Woodland caribou calving fidelity: Spatial location, habitat, or both?

Individuals that isolate themselves to give birth can use more than one strategy in choosing birth sites to maximize reproductive success. Previous research has focused on the consistency in the use of the same birth-site across years (i.e., spatial fidelity), but individuals alternatively may use similar habitat conditions across years (i.e., habitat fidelity). Using GPS telemetry, we determined whether woodland caribou expressed spatial or habitat fidelity during calving, and evaluated intrinsic and extrinsic factors associated with expressing either type of fidelity. We identified 56 individuals with ≥2 putative birth events, via a movement-based model, across northern Ontario between 2010 and 2014. Individuals were classified as expressing (1) spatial fidelity by comparing sequential calving locations to a random spatial distribution of available calving locations, (2) habitat fidelity using a logistic use model compared to a null (intercept only) model, (3) no fidelity (neither criterion met), or (4) both spatial and habitat fidelity (both criteria met). Across all individuals, 37% expressed no fidelity (36 of 98), 15% expressed only spatial fidelity (15 of 99), 35% expressed only habitat fidelity (34 of 98), and 14% expressed both spatial and habitat fidelity (14 of 98). Older individuals were more likely to express spatial fidelity, whereas lower availability of upland and lowland conifer forests without linear features increased the probability an individual expressed habitat fidelity. Our results indicate that managing for caribou calving needs to consider protecting both specific, known birthing sites, but also broad-scale areas of preferred habitat for calving. Understanding the mechanisms that influence caribou expressing calving fidelity, and associated fitness costs, is crucial for the conservation of the species.

Conventional type 1 dendritic cells are essential for the development of primary biliary cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is a progressive-cholestatic autoimmune liver disease. Dendritic cells (DC) are professional antigen-presenting cells and their prominent presence around damaged bile ducts of PBC patients are documented. cDC1 is a rare subset of DC known for its cross-presentation abilities and interleukin 12 production. Our aim was to assess the role of cDC1 in the pathogenesis of PBC. METHODS: We utilized an inducible murine model of PBC and took advantage of the DC reporter mice Zbtb46gfp and the Batf3-/- mice that specifically lack the cDC1 subset. cDC1 cells were sorted from blood of PBC patients and healthy individuals and subjected to Bulk-MARS-seq transcriptome analysis. RESULTS: Histopathology assessment demonstrated peri-portal inflammation in wild type (WT) mice, whereas only minor abnormalities were observed in Batf3-/- mice. Flow cytometry analysis revealed a two-fold reduction in hepatic CD8/CD4 T cells ratio in Batf3-/- mice, suggesting reduced intrahepatic CD8 T cells expansion. Histological evidence of portal fibrosis was detected only in the WT but not in Batf3-/- mice. This finding was supported by decreased expression levels of pro-fibrotic genes in the livers of Batf3-/- mice. Transcriptome analysis of human cDC1, revealed 78 differentially expressed genes between PBC patients and controls. Genes related to antigen presentation, TNF and IFN signalling and mitochondrial dysfunction were significantly increased in cDC1 isolated from PBC patients. CONCLUSION: Our data illustrated the contribution the cDC1 subset in the pathogenesis of PBC and provides a novel direction for immune based cell-specific targeted therapeutic approach in PBC.

Bacteria Colonies Modify Their Shear and Compressive Mechanical Properties in Response to Different Growth Substrates.

Bacteria build multicellular communities termed biofilms, which are often encased in a self-secreted extracellular matrix that gives the community mechanical strength and protection against harsh chemicals. How bacteria assemble distinct multicellular structures in response to different environmental conditions remains incompletely understood. Here, we investigated the connection between bacteria colony mechanics and the colony growth substrate by measuring the oscillatory shear and compressive rheology of bacteria colonies grown on agar substrates. We found that bacteria colonies modify their own mechanical properties in response to shear and uniaxial compression in a manner that depends on the concentration of agar in their growth substrate. These findings highlight that mechanical interactions between bacteria and their microenvironments are an important element in bacteria colony development, which can aid in developing strategies to disrupt or reduce biofilm growth.

Predation risk drives long-term shifts in migratory behaviour and demography in a large herbivore population.

