Equipped for Life in the Boreal Forest: The Role of the Stress Axis in Mammals

The hypothalamic-pituitary-adrenal axis (stress axis) plays a central role in equipping mammals to succeed in the challenging environment of the boreal forest. Over the last 20 years, we have tackled a broad range of topics to understand how the stress axis functions in four key herbivore species. The central challenge for snowshoe hares is coping with their predators, whereas for the others, it is primarily coping with each other (especially during reproduction) and with their physical environment. Hares are severely stressed by their predators during the population decline. The predator threat causes major changes in the stress axis of hares and reduces their reproduction; in addition, acting through maternal programming, it is the most plausible explanation for the extended period of low numbers following the population decline. Arctic ground squirrel males have an intense breeding season for two to three weeks in early spring, after which many of them die. The functioning of their stress axis changes markedly and is key in meeting their energy demands during this period. In contrast, red-backed vole males, though also short-lived, breed repeatedly only in the summer of their life, and their stress axis shows no change in function. However, their reproductive effort negatively affects their long-term survival. Territorial red squirrels experience marked interannual fluctuations in their major food source (white spruce seed), resulting in major fluctuations in their densities and consequently in the intensity of territorial competition. Changes in the densities of red squirrels also alter maternal stress hormone levels, inducing adaptive plasticity in offspring postnatal growth rates that prepares offspring for the environment they will encounter at independence. To survive winter, red squirrels need to defend their territories year-round, and the basis of this defense appears to be adrenal dehydroepiandrosterone, which has the benefits, but not the costs, of gonadal steroids. Arctic ground squirrels survive winter by hibernating in deeply frozen ground. Unlike all other hibernators, they have evolved a unique adaptation: high levels of adrenal androgens in summer to accumulate protein reserves that they then burn in winter. With a rapidly changing climate, the stress axis will play a key role in permitting northern animals to adapt, but the linkages between the changes in the abiotic and biotic components of the boreal forest and the phenotypic plasticity in the stress response of its inhabitants are not well understood for these or any other herbivore species.L’axe hypothalamo-hypophyso-surrénalien (l’axe du stress) joue un rôle central pour aider les mammifères à réussir dans l’environnement difficile de la forêt boréale. Ces 20 dernières années, nous nous sommes penchés sur une vaste gamme de sujets afin de comprendre comment fonctionne l’axe du stress chez quatre grandes espèces herbivores. Pour le lièvre d’Amérique, le défi central consiste à faire face à ses prédateurs, tandis que pour les autres espèces, ce défi consiste à se faire face mutuellement (surtout pendant la reproduction) de même qu’à faire face à leur environnement physique. Les lièvres subissent beaucoup de stress de la part de leurs prédateurs pendant la diminution de la population. La menace des prédateurs est la cause de changements majeurs sur l’axe du stress des lièvres, ce qui a pour effet de réduire leur reproduction. De plus, en raison de leur programmation maternelle, il s’agit de l’explication la plus plausible justifiant la période prolongée de leur faible nombre suivant la diminution de la population. Le spermophile arctique mâle a une période de reproduction intense pendant deux à trois semaines au début du printemps et après cela, un grand nombre d’entre eux meurent. Le fonctionnement de son axe de stress change de façon marquée, ce qui est essentiel à sa demande en énergie pendant cette période. Par contraste, le campagnol à dos roux mâle, même s’il ne vit également pas longtemps, se reproduit à répétition seulement pendant l’été de sa vie, et le fonctionnement de son axe de stress ne montre aucun changement. Cependant, ses efforts de reproduction ont des incidences négatives sur sa survie à long terme. Pour sa part, la principale source d’alimentation (les graines d’épinette blanche) de l’écureuil roux territorial connaît des fluctuations interannuelles marquées, ce qui se traduit par une fluctuation majeure en matière de densité de cette espèce animale et, par conséquent, en matière d’intensité de la concurrence pour le territoire. Les changements de densité d’écureuils roux exercent également une influence sur les taux d’hormone maternelle de stress, ce qui donne lieu à une plasticité adaptative des taux de croissance postnatale de la progéniture qui prépare la progéniture pour faire face à l’environnement dans lequel ils évolueront au stade de l’indépendance. Pour survivre à l’hiver, l’écureuil roux doit défendre son territoire à l’année et pour y parvenir, il se sert de la déhydroépiandrostérone surrénalienne, qui comporte les avantages des stéroïdes gonades, sans les coûts. Le spermophile arctique survit à l’hiver en hibernant dans le sol gelé en profondeur. Contrairement à tous les autres hibernateurs, il s’est développé une adaptation unique en son genre, soit des taux élevés d’androgènes surrénaliens en été qui lui permettent d’accumuler les réserves de protéines qu’il brûle ensuite pendant l’hiver. À la lumière du changement climatique rapide, l’axe de stress jouera un rôle-clé pour permettre aux animaux du Nord de s’adapter, mais les liens entre les changements des composantes abiotiques et biotiques de la forêt boréale et la plasticité phénotypique de la réaction de stress de ses habitants ne sont pas bien compris dans le cas de ces espèces herbivores ou de toute autre espèce herbivore

