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Decreased appetite is a common clinical problem in captive rhesus macaques (Macaca mulatta). Mirtazapine, a tetracyclic antidepressant originally developed for humans, has shown promise as a safe and effective promoter of weight gain and appetite in several veterinary species including rhesus and cynomolgus macaques. Although mirtazapine is available as oral formulations, transdermal delivery in macaques with reduced appetite would allow quick, painless, topical application. Here we describe the pharmacokinetics of a single application of a widely available veterinary transdermal mirtazapine formulation in 6 rhesus macaques. A dose of 0.5 mg/kg of transdermal mirtazapine ointment that has proven to be effective in rhesus was applied to the caudal pinnae of 3 female and 3 male young adult macaques. Serum was collected at 0, 0.5, 1, 3, 6, 8, 12, 24, 36, 48, and 72 h after administration. Our data indicate transdermal mirtazapine is absorbed at a lower level in rhesus as compared with published values in domestic cats (rhesus peak serum concentration: 1.2 ± 0.3 ng/mL), while drug half-life is longer than that reported in cats (rhesus: 33 ± 7 h). Mirtazapine reaches peak plasma concentrations in rhesus at 16 ± 10 h after administration; our model indicates that up to 5 d of serial dosing may be necessary to reach steady state. Our preliminary data also suggest that sex differences may contribute to efficacy and/or indicate sex-based differences, as male macaques reached Tmax more quickly than females (19 ± 2 h in females and 8 ± 3 h in males) and showed higher variation in half-life (33 ± 4 h in females and 34 ± 11 h in males). While previous work indicates clinical efficacy of the 0.5-mg/kg dosage in macaques, further investigation is warranted to determine if rhesus may benefit from higher recommended doses than companion animal species.

Abstract Although continuum-scale segregation is a well-documented behavior in multi-species materials, detailed site-specific behavior remains largely unexplored. This is partially due to the complexity of analyzing materials at the requisite time and length scales for describing segregation with full atomic accuracy. Here, we better evaluate the segregation behavior of disordered grain boundary (GB) atomic environments through leveraging a set of Strain Functional Descriptors (SFDs) to generate an atomic descriptor (i.e., fingerprint). Using this atomic fingerprint, we resolve key relationships between atomic structure and segregation energy. Machine learning (ML) techniques are utilized in concert with this SFD fingerprint to elucidate complex relationships relating segregation potential to changes in specific features of the local Gaussian density captured by the SFDs. Finally, we identify relationships that indicate both individual and joint structure-property correlations. Linking atomic segregation energy to key structural features demonstrates the value of higher-order descriptors for uncovering complex structure-property relationships at an atomic scale.

Species distribution models (SDMs) are becoming an important tool for marine conservation and management. Yet while there is an increasing diversity and volume of marine biodiversity data for training SDMs, little practical guidance is available on how to leverage distinct data types to build robust models. We explored the effect of different data types on the fit, performance and predictive ability of SDMs by comparing models trained with four data types for a heavily exploited pelagic fish, the blue shark (Prionace glauca), in the Northwest Atlantic: two fishery dependent (conventional mark-recapture tags, fisheries observer records) and two fishery independent (satellite-linked electronic tags, pop-up archival tags). We found that all four data types can result in robust models, but differences among spatial predictions highlighted the need to consider ecological realism in model selection and interpretation regardless of data type. Differences among models were primarily attributed to biases in how each data type, and the associated representation of absences, sampled the environment and summarized the resulting species distributions. Outputs from model ensembles and a model trained on all pooled data both proved effective for combining inferences across data types and provided more ecologically realistic predictions than individual models. Our results provide valuable guidance for practitioners developing SDMs. With increasing access to diverse data sources, future work should further develop truly integrative modeling approaches that can explicitly leverage the strengths of individual data types while statistically accounting for limitations, such as sampling biases.