Migration is an adaptive life-history strategy across taxa that helps individuals maximise fitness by obtaining forage and avoiding predation risk. The mechanisms driving migratory changes are poorly understood, and links between migratory behaviour, space use, and demographic consequences are rare. Here, we use a nearly 20-year record of individual-based monitoring of a large herbivore, elk (Cervus canadensis) to test hypotheses for changing patterns of migration in and adjacent to a large protected area in Banff National Park (BNP), Canada. We test whether bottom-up (forage quality) or top-down (predation risk) factors explained trends in (i) the proportion of individuals using 5 different migratory tactics, (ii) differences in survival rates of migratory tactics during migration and whilst on summer ranges, (iii) cause-specific mortality by wolves and grizzly bears, and (iv) population abundance. We found dramatic shifts in migration consistent with behavioural plasticity in individual choice of annual migratory routes. Shifts were inconsistent with exposure to the bottom-up benefits of migration. Instead, exposure to landscape gradients in predation risk caused by exploitation outside the protected area drove migratory shifts. Carnivore exploitation outside the protected area led to higher survival rates for female elk remaining resident or migrating outside the protected area. Cause-specific mortality aligned with exposure to predation risk along migratory routes and summer ranges. Wolf predation risk was higher on migratory routes than summer ranges of montane-migrant tactics, but wolf predation risk traded-off with heightened risk from grizzly bears on summer ranges. A novel eastern migrant tactic emerged following a large forest fire that enhanced forage in an area with lower predation risk outside of the protected area. The changes in migratory behaviour translated to population abundance, where abundance of the montane-migratory tactics declined over time. The presence of diverse migratory life histories maintained a higher total population abundance than would have been the case with only one migratory tactic in the population. Our study demonstrates the complex ways in which migratory populations change over time through behavioural plasticity and associated demographic consequences because of individuals balancing predation risk and forage trade-offs.

A Qualitative Exploration of Stakeholders' Preferences for Early-Stage Rectal Cancer Treatment.

As treatment options for patients with rectal cancer evolve, patients with early-stage rectal cancer may have a treatment choice between surgery and a trial of nonoperative management. Patients must consider the treatments' clinical tradeoffs alongside their personal goals and preferences. Shared decision-making (SDM) between patients and clinicians can improve decision quality when patients are faced with preference-sensitive care options. We interviewed 28 stakeholders (13 clinicians and 15 patients) to understand their perspectives on early-stage rectal cancer treatment decision-making. Clinicians included surgeons, medical oncologists, and radiation oncologists who treat rectal cancer. Adult patients included those diagnosed with early-stage rectal cancer in the past 5 years, recruited from an institutional database. A semi-structured interview guide was developed based on a well-established decision support framework and reviewed by the research team and stakeholders. Interviews were conducted between January 2022 and January 2023. Transcripts were coded by 2 raters and analyzed using thematic analysis. Both clinicians and patients recognized the importance of SDM to support high-quality decisions about the treatment of early-stage rectal cancer. Barriers to SDM included variable clinician motivation due to lack of training or perception of patients' desires or abilities to engage, as well as time-constrained encounters. A decision aid could help facilitate SDM for early-stage rectal cancer by providing standardized, evidence-based information about treatment options that align with clinicians' and patients' decision needs.

Mechanobiology as a tool for addressing the genotype-to-phenotype problem in microbiology.

The central hypothesis of the genotype-phenotype relationship is that the phenotype of a developing organism (i.e., its set of observable attributes) depends on its genome and the environment. However, as we learn more about the genetics and biochemistry of living systems, our understanding does not fully extend to the complex multiscale nature of how cells move, interact, and organize; this gap in understanding is referred to as the genotype-to-phenotype problem. The physics of soft matter sets the background on which living organisms evolved, and the cell environment is a strong determinant of cell phenotype. This inevitably leads to challenges as the full function of many genes, and the diversity of cellular behaviors cannot be assessed without wide screens of environmental conditions. Cellular mechanobiology is an emerging field that provides methodologies to understand how cells integrate chemical and physical environmental stress and signals, and how they are transduced to control cell function. Biofilm forming bacteria represent an attractive model because they are fast growing, genetically malleable and can display sophisticated self-organizing developmental behaviors similar to those found in higher organisms. Here, we propose mechanobiology as a new area of study in prokaryotic systems and describe its potential for unveiling new links between an organism's genome and phenome.

GWAS and autoimmunity: What have we learned and what next.

