Bat pluripotent stem cells reveal unusual entanglement between host and viruses.

Bats are distinctive among mammals due to their ability to fly, use laryngeal echolocation, and tolerate viruses. However, there are currently no reliable cellular models for studying bat biology or their response to viral infections. Here, we created induced pluripotent stem cells (iPSCs) from two species of bats: the wild greater horseshoe bat (Rhinolophus ferrumequinum) and the greater mouse-eared bat (Myotis myotis). The iPSCs from both bat species showed similar characteristics and had a gene expression profile resembling that of cells attacked by viruses. They also had a high number of endogenous viral sequences, particularly retroviruses. These results suggest that bats have evolved mechanisms to tolerate a large load of viral sequences and may have a more intertwined relationship with viruses than previously thought. Further study of bat iPSCs and their differentiated progeny will provide insights into bat biology, virus host relationships, and the molecular basis of bats' special traits.

Convergent dopamine and ALK4 signaling to PCBP1 controls FosB alternative splicing and cocaine behavioral sensitization.

ΔfosB is an alternatively spliced product of the FosB gene that is essential for dopamine-induced reward pathways and that acts as a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown. Here, we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ΔFosB mRNA in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) via activation of the RNA-binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon-4 and intron-4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Finally, ALK4 is required in NAc MSNs of adult mice for behavioral sensitization to cocaine. These findings uncover an unexpected mechanism for ΔFosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.

RhoGDI phosphorylation by PKC promotes its interaction with death receptor p75NTR to gate axon growth and neuron survival.

How receptors juggle their interactions with multiple downstream effectors remains poorly understood. Here we show that the outcome of death receptor p75NTR signaling is determined through competition of effectors for interaction with its intracellular domain, in turn dictated by the nature of the ligand. While NGF induces release of RhoGDI through recruitment of RIP2, thus decreasing RhoA activity in favor of NFkB signaling, MAG induces PKC-mediated phosphorylation of the RhoGDI N-terminus, promoting its interaction with the juxtamembrane domain of p75NTR, disengaging RIP2, and enhancing RhoA activity in detriment of NF-kB. This results in stunted neurite outgrowth and apoptosis in cerebellar granule neurons. If presented simultaneously, MAG prevails over NGF. The NMR solution structure of the complex between the RhoGDI N-terminus and p75NTR juxtamembrane domain reveals previously unknown structures of these proteins and clarifies the mechanism of p75NTR activation. These results show how ligand-directed competition between RIP2 and RhoGDI for p75NTR engagement determine axon growth and neuron survival. Similar principles are likely at work in other receptors engaging multiple effectors and signaling pathways.

Inactive variants of death receptor p75NTR reduce Alzheimer's neuropathology by interfering with APP internalization.

A prevalent model of Alzheimer's disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. The molecular pathways that regulate APP internalization and intracellular trafficking in neurons are incompletely understood. Here, we report that 5xFAD mice, an animal model of AD, expressing signaling-deficient variants of the p75 neurotrophin receptor (p75NTR ) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75NTR knock-in mice lacking the death domain or transmembrane Cys259 showed lower levels of Aß species, amyloid plaque burden, gliosis, mitochondrial stress, and neurite dystrophy than global knock-outs. Strikingly, long-term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock-in mice. Mechanistically, we found that p75NTR interacts with APP at the plasma membrane and regulates its internalization and intracellular trafficking in hippocampal neurons. Inactive p75NTR variants internalized considerably slower than wild-type p75NTR and showed increased association with the recycling pathway, thereby reducing APP internalization and co-localization with BACE1, the critical protease for generation of neurotoxic APP fragments, favoring non-amyloidogenic APP cleavage. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing, and disease progression, and suggest that inhibitors targeting the p75NTR transmembrane domain may be an effective therapeutic strategy in AD.

Sphingomyelin is involved in regulating UCP1-mediated nonshivering thermogenesis.

