex, with pervasive epistatic interactions that constrain evolution and make function difficult to predict from sequence. Most of this work has considered only the amino acid states present in two sequences of interest and the direct paths between them, but real proteins evolve in a multidimensional space of 20 possible amino acids per site. Moreover, almost all prior work has assayed the effect of sequence variation on a single protein function, leaving unaddressed the genetic architecture of functional specificity and its impacts on the evolution of new functions. Here we develop a new logistic regression-based method to directly characterize the global causal rules of the genetic architecture of multiple protein functions from 20-state combinatorial deep mutational scanning (DMS) experiments. We apply it to dissect the genetic architecture and evolution of a transcription factor’s specificity for DNA, using data from a combinatorial DMS of an ancient steroid hormone receptor’s capacity to activate transcription from two biologically relevant DNA elements. We show that the genetic architecture of DNA recognition and specificity consists of a dense set of main and pairwise effects that involve virtually every possible amino acid state in the protein-DNA interface, but higher-order epistasis plays only a tiny role. Pairwise interactions enlarge the set of functional sequences and are the primary determinants of specificity for different DNA elements. Epistasis also massively expands the number of opportunities for single-residue mutations to switch specificity from one DNA target to another. By bringing variants with different functions close together in sequence space, pairwise epistasis therefore facilitates rather than constrains the evolution of new functions.

Biodiversity is crucial for supporting ecosystem functioning, yet some species play a disproportionate role in maintaining complex ecological processes. Ecosystem engineers are species that directly influence ecosystems by modifying biophysical environments, creating novel habitats, altering biogeochemical cycles, increasing biodiversity and/or modulating ecological processes. Although these species may substantially influence ecosystem functioning, their role is often overlooked and difficult to quantify. Understanding the status, dynamics and trends of ecosystem engineers is essential for mitigating biodiversity loss and maintaining healthy ecosystems. This review reveals the common but underappreciated roles that ecosystem engineers play in ecosystem functioning across many different taxa, biomes and ecological processes. We first synthesise how knowledge of ecosystem engineering improves our understanding of species interactions and the ecological processes underlying both ecosystem functioning and BEF relationships. We provide a conceptual model for addressing the effects of ecosystem engineers in BEF research and ecological dynamics. We provide a ‘how to’ analytical framework for monitoring and quantifying changes in ecosystem engineers and their effects on ecosystem functioning. This framework includes (i) what variables to measure, how and at which scale; (ii) experiments involving species exclusion or removal, introduction and comparative designs when experimental manipulation is not feasible and (iii) statistical, data-driven and theory-driven models. We discuss how to leverage ecosystem engineering in the context of current global change and ecosystem restoration efforts. Including ecosystem engineers in conservation and restoration programs, when implemented in the appropriate context and supported by an understanding of ecological mechanisms and processes, may be crucial for sustaining biological diversity and functional ecosystems.

Two different sarbecoviruses have caused major human outbreaks in the past two decades1,2. Both of these sarbecoviruses, SARS-CoV-1 and SARS-CoV-2, engage ACE2 through the spike receptor-binding domain2–6. However, binding to ACE2 orthologues of humans, bats and other species has been observed only sporadically among the broader diversity of bat sarbecoviruses7–11. Here we use high-throughput assays12 to trace the evolutionary history of ACE2 binding across a diverse range of sarbecoviruses and ACE2 orthologues. We find that ACE2 binding is an ancestral trait of sarbecovirus receptor-binding domains that has subsequently been lost in some clades. Furthermore, we reveal that bat sarbecoviruses from outside Asia can bind to ACE2. Moreover, ACE2 binding is highly evolvable—for many sarbecovirus receptor-binding domains, there are single amino-acid mutations that enable binding to new ACE2 orthologues. However, the effects of individual mutations can differ considerably between viruses, as shown by the N501Y mutation, which enhances the human ACE2-binding affinity of several SARS-CoV-2 variants of concern12 but substantially decreases it for SARS-CoV-1. Our results point to the deep ancestral origin and evolutionary plasticity of ACE2 binding, broadening the range of sarbecoviruses that should be considered to have spillover potential.

A downstream process was developed for producing pure monopotassium glucarate and crystalline glucaric acid from a fermentation broth.

