Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia.

The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway-specific modulation of target regions are not well understood. Here, we dissect the mechanisms underlying BG direct and indirect pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of BG that is critical for locomotion. We optogenetically dissect the locomotor function of the three neurochemically distinct cell types within the MLR: glutamatergic, GABAergic, and cholinergic neurons. We find that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further show activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how BG can initiate or suppress a motor program through cell-type-specific regulation of neurons linked to specific actions.

Plasticity of neuronal dynamics in the lateral habenula for cue-punishment associative learning.

The brain's ability to associate threats with external stimuli is vital to execute essential behaviours including avoidance. Disruption of this process contributes instead to the emergence of pathological traits which are common in addiction and depression. However, the mechanisms and neural dynamics at the single-cell resolution underlying the encoding of associative learning remain elusive. Here, employing a Pavlovian discrimination task in mice we investigate how neuronal populations in the lateral habenula (LHb), a subcortical nucleus whose excitation underlies negative affect, encode the association between conditioned stimuli and a punishment (unconditioned stimulus). Large population single-unit recordings in the LHb reveal both excitatory and inhibitory responses to aversive stimuli. Additionally, local optical inhibition prevents the formation of cue discrimination during associative learning, demonstrating a critical role of LHb activity in this process. Accordingly, longitudinal in vivo two-photon imaging tracking LHb calcium neuronal dynamics during conditioning reveals an upward or downward shift of individual neurons' CS-evoked responses. While recordings in acute slices indicate strengthening of synaptic excitation after conditioning, support vector machine algorithms suggest that postsynaptic dynamics to punishment-predictive cues represent behavioral cue discrimination. To examine the presynaptic signaling in LHb participating in learning we monitored neurotransmitter dynamics with genetically-encoded indicators in behaving mice. While glutamate, GABA, and serotonin release in LHb remain stable across associative learning, we observe enhanced acetylcholine signaling developing throughout conditioning. In summary, converging presynaptic and postsynaptic mechanisms in the LHb underlie the transformation of neutral cues in valued signals supporting cue discrimination during learning.

Mild stress accumulation limits GABAergic synaptic plasticity in the lateral habenula.

Animals can cope with isolated stressful situations without enduring long-term consequences. However, when exposure to stressors becomes recurrent, behavioural symptoms of anxiety and depression can emerge. Yet, the neuronal mechanisms governing responsivity to isolated stressor remain elusive. Here, we investigate synaptic adaptations following mild stress in the lateral habenula (LHb), a structure engaged in aversion encoding and dysfunctional in depression. We describe that neuronal depolarization in the LHb drives long-term depression of inhibitory, but not excitatory, synaptic transmission (GABA LTD). This plasticity requires nitric oxide and presynaptic GABAB receptors, leading to a decrease in probability of GABA release. Mild stressors such as brief social isolation, or exposure to novel environment in the company of littermates, do not alter GABA LTD. In contrast, GABA LTD is absent after mice experience a novel environment in social isolation. Altogether, our results suggest that LHb GABAergic plasticity is sensitive to stress accumulation, which could represent a threshold mechanism for long-term alterations of LHb function.

Forecasting seasonal peaks in roadkill patterns for improving road management.

For several species, roadkill is not spatially aggregated on hotspots, having instead a more diffuse pattern along the roads. For such species, management measures such as road passages may be insufficient for effective mitigation, since a large part of the road crossings is likely to occur outside the influence of those structures. One complementary approach could be to implement temporary mitigation actions, such as traffic calming. This requires understanding when roadkill peaks may occur. We tested the feasibility of predicting seasonal peaks of roadkill using data from a 3-year systematic monitoring (78 surveys over ca. 960 km of roads) from eight non-flying vertebrate species from Mato Grosso do Sul, Brazil, with different body size and life history traits (ca. 6400 records from focal species). We modelled the time-series of the roadkill of these species at large scale (state level) using generalized additive mixed models (GAMMs). We used the data of the first 2 years as training datasets, and the information from the third year of surveys as testing datasets to evaluate the prediction performance of models. Overall, the models of species feed with a higher number of records were able to follow reasonably well the variations of roadkill over time, although they were not able to correctly predict the number of collisions. For species with fewer observations, the models presented a poorer goodness-of-fit and prediction ability. Our results suggest that, at least for those species with higher roadkill rates, it can be possible to forecast periods of higher probability of occurring hot-moments of mortality. Such models can provide valuable information to implement seasonal management actions.