Abstract Background Physician burnout is rising, especially among academic physicians facing pressures to increase their clinical workload, lead administrative tasks and committees, and be active in research. There is a concern this could have downstream effects on learners’ experiences and academic physician’s ability to teach learners on the team. Methods A 29-question RedCap survey was electronically distributed to 54 attending physicians within an academic learning health system who oversaw the General Medicine inpatient teaching services during the 2022–2023 academic year. The aims were to assess this cohort of attending physicians’ experiences, attitudes, and perceptions on their ability to effectively teach learners on the team, feeling valued, contributors to work-life balance and symptoms of burnout, Fisher’s Exact Tests were used for data analysis. Results Response rate was 56%. Attendings splitting time 50% inpatient / 50% outpatient felt that team size and type of admissions model affected their ability to effectively teach learners (p = 0.022 and p = 0.049). Attendings with protected administrative time felt that non-patient care obligations affected their ability to effectively teach the learners (p = 0.019). Male attendings and attendings with ≤ 5 years of General Medicine inpatient teaching experience felt less valued by residency leadership (p = 0.019 and p = 0.026). 80% of attendings experienced emotional exhaustion, and those with > 10 weeks on a General Medicine inpatient teaching service were more likely to experience emotional exhaustion (p = 0.041). Attendings with > 10 weeks on a General Medicine inpatient teaching service and those who were a primary caregiver were more likely to experience depersonalization (p = 0.012 and p = 0.031). 57% of attendings had reduced personal achievement. Conclusions Institutions should seek an individual and organizational approach to professional fulfillment. Special attention to these certain groups is warranted to understand how they can be better supported. Further research, such as with focus groups, is needed to address these challenges.

Abstract Cytokinesis is the final step of the cell division cycle that leads to the formation of two new cells. Successful cytokinesis requires significant remodelling of the plasma membrane by spatially distinct β- and γ-actin networks. These networks are generated by the formin family of actin nucleators, DIAPH3 and DIAPH1 respectively. Here we show that β- and γ-actin perform specialized and non-redundant roles in cytokinesis and cannot substitute for one another. Expression of hybrid DIAPH1 and DIAPH3 proteins with altered actin isoform specificity relocalized cytokinetic actin isoform networks within the cell, causing cytokinetic failure. Consistent with this we show that β-actin networks, but not γ-actin networks, are required for the maintenance of non-muscle myosin II and RhoA at the cytokinetic furrow. These data suggest that independent and spatially distinct actin isoform networks form scaffolds of unique interactors that facilitate localized biochemical activities to ensure successful cell division.

Despite studies showing that dams have significant effects on the sediment dynamics and evolution of a river upstream of a dam, the knowledge of relationships between river topography and sediment transport in a dam's backwater zone has hardly been applied in reservoir sedimentation management. This study investigated the potential of an alternating sequence of engineered topographic nozzles and oversized landforms, utilizing flow convergence routing theory, to redistribute sediment erosion foci in a dam's backwater zone for remote mountain reservoirs with a sediment storage capacity of ~105 m3. To test scientific ideas and engineering alternatives, the current topography of the backwater zone upstream from Our House Dam on the confined, mountainous Middle Yuba River, California, was virtually re-contoured into different scenarios for numerical experimentation. As most of the dam's backwater zone is filled with sediment (a common global problem) in a narrow, confined canyon, two-dimensional hydrodynamic modeling was useful for evaluating erosion patterns resulting from different manipulations. The results found that high velocity concentrates through nozzles and dissipates through oversized landforms, resulting in the latter exhibiting hydraulics indicative of functioning as sediment settling basins. These basins can be located away from the dam where key infrastructure needs clearance from sedimentation. As flow increases through the sequence of nozzles and oversized landforms, each nozzle's hydraulic jet will persist farther into the oversized area. Moderate in-channel flow (daily recurrence of ~5–30 %) was best for creating conditions to force deposition of sediment in oversized landforms. At high enough discharge (recurrence of

In light of the numerous studies identifying post-transcriptional regulators on the surface of the endoplasmic reticulum (ER), we asked whether there are factors that regulate compartment specific mRNA translation in human cells. Using a proteomic survey of spatially regulated polysome interacting proteins, we identified the glycolytic enzyme Pyruvate Kinase M (PKM) as a cytosolic (i.e. ER-excluded) polysome interactor and investigated how it influences mRNA translation. We discovered that the PKM-polysome interaction is directly regulated by ADP levels-providing a link between carbohydrate metabolism and mRNA translation. By performing enhanced crosslinking immunoprecipitation-sequencing (eCLIP-seq), we found that PKM crosslinks to mRNA sequences that are immediately downstream of regions that encode lysine- and glutamate-enriched tracts. Using ribosome footprint protection sequencing, we found that PKM binding to ribosomes causes translational stalling near lysine and glutamate encoding sequences. Lastly, we observed that PKM recruitment to polysomes is dependent on poly-ADP ribosylation activity (PARylation)-and may depend on co-translational PARylation of lysine and glutamate residues of nascent polypeptide chains. Overall, our study uncovers a novel role for PKM in post-transcriptional gene regulation, linking cellular metabolism and mRNA translation.