Adipogenesis is one of the major mechanisms for adipose tissue expansion, during which spindle-shaped mesenchymal stem cells commit to the fate of adipocyte precursors and differentiate into round-shaped fat-laden adipocytes. Here, we investigated the lipidomic profile dynamics of ex vivo-differentiated brown and white adipocytes derived from the stromal vascular fractions of interscapular brown (iBAT) and inguinal white adipose tissues. We showed that sphingomyelin was specifically enriched in terminally differentiated brown adipocytes, but not white adipocytes. In line with this, freshly isolated adipocytes of iBAT showed higher sphingomyelin content than those of inguinal white adipose tissue. Upon cold exposure, sphingomyelin abundance in iBAT gradually decreased in parallel with reduced sphingomyelin synthase 1 protein levels. Cold-exposed animals treated with an inhibitor of sphingomyelin hydrolases failed to maintain core body temperature and showed reduced oxygen consumption and iBAT UCP1 levels. Conversely, blockade of sphingomyelin synthetic enzymes resulted in enhanced nonshivering thermogenesis, reflected by elevated body temperature and UCP1 levels. Taken together, our results uncovered a relation between sphingomyelin abundance and fine-tuning of UCP1-mediated nonshivering thermogenesis.

Activin receptor ALK4 promotes adipose tissue hyperplasia by suppressing differentiation of adipocyte precursors.

Adipocyte hyperplasia and hypertrophy are the two main processes contributing to adipose tissue expansion, yet the mechanisms that regulate and balance their involvement in obesity are incompletely understood. Activin B/GDF-3 receptor ALK7 is expressed in mature adipocytes and promotes adipocyte hypertrophy upon nutrient overload by suppressing adrenergic signaling and lipolysis. In contrast, the role of ALK4, the canonical pan-activin receptor, in adipose tissue is unknown. Here, we report that, unlike ALK7, ALK4 is preferentially expressed in adipocyte precursors, where it suppresses differentiation, allowing proliferation and adipose tissue expansion. ALK4 expression in adipose tissue increases upon nutrient overload and positively correlates with fat depot mass and body weight, suggesting a role in adipose tissue hyperplasia during obesity. Mechanistically, ALK4 signaling suppresses expression of CEBPα and PPARγ, two master regulators of adipocyte differentiation. Conversely, ALK4 deletion enhances CEBPα/PPARγ expression and induces premature adipocyte differentiation, which can be rescued by CEBPα knockdown. These results clarify the function of ALK4 in adipose tissue and highlight the contrasting roles of the two activin receptors in the regulation of adipocyte hyperplasia and hypertrophy during obesity.

Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function.

The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown. Using spatiotemporally controlled Cre-mediated recombination in adult mice, we found that the glial cell-derived neurotrophic factor receptor alpha 1 (GFRα1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFRα1 in the mouse brain, and acute ablation of GFRα1 results in loss of septohabenular and habenulointerpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and optogenetic studies in mice lacking GFRα1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index (R.I.) of AMPARs, suggesting reduced Ca2+ permeability. Further biochemical and proximity ligation assay (PLA) studies defined the presence of GluA1/GluA2 (Ca2+ impermeable) as well as GluA1/GluA4 (Ca2+ permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFRα1. Finally, acute loss of GFRα1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb. These results uncover an unexpected function for GFRα1 in the maintenance and function of adult glutamatergic synapses and reveal a potential new mechanism for regulating synaptic plasticity in the septohabenulointerpeduncular pathway and attuning of anxiety and fear behaviors.

Community-Based Prevention of Substance Use in Adolescents: Outcomes Before and During the COVID-19 Pandemic in Santiago, Chile.