Extracts from the seeds of milk thistle, Silybum marianum, are known commonly as silibinin and silymarin and possess anticancer actions on human prostate carcinoma in vitro and in vivo. Seven distinct flavonolignan compounds and a flavonoid have been isolated from commercial silymarin extracts. Most notably, two pairs of diastereomers, silybin A and silybin B and isosilybin A and isosilybin B, are among these compounds. In contrast, silibinin is composed only of a 1:1 mixture of silybin A and silybin B. With these isomers now isolated in quantities sufficient for biological studies, each pure compound was assessed for antiproliferative activities against LNCaP, DU145, and PC3 human prostate carcinoma cell lines. Isosilybin B was the most consistently potent suppressor of cell growth relative to either the other pure constituents or the commercial extracts. Isosilybin A and isosilybin B were also the most effective suppressors of prostate-specific antigen secretion by androgen-dependent LNCaP cells. Silymarin and silibinin were shown for the first time to suppress the activity of the DNA topoisomerase IIα gene promoter in DU145 cells and, among the pure compounds, isosilybin B was again the most effective. These findings are significant in that isosilybin B composes no more than 5% of silymarin and is absent from silibinin. Whereas several other more abundant flavonolignans do ultimately influence the same end points at higher exposure concentrations, these findings are suggestive that extracts enriched for isosilybin B, or isosilybin B alone, might possess improved potency in prostate cancer prevention and treatment.

Supplementary Figure 2 from Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells

Supplementary Figure Legends from Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells

Supplementary Figure 1B from Milk Thistle and Prostate Cancer: Differential Effects of Pure Flavonolignans from Silybum marianum on Antiproliferative End Points in Human Prostate Carcinoma Cells

In promiscuous species, fitness estimates obtained from genetic parentage may often reflect both pre- and post-copulatory components of sexual selection. Directly observing copulations can help isolate the role of pre-copulatory selection, but such behavioral data are difficult to obtain in the wild and may also overlook post-copulatory factors that alter the relationship between mating success and reproductive success. To overcome these limitations, we combined genetic parentage analysis with behavioral estimates of size-specific mating in a wild population of brown anole lizards (Anolis sagrei). Males of this species are twice as large as females and multiple mating among females is common, suggesting the scope for both pre- and post-copulatory processes to shape sexual selection on male body size. Our genetic estimates of reproductive success revealed strong positive directional selection for male size, which was also strongly associated with the number of mates inferred from parentage. In contrast, a male’s size was not associated with the fecundity of his mates or his competitive fertilization success. By simultaneously tracking copulations in the wild via the transfer of colored powder to females by males from different size quartiles, we independently confirmed that large males were more likely than small males to mate. We conclude that body size is primarily under pre-copulatory sexual selection in brown anoles, and that post-copulatory processes do not substantially alter this pre-copulatory selection. Our study also illustrates the utility of combining both behavioral and genetic methods to estimate mating success to disentangle pre- and post-copulatory processes in promiscuous species.

Feather growth patterns are important anatomical phenotypes for investigating the underlying genomic regulation of skin and epidermal appendage development. However, characterization of feather growth patterns previously relied on manual examination and visual inspection, which are both subjective and practically prohibitive for large sample sizes. Here, we report a new high-throughput technique to quantify the location and spatial extent of reversed feathers that comprise head crests in domestic pigeons. Phenotypic variation in pigeon feather growth patterns were rendered by computed tomography (CT) scans as point clouds. We then developed machine learning based, feature extraction techniques to isolate the feathers, and map the growth patterns on the skin in a quantitative, automated, and non-invasive way. Results from five test animals were in excellent agreement with “ground truth” results obtained via visual inspection, which demonstrates the viability of this method for quantification of feather growth patterns. Our findings underscore the potential and increasingly indispensable role of modern computer vision and machine learning techniques at the interface of organismal biology and genetics.

Cyclopeptide alkaloids are an abundant class of plant cyclopeptides with over 200 analogs described and bioactivities ranging from analgesic to antiviral. While these natural products have been known for decades, their biosynthetic basis remains unclear. Using a transcriptome-mining approach, we link the cyclopeptide alkaloids from Ceanothus americanus to dedicated RiPP precursor peptides and identify new, widely distributed split BURP peptide cyclase containing gene clusters. Guided by our bioinformatic analysis, we identify and isolate new cyclopeptides from Coffea arabica, which we named arabipeptins. Reconstitution of the enzyme activity for the BURP found in the biosynthesis of arabipeptin A validates the activity of the newly discovered split BURP peptide cyclases. These results expand our understanding of the biosynthetic pathways responsible for diverse cyclic plant peptides and suggest that these side chain cross-link modifications are widely distributed in eudicots.