Geometric modelling of river channel topography is a method of design synthesis wherein specific 2D geometric elements of river topography, such as the bed profile, cross-sectional shape and channel planform contours, are expressed mathematically in isolation and then combined to produce a 3D heightmap. We utilized the geometric modelling framework to synthesize channel terrains that reveal flow–form–function linkages to investigate what roles variability in bed roughness, thalweg elevation and channel width play in defining hydraulic and ecohydraulic conditions of a channel reach from baseflow to bankfull discharge. To achieve a robust inquiry for a range of settings, this study developed four distinct synthetic channel terrain models for each of three stream reaches of different channel types in the South Fork Eel River in northern coastal California, USA. To test the process-based effects of these diverse terrain synthesis options, we compared the resulting hydraulic patterns and preferred habitat availability for fry/juvenile steelhead trout and coho salmon over a range of discharges. Among thalweg bed undulation, width variation and bed roughness, we found thalweg bed undulation was the key factor affecting the channel ecohydraulic response at baseflow condition. At bankfull condition, thalweg bed elevation had the largest effect in high-order mainstem streams identified by gravel-cobble dominated high width-to-depth, riffle-pool sequences, width variation had the largest effect in mid-order confined channels with gravel-cobble, high width-to-depth ratio with expansions/contractions and bed roughness in low-order streams with low width-to-depth ratio, high-gradient, cobble-boulder and step-pool/cascade channels.

Mid-infrared microscopy is an important tool for biological analyses, allowing a direct probe of molecular bonds in their low energy landscape. In addition to the label-free extraction of spectroscopic information, the application of broadband sources can provide a third dimension of chemical specificity. However, to enable widespread deployment, mid-infrared microscopy platforms need to be compact and robust while offering high speed, broad bandwidth, and high signal-to-noise ratio. In this study, we experimentally showcase the integration of a broadband, high-repetition-rate dual-comb spectrometer (DCS) in the mid-infrared range with a scanning microscope. We employ a set of 1-GHz mid-infrared frequency combs, demonstrating their capability for high-speed and broadband hyperspectral imaging of polymers and ovarian tissue. The system covers 1000 cm−1 at νc = 2941 cm−1 with 12.86 kHz spectra acquisition rate and 5 µm spatial resolution. Taken together, our experiments and analysis elucidate the trade-off between bandwidth and speed in DCS as it relates to microscopy. This provides a roadmap for the future advancement and application of high-repetition-rate DCS hyperspectral imaging.

ABSTRACT During its cell cycle, the bacterium Caulobacter crescentus switches from a motile, free-living state, to a sessile surface-attached cell. During this coordinated process, cells undergo irreversible morphological changes, such as shedding of their polar flagellum and synthesis of an adhesive holdfast at the same pole. In this work, we used genetic screens to identify genes involved in the regulation of the transition from the motile to the sessile lifestyle. We identified a predicted hybrid histidine kinase that inhibits biofilm formation and promotes the motile lifestyle: HmrA (holdfast and motility regulator A). Genetic screens and genomic localization led to the identification of additional genes that form a putative phosphorelay pathway with HmrA. We postulate that the Hmr pathway acts as a rheostat to control the proportion of cells harboring a flagellum or a holdfast in the population. Further genetic analysis suggests that the Hmr pathway impacts c-di-GMP synthesis through the diguanylate cyclase DgcB pathway. Our results also indicate that the Hmr pathway is involved in the regulation of motile to sessile lifestyle transition as a function of various environmental factors: biofilm formation is repressed when excess copper is present and derepressed under non-optimal temperatures. Finally, we provide evidence that the Hmr pathway regulates motility and adhesion without modulating the transcription of the holdfast synthesis regulator HfiA.IMPORTANCEComplex communities attached to a surface, or biofilms, represent the major lifestyle of bacteria in the environment. Such a sessile state enables the inhabitants to be more resistant to adverse environmental conditions. Thus, having a deeper understanding of the underlying mechanisms that regulate the transition between the motile and the sessile states could help design strategies to improve biofilms when they are beneficial or impede them when they are detrimental. For Caulobacter crescentus motile cells, the transition to the sessile lifestyle is irreversible, and this decision is regulated at several levels. In this work, we describe a putative phosphorelay that promotes the motile lifestyle and inhibits biofilm formation, providing new insights into the control of adhesin production that leads to the formation of biofilms.