Changes in quality of life in relation to disease activity in systemic lupus erythematosus: post-hoc analysis of the BLISS-52 Trial.

OBJECTIVES: To quantify changes in generic patient-reported outcomes against clinically meaningful, disease activity measures in systemic lupus erythematosus (SLE). METHODS: Using BLISS-52 trial data (867 SLE patients), we estimated the mean difference in change of patient-reported outcome scores (Medical Outcomes Study SF-36 and FACIT-fatigue) in relation to disease activity (SELENA-SLEDAI, SELENA-SLEDAI flare index, SLE responder index and British Isles Lupus Assessment Group (BILAG)), considering all study visits by the mean of multivariate mixed models. Predefined disease activity criteria were used to define for improvement and worsening. RESULTS: Mean changes in physical component summary/mental component summary and FACIT-fatigue in response to changes in SELENA-SLEDAI and SELENA-SLEDAI flare index were significantly lower than 2.5. New SELENA-SLEDAI flare index flare led to a significant change in all patient-reported outcome scores, except role emotional. Mean improvement in patient-reported outcomes with achievement of SLE responder index ranged between +6.2 (physical function) and +11.3 (bodily pain) for SF-36 domains, + 3.4 and +3.3 for mental component summary and physical component summary, and was +4.2 for FACIT-fatigue. When considering disease activity changes by organ system, changes in BILAG (constitutional) was independently associated with significant changes in FACIT-fatigue and all SF-36 domains (except physical function), changes in BILAG (musculoskeletal and hematological) were independently associated with significant changes in patient-reported outcome scores, except for role emotional (musculoskeletal) and general health/mental health (hematological). Mean changes in every SF-36 domain varied (and was >5) with SLE responder index attainment. CONCLUSIONS: Knowledge of changes in patient-reported outcomes, against clinically meaningful changes in SLE disease activity measures, is crucial for designing of clinical trials, interpretation of results and shared decision-making for patient care.

New insights into the tetrameric family of the Fur metalloregulators.

The ferric uptake regulator (Fur) belongs to the family of the metal-responsive transcriptional regulators. Fur is a global regulator found in all proteobacteria. It controls the transcription of a wide variety of genes involved in iron metabolism but also in oxidative stress or virulence factor synthesis. As a general view, Fur proteins were considered to be dimeric proteins both in solution and when bound to DNA. However, our recent data demonstrate that Fur proteins can be classified into two subfamilies, according to their quaternary structure. The group of dimers is represented by E. coli, V. cholerae and Y. pestis Fur and the group of highly stable tetramers by P. aeruginosa and F. tularensis Fur. Here, another tetrameric structure of a PaFur mutant containing manganese and zinc metal ions is described. Through biochemical, structural and computational studies, we have deciphered the important structural characteristics of the tetramers and studied the main interactions responsible for their strength. Potential or mean force calculations for tetramer formation have been determinant to quantify these interactions. Moreover calculations allow us to propose that some conserved residues prevent the tetramerization in the subfamily of dimeric Fur.

Roux-en-Y gastric bypass reduces plasma cholesterol in diet-induced obese mice by affecting trans-intestinal cholesterol excretion and intestinal cholesterol absorption.