Autoimmune diseases are common conditions characterized by loss of tolerance, female predominance and a remarkable heterogeneity among different populations. Most often they are polygenic and several genetic loci have been linked with the risk of developing autoimmune diseases. However, causal inference is difficult. When the genomic revolution began there were high hopes of translating fast genetic analyses to the bedside but this has proven to be challenging. Nonetheless, over the last decade, fine-mapping strategies have greatly improved; one of the most significant research lines focuses on the in vivo and ex vivo definition of the effect of genetic variants within the target tissues and within specific subpopulations of immune cells that are involved in the disease pathogenesis. This strategy also includes the longitudinal tracking of a large number of immunophenotypes in many individuals to build a large reference atlas for variant characterization. In this review, we discuss the results obtained by GWAS in autoimmune diseases and review recent advances in fine mapping strategies. More importantly, we discuss gaps and future directions.

Materials science and mechanosensitivity of living matter.

Living systems are composed of molecules that are synthesized by cells that use energy sources within their surroundings to create fascinating materials that have mechanical properties optimized for their biological function. Their functionality is a ubiquitous aspect of our lives. We use wood to construct furniture, bacterial colonies to modify the texture of dairy products and other foods, intestines as violin strings, bladders in bagpipes, and so on. The mechanical properties of these biological materials differ from those of other simpler synthetic elastomers, glasses, and crystals. Reproducing their mechanical properties synthetically or from first principles is still often unattainable. The challenge is that biomaterials often exist far from equilibrium, either in a kinetically arrested state or in an energy consuming active state that is not yet possible to reproduce de novo. Also, the design principles that form biological materials often result in nonlinear responses of stress to strain, or force to displacement, and theoretical models to explain these nonlinear effects are in relatively early stages of development compared to the predictive models for rubberlike elastomers or metals. In this Review, we summarize some of the most common and striking mechanical features of biological materials and make comparisons among animal, plant, fungal, and bacterial systems. We also summarize some of the mechanisms by which living systems develop forces that shape biological matter and examine newly discovered mechanisms by which cells sense and respond to the forces they generate themselves, which are resisted by their environment, or that are exerted upon them by their environment. Within this framework, we discuss examples of how physical methods are being applied to cell biology and bioengineering.

Spreading rates of bacterial colonies depend on substrate stiffness and permeability.

The ability of bacteria to colonize and grow on different surfaces is an essential process for biofilm development. Here, we report the use of synthetic hydrogels with tunable stiffness and porosity to assess physical effects of the substrate on biofilm development. Using time-lapse microscopy to track the growth of expanding Serratia marcescens colonies, we find that biofilm colony growth can increase with increasing substrate stiffness, unlike what is found on traditional agar substrates. Using traction force microscopy-based techniques, we find that biofilms exert transient stresses correlated over length scales much larger than a single bacterium, and that the magnitude of these forces also increases with increasing substrate stiffness. Our results are consistent with a model of biofilm development in which the interplay between osmotic pressure arising from the biofilm and the poroelastic response of the underlying substrate controls biofilm growth and morphology.

MAIT cells are imprinted by the microbiota in early life and promote tissue repair.

How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T (MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury.

Primary Cutaneous T-Cell Lymphomas Showing Gamma-Delta (γδ) Phenotype and Predominantly Epidermotropic Pattern are Clinicopathologically Distinct From Classic Primary Cutaneous γδ T-Cell Lymphomas.

Primary cutaneous gamma-delta (γδ) T-cell lymphoma is a rare disease that typically involves the dermis and subcutis. Cases of primary cutaneous T-cell lymphomas showing γδ phenotype and predominantly epidermotropic pattern (EγδTCL) are not well defined. In this series, cases of primary cutaneous T-cell lymphomas showing γδ phenotype were reviewed and classified as predominantly epidermotropic (EγδTCL) when >75% of lymphoma cells resided in the epidermis or predominantly dermal and/or subcutaneous (DSγδTCL). Clinical, pathologic, and immunophenotypic features were compared in 27 biopsies from 13 patients of EγδTCL and 13 biopsies from 7 patients of DSγδTCL. The lymphoma cells were diffusely positive for CD3 and T-cell receptor (TCR)γ, mostly positive for granzyme B and TIA-1, variably positive for CD8, CD7, and CD30, and negative for CD4 and TCRß. Two patients with EγδTCL had dissemination to lymph nodes and 1 to the lung; 1 patient with DSγδTCL had gastrointestinal involvement. The median survival of patients with EγδTCL was not reached, and with a median follow-up of 19.2 months, 3/13 died. In contrast, the median survival of patients with DSγδTCL was 10 months, and after a median follow-up of 15.6 months, 5/5 died (P<0.01). EγδTCL is a rare presentation of cutaneous T-cell lymphoma that can be distinguished from DSγδTCL based on the extent of epidermotropism and has a better prognosis and longer median survival than DSγδTCL. However, although EγδTCL resembles mycosis fungoides clinically and histologically, a subset of EγδTCL is more likely to behave more aggressively than typical mycosis fungoides.