A primary community prevention approach in Iceland was associated with strong reductions of substance use in adolescents. Two years into the implementation of this prevention model in Chile, the aim of this study was to assess changes in the prevalence of adolescent alcohol and cannabis use and to discuss the impact of the COVID-19 pandemic on the substance use outcomes. In 2018, six municipalities in Greater Santiago, Chile, implemented the Icelandic prevention model, including structured assessments of prevalence and risk factors of substance use in tenth grade high school students every 2 years. The survey allows municipalities and schools to work on prevention with prevalence data from their own community. The survey was modified from an on-site paper format in 2018 to an on-line digital format in a shortened version in 2020. Comparisons between the cross-sectional surveys in the years 2018 and 2020 were performed with multilevel logistic regressions. Totally, 7538 participants were surveyed in 2018 and 5528 in 2020, nested in 125 schools from the six municipalities. Lifetime alcohol use decreased from 79.8% in 2018 to 70.0% in 2020 (X2 = 139.3, p < 0.01), past-month alcohol use decreased from 45.5 to 33.4% (X2 = 171.2, p < 0.01), and lifetime cannabis use decrease from 27.9 to 18.8% (X2 = 127.4, p < 0.01). Several risk factors improved between 2018 and 2020: staying out of home after 10 p.m. (X2 = 105.6, p < 0.01), alcohol use in friends (X2 = 31.8, p < 0.01), drunkenness in friends (X2 = 251.4, p < 0.01), and cannabis use in friends (X2 = 217.7, p < 0.01). However, other factors deteriorated in 2020: perceived parenting (X2 = 63.8, p < 0.01), depression and anxiety symptoms (X2 = 23.5, p < 0.01), and low parental rejection of alcohol use (X2 = 24.9, p < 0.01). The interaction between alcohol use in friends and year was significant for lifetime alcohol use (ß = 0.29, p < 0.01) and past-month alcohol use (ß = 0.24, p < 0.01), and the interaction between depression and anxiety symptoms and year was significant for lifetime alcohol use (ß = 0.34, p < 0.01), past-month alcohol use (ß = 0.33, p < 0.01), and lifetime cannabis use (ß = 0.26, p = 0.016). The decrease of substance use prevalence in adolescents was attributable at least in part to a reduction of alcohol use in friends. This could be related to social distancing policies, curfews, and homeschooling during the pandemic in Chile that implied less physical interactions between adolescents. The increase of depression and anxiety symptoms may also be related to the COVID-19 pandemic. The factors rather attributable to the prevention intervention did not show substantial changes (i.e., sports activities, parenting, and extracurricular activities).

Brain Function and Marijuana: Are there Changes after Abstinence of Consumption? Preliminary Results.

BACKGROUND: The legalization of cannabis use and false claims about the plant Cannabis sativa to be considered a pharmaceutical product have been found to increase consumption, lower risk perception, and lead to more health problems, without reducing criminal activity. Brain function, typically assessed by neuropsychological tests, shows abnormalities with acute marijuana use, but inconsistent results have been published after abstinence, with a maximum follow-up of 28 days. Our previous research, using neuropsychological tests and brain perfusion single photon emission computed tomography (neuroSPECT), demonstrated consistent abnormalities in brain function among schoolchildren who consume marijuana compared to their non-consuming peers. The aim of this study is to investigate whether brain function changes in 20 adult marijuana users after 6 months of abstinence. METHODOLOGY: Comparison of neuropsychological tests (Rey Complex Figure; Porteus Maze; Four subtests of WAIS-IV Intellectual Tests; STROOP; D2) and perfusion neuroSPECT (functional images), obtained in relation to recent consumption and after 6 months of serial drug-screening test confirmed abstinence. RESULTS: In a one-year period (2020-2021) only five compliant participants were recruited. The COVID-19 pandemic was a limiting factor. Preliminary results of neuropsychological tests, functional brain perfusion images and limited statistical analysis are presented. The results of the neuropsychological tests of the three subjects who completed the abstinence period so far show some improvement in working memory and attention after abstinence. NeuroSPECT shows disorganized hypoperfusion of variable severity in relation to recent consumption, involving areas associated with cognitive function such as the posterior cingulate and temporal lobes, in our five initially enrolled patients, when compared to a normal database. Of these, only two participants have already been re-evaluated with neuroSPECT after 6 months of abstinence, one of whom showed some improvement on the post-abstinence images. CONCLUSION: We analyze the methodological challenges of this research, including the pandemic, to incorporate the appropriate corrections in the next phase of our investigation. Our final findings may provide clinicians and users with information about the long-term effects of marijuana use on brain function.

Abnormal TDP-43 function impairs activity-dependent BDNF secretion, synaptic plasticity, and cognitive behavior through altered Sortilin splicing.

Aberrant function of the RNA-binding protein TDP-43 has been causally linked to multiple neurodegenerative diseases. Due to its large number of targets, the mechanisms through which TDP-43 malfunction cause disease are unclear. Here, we report that knockdown, aggregation, or disease-associated mutation of TDP-43 all impair intracellular sorting and activity-dependent secretion of the neurotrophin brain-derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice lacking TDP-43 specifically in hippocampal CA1 show memory impairment and synaptic plasticity defects that can be rescued by restoring Sortilin splicing or extracellular BDNF. Human neurons derived from patient iPSCs carrying mutated TDP-43 also show altered Sortilin splicing and reduced levels of activity-dependent BDNF secretion, which can be restored by correcting the mutation. We propose that major disease phenotypes caused by aberrant TDP-43 activity may be explained by the abnormal function of a handful of critical proteins, such as BDNF.