OBJECTIVE: Bariatric surgery appears as the most efficient therapeutic alternative in morbidly obese patients. In addition to its efficiency to decrease body weight, it also improves metabolic complications associated to morbid obesity, including dyslipidemia. Although the cholesterol-lowering effect varies with the bariatric procedures, the underlying molecular mechanisms remain poorly defined. This study aims to assess the consequence of both restrictive (sleeve gastrectomy; SG) and malabsorptive (Roux-en-Y gastric bypass; RYGB) procedures on cholesterol metabolism in mice. SUBJECTS: Ten-week-old C57BL6/J males were fed with a high-fat diet for 8-14 weeks before sleeve or RYGB surgery. RESULTS: SG has a modest and transient effect on plasma cholesterol levels, linked to a reduction in food intake. In contrast, modified RYGB led to a sustained ≈35% reduction in plasma cholesterol concentrations with a drastic increase in fecal cholesterol output. Mechanistically, RYGB exerts a synergystic effect on cholesterol metabolism by inducing the trans-intestinal cholesterol efflux and reducing the intestinal cholesterol absorption. CONCLUSIONS: In mice, RYGB, but not sleeve, strongly favors plasma cholesterol elimination by concomitantly increasing trans-intestinal cholesterol excretion and by decreasing intestinal cholesterol absorption. Our models open new perspective for deciphering the hypocholesterolemic effects of bariatric procedures.

Relationship between glucocorticoid dose and adverse events in systemic lupus erythematosus: data from a randomized clinical trial.

OBJECTIVE: The aim was to obtain a better understanding of the relationship between exposure to glucocorticoids (GCs) and adverse events (AEs) reported in a randomized controlled trial (RCT) in systemic lupus erythematosus (SLE) patients. METHOD: We used data from the BLISS-76 trial on belimumab. The data were accessed through an agreement under the SHARE mechanism. AEs were grouped according to medical relevance, i.e. based on similarity of symptoms and pathophysiology. We studied the relationship between AEs and exposure to GCs at baseline and at any time-point, and compared the frequencies of each AE and groups of AEs between tertiles of cumulative GC dose. RESULTS: In total, 991 AEs were reported in the 819 patients of the trial. The frequencies of anaemia, pyrexia, oral herpes, and malaise were significantly higher (p < 0.05) in patients who were on GCs at baseline than in those who were not. The frequencies of several other AEs, including nausea, seasonal allergy, bacterial sinusitis, and viral upper respiratory infection, were significantly higher in patients without GCs. For cumulative GCs, tachycardia and proteinuria were significantly more frequent in the highest tertile than in the lowest tertile, but other AEs and groups of AEs were significantly more frequent in the lowest tertile. CONCLUSION: This study highlights the feasibility of post-hoc analyses of RCTs using the SHARE mechanism and demonstrates the association of GCs with various AEs. Contrary to expectations, there were also associations between lower cumulative GC dose and several other AEs.

Efficacy and comparison of antimalarials in cutaneous lupus erythematosus subtypes: a systematic review and meta-analysis.

BACKGROUND: The antimalarials (AMs) hydroxychloroquine (HCQ) and chloroquine (CQ) have demonstrated variable cutaneous response rates in cutaneous lupus erythematosus (CLE). OBJECTIVES: We sought to assess the global cutaneous response rates to HCQ and CQ, with respect to CLE subtypes, based on previously published studies. METHODS: We performed a systematic review and meta-analysis of studies published in MEDLINE, Embase and the Cochrane Library between 1965 and December 2015. The proportions of responders to AMs according to CLE subtypes were extracted from individual studies and pooled using random-effects or fixed models. The odds ratio (OR) was used as the measure of association to compare the response rates between CLE subtypes and AMs. RESULTS: Among 1990 courses of treatment with AMs from 31 included studies, the overall response rate to AMs was 63% [95% confidence interval (CI) 55-70], with important statistical heterogeneity across the included studies. HCQ had a higher overall efficacy than CQ, but this was not significant (OR 1·48, 95% CI 0·98-2·23). The response rate to AMs was different between CLE subtypes, ranging from 31% (95% CI 20-44) for chilblain lupus to 91% (95% CI 87-93) for acute CLE. The response was significantly higher for acute CLE than for subacute CLE and intermittent CLE. In case of failure of monotherapy with AM, the combination of quinacrine with HCQ or CQ seemed effective, whereas too little data were available to assess the efficacy of the switch to another AM agent. CONCLUSIONS: Wide discrepancies in cutaneous response to AMs are observed between CLE subtypes. A specific therapeutic approach considering CLE subtypes may improve CLE management.