Background: This study determined whether prolonged load carriage increased the magnitude and velocity of knee adduction biomechanics and whether increases were related to knee varus thrust or alignment. Methods: Seventeen participants (eight varus thrust and nine control) had knee adduction quantified during 60-min of walking (1.3 m/s) with three body-borne loads (0 kg, 15 kg, and 30 kg). Magnitude, average and maximum velocity, and time to peak of knee adduction biomechanics were submitted to a mixed model ANOVA. Results: With the 0 and 15 kg loads, varus thrust participants exhibited greater magnitude (p ≤ 0.037, 1.9–2.3°), and average (p ≤ 0.027, up to 60%) and maximum velocity (p ≤ 0.030, up to 44%) of varus thrust than control, but differences were not observed with the 30 kg load. The 15 and 30 kg loads led to significant increases in magnitude (p ≤ 0.017, 15–25%) and maximum velocity (p ≤ 0.017, 11–20%) of knee adduction moment, while participants increased magnitude (p ≤ 0.043, up to 0.3°) and maximum velocity (p ≤ 0.022, up to 5.9°/s and 6.7°/s) for knee adduction angle and varus thrust at minutes 30 and 60. Static alignment did not differ between groups (p = 0.412). Conclusion: During prolonged load carriage, all participants increased the magnitude and velocity of knee adduction biomechanics and the potential risk of knee OA.

The antiviral benefit of antibodies can be compromised by viral escape especially for rapidly evolving viruses. Therefore, durable, effective antibodies must be both broad and potent to counter newly emerging, diverse strains. Discovery of such antibodies is critically important for SARS-CoV-2 as the global emergence of new variants of concern (VOC) has compromised the efficacy of therapeutic antibodies and vaccines. We describe a collection of broad and potent neutralizing monoclonal antibodies (mAbs) isolated from an individual who experienced a breakthrough infection with the Delta VOC. Four mAbs potently neutralize the Wuhan-Hu-1 vaccine strain, the Delta VOC, and also retain potency against the Omicron VOCs through BA.4/BA.5 in both pseudovirus-based and authentic virus assays. Three mAbs also retain potency to recently circulating VOCs XBB.1.5 and BQ.1.1 and one also potently neutralizes SARS-CoV-1. The potency of these mAbs was greater against Omicron VOCs than all but one of the mAbs that had been approved for therapeutic applications. The mAbs target distinct epitopes on the spike glycoprotein, three in the receptor binding domain (RBD) and one in an invariant region downstream of the RBD in subdomain 1 (SD1). The escape pathways we defined at single amino acid resolution with deep mutational scanning show they target conserved, functionally constrained regions of the glycoprotein, suggesting escape could incur a fitness cost. Overall, these mAbs are novel in their breadth across VOCs, their epitope specificity, and include a highly potent mAb targeting a rare epitope outside of the RBD in SD1.Significance StatementSARS-CoV-2 infections can result in diverse clinical outcomes, including severe disease. Monoclonal antibodies (mAbs) have been used therapeutically to treat infection, but the emergence of variants has compromised their efficacy. Thus, identifying mAbs that are more durable in the face of SARS-CoV-2 evolution is a pressing need. Here, we describe four new mAbs isolated from a Delta-breakthrough infection, that can potently neutralize diverse variants, including multiple Omicron variants. In addition, one mAb shows broader activity against coronaviruses. The breadth of these mAbs is due to their focus on highly conserved regions of the viral protein antigen, including regions that are required for the virus to enter the cell. These properties make them promising candidates for therapeutic use.

Differential gene expression is associated with diabetic cardiomyopathy (DMCM) and culminates in adverse remodeling in the diabetic heart. Genome editing is a technology utilized to alter endogenous genes. Genome editing also provides an option to induce cardioprotective genes or inhibit genes linked to adverse cardiac remodeling and thus has promise in ameliorating DMCM. Non-coding genes have emerged as novel regulators of cellular signaling and may serve as potential therapeutic targets for DMCM. Specifically, there is a widespread change in the gene expression of fetal cardiac genes and microRNAs, termed genetic reprogramming, that promotes pathological remodeling and contributes to heart failure in diabetes. This genetic reprogramming of both coding and non-coding genes varies with the progression and severity of DMCM. Thus, genetic editing provides a promising option to investigate the role of specific genes/non-coding RNAs in DMCM initiation and progression as well as developing therapeutics to mitigate cardiac remodeling and ameliorate DMCM. This chapter will summarize the research progress in genome editing and DMCM and provide future directions for utilizing genome editing as an approach to prevent and/or treat DMCM.