Monsoon extremes and society over the past millennium on mainland Southeast Asia

The early 21st century has seen vigorous scientific interest in the Asian monsoon and significant development of paleo-proxies of monsoon strength. These include the Monsoon Asian Drought Atlas – a 700-year, gridded reconstruction of hydroclimate derived from 327 tree ring records – and several long speleothem records from China and India. Similar progress has been made on the study of monsoon climate dynamics through re-analysis data products and General Circulation Model diagnostics. The story has emerged of a variable monsoon over the latter Holocene, with extended droughts and anomalously wet episodes that occasionally and profoundly influenced the course of human history. We focus on Southeast Asia where an anomalous period of unstable climate coincided with the demise of the capital of the Khmer Empire at Angkor between the 14th and the 16th centuries, and we suggest that protracted periods of drought and deluge rain events, the latter of which damaged Angkor's extensive water management systems, may have been a significant factor in the subsequent transfer of the political capital away from Angkor. The late 16th and early 17th century experienced climate instability and the collapse of the Ming Dynasty in China under a period of drought, while Tonkin experienced floods and droughts throughout the 17th century. The 18th century was a period of great turmoil across Southeast Asia, when all of the region's polities saw great unrest and rapid realignment during one of the most extended periods of drought of the past millennium. New paleo-proxy records and the incorporation of historical documentation will improve future analyses of the interaction between climate extremes, social behavior and the collapse or disruption of regional societies, a subject of increasing concern given the uncertainties surrounding projections for future climate

Human-Robot Team Performance Compared to Full Robot Autonomy in 16 Real-World Search and Rescue Missions: Adaptation of the DARPA Subterranean Challenge

Human operators in human-robot teams are commonly perceived to be critical for mission success. To explore the direct and perceived impact of operator input on task success and team performance, 16 real-world missions (10 hrs) were conducted based on the DARPA Subterranean Challenge. These missions were to deploy a heterogeneous team of robots for a search task to locate and identify artifacts such as climbing rope, drills and mannequins representing human survivors. Two conditions were evaluated: human operators that could control the robot team with state-of-the-art autonomy (Human-Robot Team) compared to autonomous missions without human operator input (Robot-Autonomy). Human-Robot Teams were often in directed autonomy mode (70% of mission time), found more items, traversed more distance, covered more unique ground, and had a higher time between safety-related events. Human-Robot Teams were faster at finding the first artifact, but slower to respond to information from the robot team. In routine conditions, scores were comparable for artifacts, distance, and coverage. Reasons for intervention included creating waypoints to prioritise high-yield areas, and to navigate through error-prone spaces. After observing robot autonomy, operators reported increases in robot competency and trust, but that robot behaviour was not always transparent and understandable, even after high mission performance.Comment: Submitted to Transactions on Human-Robot Interactio

A morphologic and molecular reappraisal of myoepithelial tumors of soft tissue, bone, and viscera with EWSR1 and FUS gene rearrangements

Myoepithelial tumors (MET) represent a clinicopathologically heterogeneous group of tumors, ranging from benign to highly aggressive lesions. Although MET arising in soft tissue, bone, or viscera share morphologic and immunophenotypic overlap with their salivary gland and cutaneous counterparts, there is still controversy regarding their genetic relationship. Half of MET of soft tissue and bone harbor EWSR1 or FUS related fusions, while MET arising in the salivary gland and skin often show PLAG1 and HMGA2 gene rearrangements. Regardless of the site of origin, the gold standard in diagnosing a MET relies on demonstrating its "myoepithelial immunophenotype" of positivity for EMA/CK and S100 protein or GFAP. However, the morphologic spectrum of MET in soft tissue and bone is quite broad and the above immunoprofile is nonspecific, being shared by other pathogenetically unrelated neoplasms. Moreover, rare MET lack a diagnostic immunoprofile but shows instead the characteristic gene fusions. In this study, we analyzed a large cohort of 66 MET with EWSR1 and FUS gene rearrangements spanning various clinical presentations, to better define their morphologic spectrum and establish relevant pathologic-molecular correlations. Genetic analysis was carried out by FISH for EWSR1/FUS rearrangements and potential partners, and/or by targeted RNA sequencing. Then, 82% showed EWSR1 rearrangement, while 18% had FUS abnormalities. EWSR1-POU5F1 occurred with predilection in malignant MET in children and young adults and these tumors had nested epithelioid morphology and clear cytoplasm. In contrast, EWSR1/FUS-PBX1/3 fusions were associated with benign and sclerotic spindle cell morphology. Tumors with EWSR1-KLF17 showed chordoma-like morphology. Our results demonstrate striking morphologic-molecular correlations in MET of bone, soft tissue and viscera, which might have implications in their clinical behavior.</p