Serum soluble tumour necrosis factor receptor-2 (sTNFR2) as a biomarker of kidney tissue damage and long-term renal outcome in lupus nephritis.

OBJECTIVES: We investigated the performance of soluble tumour necrosis factor receptor-2 (sTNFR2) as a biomarker of renal activity, damage, treatment response, and long-term outcome in lupus nephritis (LN). METHOD: Serum sTNFR2 levels were assessed in 64 LN patients (52 proliferative, 12 membranous) before and after induction treatment, and in 314 non-lupus controls. In LN patients, renal biopsies were performed at baseline and post-treatment. Patients with ≥ 50% reduced proteinuria, normal or improved estimated glomerular filtration rate (eGFR) by ≥ 25%, and inactive urinary sediment were considered clinical responders (CRs). Patients with ≥ 50% improved renal activity index were considered histopathological responders (HRs). Long-term renal outcome was determined using the chronic kidney disease (CKD) stage after a median follow-up of 11.3 years. RESULTS: sTNFR2 levels were elevated in LN patients versus controls both at baseline (p < 0.001) and post-treatment (p < 0.001), and decreased following treatment (p < 0.001). Baseline sTNFR2 correlated with Chronicity Index scores in both baseline (r = 0.34, p = 0.006) and post-treatment (r = 0.43, p < 0.001) biopsies. In membranous LN, baseline sTNFR2 levels were higher in CRs (p = 0.048) and HRs (p = 0.03) than in non-responders, and decreased only in CRs (p = 0.03). Both baseline (p = 0.02) and post-treatment (p = 0.03) sTNFR2 levels were associated with decreasing eGFR throughout long-term follow-up, and post-treatment levels were higher in patients with long-term follow-up CKD stage ≥ 3 versus 1-2 (p = 0.008). CONCLUSIONS: Our data suggest serum sTNFR2 as a marker of kidney tissue damage and a predictor of long-term prognosis in LN, and merit further evaluation of sTNFR2 as a predictor of clinical and histopathological treatment outcomes in membranous LN.

Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug: A Randomized Clinical Trial.

IMPORTANCE: One-third of patients with rheumatoid arthritis show inadequate response to tumor necrosis factor α (TNF-α) inhibitors; little guidance on choosing the next treatment exists. OBJECTIVE: To compare the efficacy of a non-TNF-targeted biologic (non-TNF) vs a second anti-TNF drug for patients with insufficient response to a TNF inhibitor. DESIGN, SETTING, AND PARTICIPANTS: A total of 300 patients (conducted between 2009-2012) with rheumatoid arthritis, with persistent disease activity (disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR] ≥ 3.2 [range, 0-9.3]) and an insufficient response to anti-TNF therapy were included in a 52-week multicenter, pragmatic, open-label randomized clinical trial. The final follow-up date was in August 2013. INTERVENTIONS: Patients were randomly assigned (1:1) to receive a non-TNF-targeted biologic agent or an anti-TNF that differed from their previous treatment. The choice of the biologic prescribed within each randomized group was left to the treating clinician. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients with good or moderate response according to the European League Against Rheumatism (EULAR) scale at week 24. Secondary outcomes included the EULAR response at weeks 12 and 52; at weeks 12, 24, and 52; DAS28ESR, low disease activity (DAS28 ≤3.2), remission (DAS28 ≤2.6); serious adverse events; and serious infections. RESULTS: Of the 300 randomized patients (243 [83.2%] women; mean [SD] age, 57.1 [12.2] years; baseline DAS28-ESR, 5.1 [1.1]), 269 (89.7%) completed the study. At week 24, 101 of 146 patients (69%) in the non-TNF group and 76 (52%) in the second anti-TNF group achieved a good or moderate EULAR response (OR, 2.06; 95% CI, 1.27-3.37; P = .004, with imputation of missing data; absolute difference, 17.2%; 95% CI, 6.2% to 28.2%). The DAS28-ESR was lower in the non-TNF group than in the second anti-TNF group (mean difference adjusted for baseline differences, -0.43; 95% CI, -0.72 to -0.14; P = .004). At weeks 24 and 52, more patients in the non-TNF group vs the second anti-TNF group showed low disease activity (45% vs 28% at week 24; OR, 2.09; 95% CI, 1.27 to 3.43; P = .004 and 41% vs 23% at week 52; OR, 2.26; 95% CI, 1.33 to 3.86; P = .003). CONCLUSIONS AND RELEVANCE: Among patients with rheumatoid arthritis previously treated with anti-TNF drugs but with inadequate primary response, a non-TNF biologic agent was more effective in achieving a good or moderate disease activity response at 24 weeks than was the second anti-TNF medication. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000441.