Bacteria live in cosmopolitan communities, where the ability to sense and respond to interspecies and environmental signals is critical for survival. We previously showed the pathogenPseudomonas aeruginosadetects secreted peptides from bacterial competitors and navigates interspecies signal gradients using pilus-based motility. Yet, it remained unknown whetherP. aeruginosautilizes a designated chemosensory system for this behavior. Here, we performed a comprehensive genetic analysis of a putative pilus chemosensory system to reveal behaviors of mutants that retain motility, but are blind to interspecies signals. The enzymes predicted to methylate (PilK) and demethylate (ChpB) the putative pilus chemoreceptor, PilJ, are necessary for cells to control the direction of migration. While these findings implicate PilJ as abona fidechemoreceptor, such function had yet to be experimentally defined, as PilJ is essential for motility. Thus, we constructed systematic genetic modifications of PilJ and found that without the predicted ligand binding domains or methylation sites cells lose the ability to detect competitor gradients, despite retaining pilus-mediated motility. Collectively, this work uncovers the chemosensory nature of PilJ, providing insight into chemotactic interactions necessary for bacterial survival in polymicrobial communities and revealing putative pathways where therapeutic intervention might disrupt bacterial communication.

Antiferromagnets have recently been propelled to the forefront of spintronics by their high potential for revolutionizing memory technologies. For this, understanding the formation and driving mechanisms of the domain structure is paramount. In this work, we investigate the domain structure in a thin-film canted antiferromagnet $α$-Fe$_2$O$_3$. We find that the internal destressing fields driving the formation of domains do not follow the crystal symmetry of $α$-Fe$_2$O$_3$, but fluctuate due to substrate clamping. This leads to an overall isotropic distribution of the Néel order with locally varying effective anisotropy in antiferromagnetic thin films. Furthermore, we show that the weak ferromagnetic nature of $α$-Fe$_2$O$_3$ leads to a qualitatively different dependence on magnetic field compared to collinear antiferromagnets such as NiO. The insights gained from our work serve as a foundation for further studies of electrical and optical manipulation of the domain structure of antiferromagnetic thin films., 9 pages, 5 figures

Antiferromagnets have recently been propelled to the forefront of spintronics by their high potential for revolutionizing memory technologies. For this, understanding the formation and driving mechanisms of the domain structure is paramount. In this work, we investigate the domain structure in a thin-film canted antiferromagnet $\alpha$-Fe$_2$O$_3$. We find that the internal destressing fields driving the formation of domains do not follow the crystal symmetry of $\alpha$-Fe$_2$O$_3$, but fluctuate due to substrate clamping. This leads to an overall isotropic distribution of the N\'eel order with locally varying effective anisotropy in antiferromagnetic thin films. Furthermore, we show that the weak ferromagnetic nature of $\alpha$-Fe$_2$O$_3$ leads to a qualitatively different dependence on magnetic field compared to collinear antiferromagnets such as NiO. The insights gained from our work serve as a foundation for further studies of electrical and optical manipulation of the domain structure of antiferromagnetic thin films., Comment: 9 pages, 5 figures

Few experiences direct affect, behavior, and cognition as thoroughly as feelings of power and powerlessness. The present study examined 403 participants’ narrated experiences feeling powerful ( n = 196) or powerless ( n = 207) using Linguistic Inquiry and Word Count (LIWC) analysis to identify social contexts that might explain the effects of power on emotion expression. Powerful narratives contained more frequent communication about work, whereas powerless narratives contained more frequent communication about sex. Moreover, powerless narratives conveyed greater negative emotionality. A parallel mediation analysis revealed that communication about work and sex helped to explain the association between self-reported feelings of power and expressions of negative emotionality. When participants felt powerful and communicated about work, they expressed lower negative emotionality; when participants felt powerless and communicated about sex, they expressed higher negative emotionality. Modest differences in emotional expression between women and men indicated that power research should report analyses including gender as a control variable. Findings provide direction to the next wave of power research, which should examine organizations and intimate relationships as contexts in which power dynamics are salient.

A preliminary vaccination trial against the emergent pathogen, SARS-CoV-2, was completed in captive black-footed ferrets (Mustela nigripes; BFF) to assess safety, immunogenicity, and anti-viral efficacy. Vaccination and boosting of 15 BFF with purified SARS-CoV-2 S1 subunit protein produced a nearly 150-fold increase in mean antibody titers compared to pre-vaccination titers. Serum antibody responses were highest in young animals, but in all vaccinees, antibody response declined rapidly. Anti-viral activity from vaccinated and unvaccinated BFF was determined in vitro, as well as in vivo with a passive serum transfer study in mice. Transgenic mice that received BFF serum transfers and were subsequently challenged with SARS-CoV-2 had lung viral loads that negatively correlated (p < 0.05) with the BFF serum titer received. Lastly, an experimental challenge study in a small group of BFF was completed to test susceptibility to SARS-CoV-2. Despite viral replication and shedding in the upper respiratory tract for up to 7 days post-challenge, no clinical disease was observed in either vaccinated or naive animals. The lack of morbidity or mortality observed indicates SARS-CoV-2 is unlikely to affect wild BFF populations, but infected captive animals pose a potential risk, albeit low, for humans and other animals.