Soft Tissue Tumors Characterized by a Wide Spectrum of Kinase Fusions Share a Lipofibromatosis-like Neural Tumor Pattern

Gene fusions resulting in oncogenic activation of various receptor tyrosine kinases, including NTRK1-3, ALK, and RET, have been increasingly recognized in soft tissue tumors (STTs), displaying a wide morphologic spectrum and therefore diagnostically challenging. A subset of STT with NTRK1 rearrangements were recently defined as lipofibromatosis-like neural tumors (LPFNTs), being characterized by mildly atypical spindle cells with a highly infiltrative growth in the subcutis and expression of S100 and CD34 immunostains. Other emerging morphologic phenotypes associated with kinase fusions include infantile/adult fibrosarcoma and malignant peripheral nerve sheath tumor-like patterns. In this study, a large cohort of 73 STT positive for various kinase fusions, including 44 previously published cases, was investigated for the presence of an LPFNT phenotype, to better define the incidence of this distinctive morphologic pattern and its relationship with various gene fusions. Surprisingly, half (36/73) of STT with kinase fusions showed at least a focal LPFNT component defined as >10%. Most of the tumors occurred in the subcutaneous tissues of the extremities (n = 25) and trunk (n = 9) of children or young adults (<30 years old) of both genders. Two-thirds (24/36) of these cases showed hybrid morphologies with alternating LPFNT and solid areas of monomorphic spindle to ovoid tumor cells with fascicular or haphazard arrangement, while one-third (12/36) had pure LPFNT morphology. Other common histologic findings included lymphocytic infiltrates, staghorn-like vessels, and perivascular or stromal hyalinization, especially in hybrid cases. Mitotic activity was generally low (<4/10 high power fields in 81% cases), being increased only in a minority of cases. Immunoreactivity for CD34 (92% in hybrid cases, 89% in pure cases) and S100 (89% in hybrid cases, 64% in pure cases) were commonly present. The gene rearrangements most commonly involved NTRK1 (75%), followed by RET (8%) and less commonly NTRK2, NTRK3, ROS1, ALK, and MET

C3d‐positive donor‐specific antibodies have a role in pretransplant risk stratification of cross‐match‐positive HLA‐incompatible renal transplantation : United Kingdom multicentre study

Anti‐HLA‐antibody characteristics aid to risk‐stratify patients and improve long‐term renal graft outcomes. Complement activation by donor‐specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross‐match‐positive). We explored the role of C3d‐positive DSAs in sub‐stratification of cross‐match‐positive cases and relate to the graft outcomes. We investigated 139 cross‐match‐positive living‐donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post‐transplant. C3d‐positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post‐transplant. Median follow‐up of patients was 48 months (IQR 20.47–77.57). In the multivariable analysis, pretreatment C3d‐positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37–7.86). The relative risk of death‐censored five‐year graft failure was 2.83 (95% CI 1.56–5.13). Patients with both pretreatment and Day 14 C3d‐positive DSAs had the worst five‐year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d‐negative DSA patients with the relative risk of death‐censored five‐year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub‐stratify the risk of poor graft outcome in cross‐match‐positive living‐donor renal transplantation

The Diagnosis of Urinary Tract infection in Young children (DUTY): a diagnostic prospective observational study to derive and validate a clinical algorithm for the diagnosis of urinary tract infection in children presenting to primary care with an acute illness