Firing modes of dopamine neurons drive bidirectional GIRK channel plasticity.

G-protein-coupled inwardly rectifying potassium (GIRK) channels contribute to the resting membrane potential of many neurons, including dopamine (DA) neurons in the ventral tegmental area (VTA). VTA DA neurons are bistable, firing in two modes: one characterized by bursts of action potentials, the other by tonic firing at a lower frequency. Here we provide evidence that these firing modes drive bidirectional plasticity of GIRK channel-mediated currents. In acute midbrain slices of mice, we observed that in vitro burst activation of VTA DA neurons potentiated GIRK currents whereas tonic firing depressed these currents. This plasticity was not specific to the metabotropic receptor activating the GIRK channels, as direct activation of GIRK channels by nonhydrolyzable GTP also potentiated the currents. The plasticity of GIRK currents required NMDA receptor and CaMKII activation, and involved protein trafficking through specific PDZ domains of GIRK2c and GIRK3 subunit isoforms. Prolonged tonic firing may thus enhance the probability to switch into burst-firing mode, which then potentiates GIRK currents and favors the return to baseline. In conclusion, activity-dependent GIRK channel plasticity may represent a slow destabilization process favoring the switch between the two firing modes of VTA DA neurons.

Gene conversion events between GYPB and GYPE abolish expression of the S and s blood group antigens.

BACKGROUND AND OBJECTIVE: The locus specifying the MNS blood group system is composed of three highly homologous genes, glycophorin A (GYPA), B (GYPB) and E (GYPE). While more than 20 hybrid genes between GYPA and GYPB have been identified, no hybrid genes between GYPB and GYPE have been reported so far. We serendipitously identified GYPB-E-B hybrid genes by studying three individuals whose rare S-s- blood phenotype failed to be predicted by our genotyping platform. MATERIALS AND METHODS: Long-range PCR amplification and extended Sanger sequencing were required to identify and characterize these GYPB-E-B hybrid genes. A PCR assay was developed to detect them in individual or pooled gDNA samples. RESULTS: The first S-s- proband appeared to have two silenced GYPB alleles, one harbouring the so-called P2 mutation and one harbouring GYPE Pseudoexon E4 in place of GYPB Exon B4 (GYPB-E-B hybrid). The two other S-s- probands were homozygous or hemizygous for other GYPB-E-B hybrid alleles, which also lack GYPB Exon B4 and thus do not carry the S/s polymorphism. CONCLUSION: The three GYPB-E-B hybrid genes reported here constitute the first evidence of recombination events between GYPB and GYPE. As these GYPB-E-B hybrid genes drive the S-s- blood phenotype, it is important to know they are a limitation for the current blood group genotyping methods, including those performed by commercial platforms.

Yellow fever impact on brown howler monkeys (Alouatta guariba clamitans) in Argentina: a metamodelling approach based on population viability analysis and epidemiological dynamics.