Primary Cutaneous Gamma-Delta (γ/δ) T-cell Lymphoma: An Unusual Case With Very Subtle Histopathological Findings.

Primary cutaneous γ/δ T-cell lymphoma (PCGDTCL) accounts for <1% of all primary cutaneous lymphomas. These rare diseases are believed to originate from γ/δ lymphocytes. Clinical presentation may vary, but its clinical behavior is regarded as aggressive and long-term survival is anecdotal. This study describes the case of a 60-year-old man with multiple, rapidly progressing skin plaques on his head, arms, torso, buttocks, and legs. The histopathological changes seen in the skin biopsy were extraordinarily subtle with mild epidermal hyperplasia and a very sparse lymphoid infiltrate involving epidermis and superficial dermis. Immunohistochemical studies revealed the atypical intraepidermal hyperchromatic cells to be mostly positive for CD3 and CD7 and negative for both CD4 and CD8. The intraepidermal atypical lymphocytes were positive for TCR gamma, and negative for betaF1 and CD56. The clinical, morphologic, and immunohistochemical findings supported the diagnosis of PCGDTCL. This case illustrates a case of epidermotropic variant of PCGDTCL that, albeit a bland histopathological presentation, was associated with an aggressive clinical behavior.

Prevent Future Profits From Going 'Down the Crack'.

Nearly all leaks, overflows, broken lines/hoses, etc. involve chemicals/oils that should not get into our streams and drinking water sources.

Foraging theory upscaled: the behavioural ecology of herbivore movement.

We outline how principles of optimal foraging developed for diet and food patch selection might be applied to movement behaviour expressed over larger spatial and temporal scales. Our focus is on large mammalian herbivores, capable of carrying global positioning system (GPS) collars operating through the seasonal cycle and dependent on vegetation resources that are fixed in space but seasonally variable in availability and nutritional value. The concept of intermittent movement leads to the recognition of distinct movement modes over a hierarchy of spatio-temporal scales. Over larger scales, periods with relatively low displacement may indicate settlement within foraging areas, habitat units or seasonal ranges. Directed movements connect these patches or places used for other activities. Selection is expressed by switches in movement mode and the intensity of utilization by the settlement period relative to the area covered. The type of benefit obtained during settlement periods may be inferred from movement patterns, local environmental features, or the diel activity schedule. Rates of movement indicate changing costs in time and energy over the seasonal cycle, between years and among regions. GPS telemetry potentially enables large-scale movement responses to changing environmental conditions to be linked to population performance.

Improved predictive model for n-decane kinetics across species, as a component of hydrocarbon mixtures.

n-Decane is considered a major component of various fuels and industrial solvents. These hydrocarbon products are complex mixtures of hundreds of components, including straight-chain alkanes, branched chain alkanes, cycloalkanes, diaromatics, and naphthalenes. Human exposures to the jet fuel, JP-8, or to industrial solvents in vapor, aerosol, and liquid forms all have the potential to produce health effects, including immune suppression and/or neurological deficits. A physiologically based pharmacokinetic (PBPK) model has previously been developed for n-decane, in which partition coefficients (PC), fitted to 4-h exposure kinetic data, were used in preference to measured values. The greatest discrepancy between fitted and measured values was for fat, where PC values were changed from 250-328 (measured) to 25 (fitted). Such a large change in a critical parameter, without any physiological basis, greatly impedes the model's extrapolative abilities, as well as its applicability for assessing the interactions of n-decane or similar alkanes with other compounds in a mixture model. Due to these limitations, the model was revised. Our approach emphasized the use of experimentally determined PCs because many tissues had not approached steady-state concentrations by the end of the 4-h exposures. Diffusion limitation was used to describe n-decane kinetics for the brain, perirenal fat, skin, and liver. Flow limitation was used to describe the remaining rapidly and slowly perfused tissues. As expected from the high lipophilicity of this semivolatile compound (log K(ow) = 5.25), sensitivity analyses showed that parameters describing fat uptake were next to blood:air partitioning and pulmonary ventilation as critical in determining overall systemic circulation and uptake in other tissues. In our revised model, partitioning into fat took multiple days to reach steady state, which differed considerably from the previous model that assumed steady-state conditions in fat at 4 h post dosing with 1200 ppm. Due to these improvements, and particularly the reconciliation between measured and fitted partition coefficients, especially fat, we have greater confidence in using the proposed model for dose, species, and route of exposure extrapolations and as a harmonized model approach for other hydrocarbon components of mixtures.