Background: It is not clear which young children presenting acutely unwell to primary care should be investigated for urinary tract infection (UTI) and whether or not dipstick testing should be used to inform antibiotic treatment.Objectives: To develop algorithms to accurately identify pre-school children in whom urine should be obtained; assess whether or not dipstick urinalysis provides additional diagnostic information; and model algorithm cost-effectiveness.Design: Multicentre, prospective diagnostic cohort study.Setting and participants: Children &lt; 5 years old presenting to primary care with an acute illness and/or new urinary symptoms.Methods: One hundred and seven clinical characteristics (index tests) were recorded from the child’s past medical history, symptoms, physical examination signs and urine dipstick test. Prior to dipstick results clinician opinion of UTI likelihood (‘clinical diagnosis’) and urine sampling and treatment intentions (‘clinical judgement’) were recorded. All index tests were measured blind to the reference standard, defined as a pure or predominant uropathogen cultured at ? 105 colony-forming units (CFU)/ml in a single research laboratory. Urine was collected by clean catch (preferred) or nappy pad. Index tests were sequentially evaluated in two groups, stratified by urine collection method: parent-reported symptoms with clinician-reported signs, and urine dipstick results. Diagnostic accuracy was quantified using area under receiver operating characteristic curve (AUROC) with 95% confidence interval (CI) and bootstrap-validated AUROC, and compared with the ‘clinician diagnosis’ AUROC. Decision-analytic models were used toidentify optimal urine sampling strategy compared with ‘clinical judgement’.Results: A total of 7163 children were recruited, of whom 50% were female and 49% were &lt; 2 years old. Culture results were available for 5017 (70%); 2740 children provided clean-catch samples, 94% of whom were ? 2 years old, with 2.2% meeting the UTI definition. Among these, ‘clinical diagnosis’ correctly identified 46.6% of positive cultures, with 94.7% specificity and an AUROC of 0.77 (95% CI 0.71 to 0.83). Four symptoms, three signs and three dipstick results were independently associated with UTI with an AUROC (95% CI; bootstrap-validated AUROC) of 0.89 (0.85 to 0.95; validated 0.88) for symptoms and signs, increasing to 0.93 (0.90 to 0.97; validated 0.90) with dipstick results. Nappy pad samples were provided from the other 2277 children, of whom 82% were &lt; 2 years old and 1.3% met the UTI definition.‘Clinical diagnosis’ correctly identified 13.3% positive cultures, with 98.5% specificity and an AUROC of 0.63 (95% CI 0.53 to 0.72). Four symptoms and two dipstick results were independently associated with UTI, with an AUROC of 0.81 (0.72 to 0.90; validated 0.78) for symptoms, increasing to 0.87 (0.80 to 0.94; validated 0.82) with the dipstick findings. A high specificity threshold for the clean-catch model was more accurate and less costly than, and as effective as, clinical judgement. The additional diagnostic utility of dipstick testing was offset by its costs. The cost-effectiveness of the nappy pad model was not clear-cut.Conclusions: Clinicians should prioritise the use of clean-catch sampling as symptoms and signs can cost-effectively improve the identification of UTI in young children where clean catch is possible. Dipstick testing can improve targeting of antibiotic treatment, but at a higher cost than waiting for a laboratory result. Future research is needed to distinguish pathogens from contaminants, assess the impact of the clean-catch algorithm on patient outcomes, and the cost-effectiveness of presumptive versus dipstick versus laboratory-guided antibiotic treatment.Funding: The National Institute for Health Research Health Technology Assessment programme.<br/

PICS-Ord: unlimited coding of ambiguous regions by pairwise identity and cost scores ordination

<p>Abstract</p> <p>Background</p> <p>We present a novel method to encode ambiguously aligned regions in fixed multiple sequence alignments by 'Pairwise Identity and Cost Scores Ordination' (PICS-Ord). The method works via ordination of sequence identity or cost scores matrices by means of Principal Coordinates Analysis (PCoA). After identification of ambiguous regions, the method computes pairwise distances as sequence identities or cost scores, ordinates the resulting distance matrix by means of PCoA, and encodes the principal coordinates as ordered integers. Three biological and 100 simulated datasets were used to assess the performance of the new method.</p> <p>Results</p> <p>Including ambiguous regions coded by means of PICS-Ord increased topological accuracy, resolution, and bootstrap support in real biological and simulated datasets compared to the alternative of excluding such regions from the analysis a priori. In terms of accuracy, PICS-Ord performs equal to or better than previously available methods of ambiguous region coding (e.g., INAASE), with the advantage of a practically unlimited alignment size and increased analytical speed and the possibility of PICS-Ord scores to be analyzed together with DNA data in a partitioned maximum likelihood model.</p> <p>Conclusions</p> <p>Advantages of PICS-Ord over step matrix-based ambiguous region coding with INAASE include a practically unlimited number of OTUs and seamless integration of PICS-Ord codes into phylogenetic datasets, as well as the increased speed of phylogenetic analysis. Contrary to word- and frequency-based methods, PICS-Ord maintains the advantage of pairwise sequence alignment to derive distances, and the method is flexible with respect to the calculation of distance scores. In addition to distance and maximum parsimony, PICS-Ord codes can be analyzed in a Bayesian or maximum likelihood framework. RAxML (version 7.2.6 or higher that was developed for this study) allows up to 32-state ordered or unordered characters. A GTR, MK, or ORDERED model can be applied to analyse the PICS-Ord codes partition, with GTR performing slightly better than MK and ORDERED.</p> <p>Availability</p> <p>An implementation of the PICS-Ord algorithm is available from <url>http://scit.us/projects/ngila/wiki/PICS-Ord</url>. It requires both the statistical software, R <url>http://www.r-project.org</url> and the alignment software Ngila <url>http://scit.us/projects/ngila</url>.</p

The mammalian gene function resource: the International Knockout Mouse Consortium.

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research

The mammalian gene function resource: The International Knockout Mouse Consortium

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed highthroughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research