In South America, yellow fever (YF) is an established infectious disease that has been identified outside of its traditional endemic areas, affecting human and nonhuman primate (NHP) populations. In the epidemics that occurred in Argentina between 2007-2009, several outbreaks affecting humans and howler monkeys (Alouatta spp) were reported, highlighting the importance of this disease in the context of conservation medicine and public health policies. Considering the lack of information about YF dynamics in New World NHP, our main goal was to apply modelling tools to better understand YF transmission dynamics among endangered brown howler monkey (Alouatta guariba clamitans) populations in northeastern Argentina. Two complementary modelling tools were used to evaluate brown howler population dynamics in the presence of the disease: Vortex, a stochastic demographic simulation model, and Outbreak, a stochastic disease epidemiology simulation. The baseline model of YF disease epidemiology predicted a very high probability of population decline over the next 100 years. We believe the modelling approach discussed here is a reasonable description of the disease and its effects on the howler monkey population and can be useful to support evidence-based decision-making to guide actions at a regional level.

Bridging the gap between movement data and connectivity analysis using the Time-Explicit Habitat Selection (TEHS) model.

BACKGROUND: Understanding how to connect habitat remnants to facilitate the movement of species is a critical task in an increasingly fragmented world impacted by human activities. The identification of dispersal routes and corridors through connectivity analysis requires measures of landscape resistance but there has been no consensus on how to calculate resistance from habitat characteristics, potentially leading to very different connectivity outcomes. METHODS: We propose a new model, called the Time-Explicit Habitat Selection (TEHS) model, that can be directly used for connectivity analysis. The TEHS model decomposes the movement process in a principled approach into a time and a selection component, providing complementary information regarding space use by separately assessing the drivers of time to traverse the landscape and the drivers of habitat selection. These models are illustrated using GPS-tracking data from giant anteaters (Myrmecophaga tridactyla) in the Pantanal wetlands of Brazil. RESULTS: The time model revealed that the fastest movements tended to occur between 8 p.m. and 5 a.m., suggesting a crepuscular/nocturnal behavior. Giant anteaters moved faster over wetlands while moving much slower over forests and savannas, in comparison to grasslands. We also found that wetlands were consistently avoided whereas forest and savannas tended to be selected. Importantly, this model revealed that selection for forest increased with temperature, suggesting that forests may act as important thermal shelters when temperatures are high. Finally, using the spatial absorbing Markov chain framework, we show that the TEHS model results can be used to simulate movement and connectivity within a fragmented landscape, revealing that giant anteaters will often not use the shortest-distance path to the destination patch due to avoidance of certain habitats. CONCLUSIONS: The proposed approach can be used to characterize how landscape features are perceived by individuals through the decomposition of movement patterns into a time and a habitat selection component. Additionally, this framework can help bridge the gap between movement-based models and connectivity analysis, enabling the generation of time-explicit connectivity results.

The ABCB6 mutation p.Arg192Trp is a recessive mutation causing the Lan- blood type.

BACKGROUND AND OBJECTIVE: The membrane transporter ABCB6 has recently been shown to carry the high-frequency red-blood-cell (RBC) antigen Lan. All the Lan- individuals genotyped so far have inherited two recessive null mutations in ABCB6. The finding of a family with the Lan- blood type occurring in two successive generations prompted this study. METHODS: Mutations in ABCB6 were searched by Sanger sequencing of exons and flanking intronic regions. Expression analysis of the Lan antigen was carried out by serology and flow cytometry. PCR-RFLP genotyping and Western blot analysis were also applied. RESULTS: All the Lan- members of this family were homozygous for c.574C>T, p.Arg192Trp in ABCB6 while the Lan+ members were heterozygous for this missense mutation encoded by the SNP rs149202834. Homozygosity for p.Arg192Trp was associated not only with absence of the Lan antigen, but also of the ABCB6 transporter in RBC membrane. The complete absence of Lan expression resulting from p.Arg192Trp homozygosity was confirmed by the subsequent identification of five unrelated Lan- individuals who were homozygous for this mutation and who developed an anti-Lan. We also provide evidence that three other single amino acid mutations in ABCB6 (c.826C >T, p.Arg276Trp; c.85_87delTTC, p.Phe29del; c.1762G >A, p.Gly588Ser) may also define ABCB6 null alleles. CONCLUSION: p.Arg192Trp is the first ABCB6 missense mutation causing the Lan- blood type and appears to be a relatively frequent cause of this rare blood type. Like the previously reported frameshift, nonsense and essential splice-site mutations in ABCB6, this missense mutation is recessive and defines an ABCB6 null allele. Other single amino acid mutations in ABCB6 may also cause the Lan- blood type.