The use of thin films made of alloys, i.e., containing multiple metal species, can enhance their properties. However, as with single-element films, residual stress in the films can limit their performance. A model is proposed for relating the stress in alloy thin films to the processing conditions (growth rate, temperature, and sputter-gas pressure), material properties (composition, atomic and defect mobilities, and elastic moduli), and microstructure (grain size and grain growth kinetics). The model is based on stress-generating processes that occur during film growth at grain boundaries and due to energetic particle impacts. While the equations are similar to those proposed for single-element films, the alloy kinetic parameters now contain the effects of the different atomic species. The model is used to explain the growth rate and composition dependence of in situ stress evolution during the deposition for various concentrations in the tungsten–vanadium system. [ABSTRACT FROM AUTHOR]

We present six case studies from a comprehensive mass range (1-109 M⊙) of astrophysical objects, each of which possess jets, emit high-energy gamma radiation and in some instances spatially identifiable ultra-high-energy cosmic rays (UHECRs). All sources are strong candidates for UHECR emission, if not already known to emit them. We surmise that wakefield acceleration in conjunction with the magnetorotational instability of the accretion disc explains both structural properties of the jets and details in their emission signals, such as correlations in neutrino and gamma-ray bursts, and in the case of blazars, anticorrelations in flux and spectral index. Furthermore, our model predicts an upper bound for the energy of UHECRs emitted from a source given the mass of its central compact object and total jet luminosity. To provide context for our model predictions, we quantitatively compare them with observational data, however, we have not accounted for the GZK limit and assumed universal values for several model parameters (e.g. jet-spreading index, p) that likely differ between sources. Since the accretion and acceleration mechanisms are independent of mass, aside from determining maximum values, blazars (∼109 M⊙), radio galaxies (∼ 108 M⊙), Seyfert galaxies (∼ 106 M⊙ ), starburst galaxies (∼ 103 M⊙ ), even microquasars (1-10 M⊙) interestingly exhibit the same physics. Other radiation bands, such as X-ray, ultraviolet, or radio, may harbour additional information, but we chose not to focus on them for brevity. However, such an endeavour may open the door to a new multimessenger approach for understanding these objects.

Migratory habitat selection in adult anadromous salmonids occurs in response to a combination of physical, chemical, and biological cues. Migratory behavioral responses to localized hydraulics are not well understood and hydraulic flow features can be particularly complex at confluence junctions. In some cases, hydraulics may play a partial role in migratory routing, with implications for population structure where wild- and hatchery-origin fish hybridize. This study investigated two questions about such confluences: (1) Can patterns in migratory microhabitat selection or migratory swimming behavior in adult Chinook salmon be attributed to micro-scale hydraulic conditions driven by discharge magnitude and ratio at a confluence? (2) What is the relative influence of selectivity for hydraulic conditions compared to temperature and/or turbidity in micro-scale habitat selection or migratory swimming behavior at a confluence? The fall 2019 migration of California Central Valley Chinook salmon (Oncorhynchus tshawytscha) at the confluence of the Feather and Yuba Rivers in northeastern California served as a testbed. Using two dual-frequency identification sonars, 12 monitoring sites representing distinct physical microhabitats upstream of, within, and downstream of the confluence were repeatedly sampled during two four-day flow periods (mean flow ratios between the Feather and Yuba Rivers were 8.66 and 4.02, respectively). Temperature magnitudes and ratios flipped between these sampling periods. We used a multiple regression analysis using the F test for significance and a corrected Akaike information criteria (AICc) analysis to identify predictors of both detection rate (# individuals/m3/min) and percent occurrence of directed, milling, and backtracking swimming behaviors. A combination of conveyance (m2/s), temperature, and turbidity was found to perform best in predicting detection rate (p < 0.001). No suitable model was found to predict directed behavior. Milling was best predicted by a combination of all hydraulic variables (p < 0.001) and although temperature alone was found to best predict backtracking (p < 0.01), we identified a candidate model including conveyance and temperature as predictors (ΔAICc = 3.66, p = 0.02) which aided in the interpretation of our results. This study provides evidence that channel hydraulics play an active role in the sum of navigation cues that are utilized by migrating adult salmon en route to spawning grounds and should be considered in future investigations of homing and straying patterns in anadromous salmonids.