High-fat diet consumption by male rat offspring of obese mothers exacerbates adipose tissue hypertrophy and metabolic alterations in adult life.

Obese mothers' offspring develop obesity and metabolic alterations in adulthood. Poor postnatal dietary patterns also contribute to obesity and its comorbidities. We aimed to determine whether in obese mothers' offspring an adverse postnatal environment, such as high-fat diet (HFD) consumption (second hit) exacerbates body fat accumulation, metabolic alterations and adipocyte size distribution. Female Wistar rats ate chow (C-5 %-fat) or HFD (maternal obesity (MO)-25 %-fat) from weaning until the end of lactation. Male offspring were weaned on either control (C/C and MO/C, maternal diet/offspring diet) or HFD (C/HF and MO/HF) diet. At 110 postnatal days, offspring were killed. Fat depots were excised to estimate adiposity index (AI). Serum glucose, triglyceride, leptin, insulin, insulin resistance index (HOMA-IR), corticosterone and dehydroepiandrosterone (DHEA) were determined. Adipocyte size distribution was evaluated in retroperitoneal fat. Body weight was similar in C/C and MO/C but higher in C/HF and MO/HF. AI, leptin, insulin and HOMA-IR were higher in MO/C and C/HF v. C/C but lower than MO/HF. Glucose increased in MO/HF v. MO/C. C/HF and MO/C had higher triglyceride and corticosterone than C/C, but lower corticosterone than MO/HF. DHEA and the DHEA/corticosterone ratio were lower in C/HF and MO/C v. C/C, but higher than MO/HF. Small adipocyte proportion decreased while large adipocyte proportions increased in MO/C and C/HF v. C/C and exacerbated in MO/HF v. C/HF. Postnatal consumption of a HFD by the offspring of obese mothers exacerbates body fat accumulation as well as the decrease of small and the increase of large adipocytes, which leads to larger metabolic abnormalities.

Facilitating Factors and Barriers to the Implementation of the Icelandic Prevention Model of Adolescent Substance Use in Chile: A Focus Group Study.

The use of alcohol and other drugs is a major public health problem in adolescence. The implementation of evidence-based prevention strategies is still scarce in the global south. This study aimed to evaluate facilitators and barriers to the implementation of the Icelandic prevention model of adolescent substance use (IPM) in Chile. We conducted a qualitative study of stakeholders during the implementation process of the IPM in six municipalities of the Metropolitan Region of Santiago, Chile. We convened six focus groups with parents and professionals from schools and municipal prevention teams (38 participants). Recordings were transcribed and submitted to a six-step thematic analysis. The following facilitators emerged: Participants valued the contribution of the IPM to articulate existing programs and teams, its community focus, and the local data obtained through the survey. There were also several barriers: Those included resistance to adopting a foreign model, the tension between generating local strategies and looking for measures to ensure the fidelity of the implementation, socioeconomic differences between and within municipalities, low-risk perception and supervision of parents in Chile, and a culture that generally does not discourage adolescent substance use. Implementation of the IPM was largely accepted by the stakeholders who agreed with the community approach of the model. The main barriers to consider were related to cultural and socioeconomic factors that need to be addressed in further research and may limit the effects of the model in Chile.

Structural basis of NF-κB signaling by the p75 neurotrophin receptor interaction with adaptor protein TRADD through their respective death domains.

The p75 neurotrophin receptor (p75NTR) is a critical mediator of neuronal death and tissue remodeling and has been implicated in various neurodegenerative diseases and cancers. The death domain (DD) of p75NTR is an intracellular signaling hub and has been shown to interact with diverse adaptor proteins. In breast cancer cells, binding of the adaptor protein TRADD to p75NTR depends on nerve growth factor and promotes cell survival. However, the structural mechanism and functional significance of TRADD recruitment in neuronal p75NTR signaling remain poorly understood. Here we report an NMR structure of the p75NTR-DD and TRADD-DD complex and reveal the mechanism of specific recognition of the TRADD-DD by the p75NTR-DD mainly through electrostatic interactions. Furthermore, we identified spatiotemporal overlap of p75NTR and TRADD expression in developing cerebellar granule neurons (CGNs) at early postnatal stages and discover the physiological relevance of the interaction between TRADD and p75NTR in the regulation of canonical NF-κB signaling and cell survival in CGNs. Our results provide a new structural framework for understanding how the recruitment of TRADD to p75NTR through DD interactions creates a membrane-proximal platform, which can be efficiently regulated by various neurotrophic factors through extracellular domains of p75NTR, to propagate downstream signaling in developing neurons.