Neuhauser syndrome: a rare association of megalocornea and mental retardation. Review of the literature and further phenotype delineation.

Megalocornea can be observed as an isolated abnormality that is inherited by an X-linked mechanism, or it can be associated with other entities. Megalocornea-mental retardation syndrome, also known as Neuhauser syndrome, is a rare autosomal recessive congenital disorder that presents with megalocornea, mental retardation, hypotonia, and facial dysmorphism, among other signs. With the report of this new case, and after an extensive review of the literature, we attempt to delineate the Neuhauser syndrome phenotype.

French practical guidelines for the diagnosis and management of relapsing polychondritis.

Relapsing polychondritis is a rare systemic disease. It usually begins in middle-aged individuals. This diagnosis is mainly suggested in the presence of chondritis, i.e. inflammatory flares on the cartilage, in particular of the ears, nose or respiratory tract, and more rarely in the presence of other manifestations. The formal diagnosis of relapsing polychondritis cannot be established with certainty before the onset of chondritis, which can sometimes occur several years after the first signs. No laboratory test is specific of relapsing polychondritis, the diagnosis is usually based on clinical evidence and the elimination of differential diagnoses. Relapsing polychondritis is a long-lasting and often unpredictable disease, evolving in the form of relapses interspersed with periods of remission that can be very prolonged. Its management is not codified and depends on the nature of the patient's symptoms and association or not with myelodysplasia/vacuoles, E1 enzyme, X linked, autoinflammatory, somatic (VEXAS). Some minor forms can be treated with non-steroidal anti-inflammatory drugs, or a short course of corticosteroids with possibly a background treatment of colchicine. However, the treatment strategy is often based on the lowest possible dosage of corticosteroids combined with background treatment with conventional immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil, rarely cyclophosphamide) or targeted therapies. Specific strategies are required if relapsing polychondritis is associated with myelodysplasia/VEXAS. Forms limited to the cartilage of the nose or ears have a good prognosis. Involvement of the cartilage of the respiratory tract, cardiovascular involvement, and association with myelodysplasia/VEXAS (more frequent in men over 50years of age) are detrimental to the prognosis of the disease.

Biologging as an important tool to uncover behaviors of cryptic species: an analysis of giant armadillos (Priodontes maximus).

Advances in biologging have increased the understanding of how animals interact with their environment, especially for cryptic species. For example, giant armadillos (Priodontes maximus) are the largest extant species of armadillo but are rarely encountered due to their fossorial and nocturnal behavior. Through the analysis of speed, turning angles, and accelerometer activity counts, we estimated behavioral states, characterized activity budgets, and investigated the state-habitat associations exhibited by individuals monitored with GPS telemetry in the Brazilian Pantanal from 2019 to 2020. This methodology is proposed as a useful framework for the identification of priority habitat. Using the non-parametric Bayesian mixture model for movement (M3), we estimated four latent behavioral states that were named 'vigilance-excavation', 'local search', 'exploratory', and 'transit'. These states appeared to correspond with behavior near burrows or termite mounds, foraging, ranging, and rapid movements, respectively. The first and last hours of activity presented relatively high proportions of the vigilance-excavation state, while most of the activity period was dominated by local search and exploratory states. The vigilance-excavation state occurred more frequently in regions between forest and closed savannas, whereas local search was more likely in high proportions of closed savanna. Exploratory behavior probability increased in areas with high proportions of both forest and closed savanna. Our results establish a baseline for behavioral complexity, activity budgets, and habitat associations in a relatively pristine environment that can be used for future work to investigate anthropogenic impacts on giant armadillo behavior and fitness. The integration of accelerometer and GPS-derived movement data through our mixture model has the potential to become a powerful methodological approach for the conservation of other cryptic species.