The histone deacetylase inhibitor FK228 given prior to adenovirus infection can boost infection in melanoma xenograft model systems.

A major limitation of adenovirus type 5-mediated cancer gene therapy is the inefficient infection of many cancer cells. Previously, we showed that treatment with low doses of the histone deacetylase inhibitor FK228 (FR901228, depsipeptide) increased coxsackie adenovirus receptor (CAR) levels, histone H3 acetylation, and adenovirus infection efficiencies as measured by viral transgene expression in cancer cell lines but not in cultured normal cells. To evaluate FK228 in vivo, the effects of FK228 therapy in athymic mice bearing LOX IMVI or UACC-62 human melanoma xenografts were examined. Groups of mice were treated with FK228 using several dosing schedules and the differences between treated and control animals were determined. In mice with LOX IMVI xenografts (n = 6), maximum CAR induction was observed 24 h following a single FK228 dose of 3.6 mg/kg with a 13.6 +/- 4.3-fold (mean +/- SD) increase in human CAR mRNA as determined by semiquantitative reverse transcription-PCR analysis. By comparison, mouse CAR levels in liver, kidney, and lung from the same animals showed little to no change. Maximum CAR protein induction of 9.2 +/- 4.8-fold was achieved with these treatment conditions and was associated with increased histone H3 acetylation. Adenovirus carrying a green fluorescent protein (GFP) transgene (2 x 10(9) viral particles) was injected into the xenografts and GFP mRNA levels were determined. A 7.4 +/- 5.2-fold increase in GFP mRNA was found 24 h following adenovirus injection into optimally FK228-treated mice (n = 10). A 4-fold increase in GFP protein-positive cells was found following FK228 treatment. These studies suggest that FK228 treatment prior to adenovirus infection could increase the efficiency of adenovirus gene therapy in xenograft model systems.

Rapid optically based measurements of diameter and length for spherical or rod-shaped bacteria in vivo.

The application in light scattering of the Mueller matrix ratio (S34)/(S11) for determining average particle size is extended to a large size parameter range for spherical or randomly oriented rod-shaped particles such as micro-organisms. It is shown that combining the graph of this ratio with a Coulter counter measurement of particle volume gives results in agreement with microscopic measurements. Thus this combination provides a method to measure particle diameter and width simultaneously in real time for elongated particles such as bacteria, which are measured in vivo with this method. An approximate empirical formula is developed to estimate the motion of the extrema in the graph of the oscillating matrix ratio as size changes occur. This formula is also shown to be consistent with wavelength changes.

Consistent mapping and automatic visual search: comparing persons with and without intellectual disability.

BACKGROUND: Merrill et al. (1996) reported that persons with intellectual disability (ID) were slower at learning a visual search task to automaticity relative to persons of the same age without ID. For persons without ID, automaticity develops most rapidly under conditions in which a response is always the same for a particular stimulus. This study was designed to investigate whether persons with and without ID are differentially sensitive to the influence of consistently mapped versus inconsistently mapped stimulus responses. METHODS: The primary manipulation was the consistency between a particular stimulus and the response to that stimulus in a visual search task. Sixteen participants with ID and 16 without ID searched displays of two, three, or four pictured objects to determine if a target was present. For half of the participants, the targets were always targets. For the other half, the targets became nontargets on 25% of the trials. RESULTS: Analyses focused on changes in response times associated with set size. Because automaticity allows for parallel processing, the elimination of significant effects of set size was taken as an index of the development of automaticity. Results indicated that inconsistent mapping significantly slowed the development of automaticity for the participants without ID but not for the participants with ID. DISCUSSION: Results were discussed in terms of the role of inhibition processes in the development of automatic search and detection. The effectiveness of inhibition processes was compromised by the consistency manipulation. The effect of the consistency manipulation was greater for the participants without ID because they were presumed to be using inhibition processes more effectively during practice than did the participants with ID.

Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist.

Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H(3) receptors regulate release of histamine and other neurotransmitters, and histamine H(3) receptor antagonists enhance neurotransmitter release. A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile] is a histamine H(3) receptor antagonist which binds potently and selectively to both human and rat histamine H(3) receptors (K(i)<==25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H(3) receptor antagonist, A-331440, has potential as an antiobesity agent.