Sustained anti-obesity effects of life-style change and anti-inflammatory interventions after conditional inactivation of the activin receptor ALK7.

Life-style change and anti-inflammatory interventions have only transient effects in obesity. It is not clear how benefits obtained by these treatments can be maintained longer term, especially during sustained high caloric intake. Constitutive ablation of the activin receptor ALK7 in adipose tissue enhances catecholamine signaling and lipolysis in adipocytes, and protects mice from diet-induced obesity. Here, we investigated the consequences of conditional ALK7 ablation in adipocytes of adult mice with pre-existing obesity. Although ALK7 deletion had little effect on its own, it synergized strongly with a transient switch to low-fat diet (life-style change) or anti-inflammatory treatment (Na-salicylate), resulting in enhanced lipolysis, increased energy expenditure, and reduced adipose tissue mass and body weight gain, even under sustained high caloric intake. By themselves, diet-switch and salicylate had only a temporary effect on weight gain. Mechanistically, combination of ALK7 ablation with either treatment strongly enhanced the levels of ß3-AR, the main adrenergic receptor for catecholamine stimulation of lipolysis, and C/EBPα, an upstream regulator of ß3-AR expression. These results suggest that inhibition of ALK7 can be combined with simple interventions to produce longer-lasting benefits in obesity.

Considering adaptive genetic variation in climate change vulnerability assessment reduces species range loss projections.

Local adaptations can determine the potential of populations to respond to environmental changes, yet adaptive genetic variation is commonly ignored in models forecasting species vulnerability and biogeographical shifts under future climate change. Here we integrate genomic and ecological modeling approaches to identify genetic adaptations associated with climate in two cryptic forest bats. We then incorporate this information directly into forecasts of range changes under future climate change and assessment of population persistence through the spread of climate-adaptive genetic variation (evolutionary rescue potential). Considering climate-adaptive potential reduced range loss projections, suggesting that failure to account for intraspecific variability can result in overestimation of future losses. On the other hand, range overlap between species was projected to increase, indicating that interspecific competition is likely to play an important role in limiting species' future ranges. We show that although evolutionary rescue is possible, it depends on a population's adaptive capacity and connectivity. Hence, we stress the importance of incorporating genomic data and landscape connectivity in climate change vulnerability assessments and conservation management.

CD137 negatively affects "browning" of white adipose tissue during cold exposure.

Prolonged cold exposure stimulates the formation of brownlike adipocytes expressing UCP1 (uncoupling-protein-1) in subcutaneous white adipose tissue which, together with classical brown adipose tissue, contributes to maintaining body temperature in mammals through nonshivering thermogenesis. The mechanisms that regulate the formation of these cells, alternatively called beige or brite adipocytes, are incompletely understood. Here we report that mice lacking CD137, a cell surface protein used in several studies as a marker for beige adipocytes, showed elevated levels of thermogenic markers, including UCP1, increased numbers of beige adipocyte precursors, and expanded UCP1-expressing cell clusters in inguinal white adipose tissue after chronic cold exposure. CD137 knockout mice also showed enhanced cold resistance. These results indicate that CD137 functions as a negative regulator of "browning" in white adipose tissue and call into question the use of this protein as a functional marker for beige adipocytes.

Piglet innate immune response to Streptococcus suis colonization is modulated by the virulence of the strain.

Streptococcus suis is a zoonotic pathogen of swine involved in arthritis, polyserositis, and meningitis. Colonization of piglets by S. suis is very common and occurs early in life. The clinical outcome of infection is influenced by the virulence of the S. suis strains and the immunity of the animals. Here, the role of innate immunity was studied in cesarean-derived colostrum-deprived piglets inoculated intranasally with either virulent S. suis strain 10 (S10) or non-virulent S. suis strain T15. Colonization of the inoculated piglets was confirmed at the end of the study by PCR and immunohistochemistry. Fever (≥40.5 °C) was more prevalent in piglets inoculated with S10 compared to T15 at 4 h after inoculation. During the 3 days of monitoring, no other major clinical signs were detected. Accordingly, only small changes in transcription of genes associated with the antibacterial innate immune response were observed at systemic sites, with S10 inducing an earlier response than T15 in blood. Local inflammatory response to the inoculation, evaluated by transcriptional analysis of selected genes in nasal swabs, was more sustained in piglets inoculated with the virulent S10, as demonstrated by transcription of inflammation-related genes, such as IL1B, IL1A, and IRF7. In contrast, most of the gene expression changes in trachea, lungs, and associated lymph nodes were observed in response to the non-virulent T15 strain. Thus, S. suis colonization in the absence of systemic infection induces an innate immune response in piglets that appears to be related to the virulence potential of the colonizing strain.

Effect of influenza vaccination in patients with asthma.

BACKGROUND: Although annual influenza vaccination is recommended for persons with asthma, its effectiveness in this patient population is not well described. We evaluated the effect of influenza vaccination in the current and previous seasons in preventing influenza among people with asthma. METHODS: Using population health data from the Navarre region of Spain for the 2015/16 to 2019/20 influenza seasons, we conducted a test-negative case-control study to assess the effect of influenza vaccination in the current and 5 previous seasons. From patients presenting to hospitals and primary health care centres with influenza-like illness who underwent testing for influenza, we estimated the effects of influenza vaccination among patients with asthma overall and between those presenting as inpatients or outpatients, as well as between patients with and without asthma. RESULTS: Of 1032 patients who had asthma and were tested, we confirmed that 421 had influenza and the remaining 611 were test-negative controls. We found that the average effect of influenza vaccination was 43% (adjusted odds ratio [OR] 0.57, 95% confidence interval [CI] 0.40 to 0.80) for current-season vaccination regardless of previous doses, and 38% (adjusted OR 0.62, 95% CI 0.39 to 0.96) for vaccination in previous seasons only. Effects were similar for outpatients and inpatients. Among patients with asthma and confirmed influenza, current-season vaccination did not reduce the odds of hospital admission (adjusted OR 1.05, 95% CI 0.51 to 2.18). Influenza vaccination effects were similar for patients with and without asthma. INTERPRETATION: We estimated that, on average, current or previous influenza vaccination of people with asthma prevented almost half of influenza cases. These results support recommendations that people with asthma receive influenza vaccination.

Interoception and alcohol addiction: Vagotomy induces long-lasting suppression of relapse-type behavior.

Drug addictions are chronic mental disorders characterized by compulsive drug seeking and drug use, despite their negative consequences. It is a priority to find therapeutic alternatives to prevent relapse, as there are still no treatments that can ensure abstinence. One of the neural systems implicated in the appearance of the states of discomfort that motivate relapse is the interoceptive system, which oversees our internal body states. However, less attention has been given to the peripheral components of the interoceptive system and their role in addictions. Within these pathways, the vagus nerve represents one of the main visceral afferents of the interoceptive system. We hypothesized that the interruption of visceral afferent pathways would decrease the motivational effects of the drug, thereby either decreasing or preventing drug cravings. To test this idea, we used rats of a high-alcohol-drinking line and measured the effect that vagus nerve resection had on the relapse-like alcohol drinking, expressed as the alcohol deprivation effect, a phenomenon that has been linked to addiction-related events such as alcohol cravings. We found that even though vagotomy completely eliminates the effect of alcohol deprivation, it has no impact on water consumption or animal weight. These results give us valuable information about the relationship between the autonomic nervous system and alcohol use disorders and allow us to propose new clinical research that might have translational options.

The p75 Neurotrophin Receptor Is an Essential Mediator of Impairments in Hippocampal-Dependent Associative Plasticity and Memory Induced by Sleep Deprivation.

Sleep deprivation (SD) interferes with hippocampal structural and functional plasticity, formation of long-term memory and cognitive function. The molecular mechanisms underlying these effects are incompletely understood. Here, we show that SD impaired synaptic tagging and capture and behavioral tagging, two major mechanisms of associative learning and memory. Strikingly, mutant male mice lacking the p75 neurotrophin receptor (p75NTR) were resistant to the detrimental effects of SD on hippocampal plasticity at both cellular and behavioral levels. Mechanistically, SD increased p75NTR expression and its interaction with phosphodiesterase. p75NTR deletion preserved hippocampal structural and functional plasticity by preventing SD-mediated effects on hippocampal cAMP-CREB-BDNF, cAMP-PKA-LIMK1-cofilin, and RhoA-ROCK2 pathways. Our study identifies p75NTR as an important mediator of hippocampal structural and functional changes associated with SD, and suggests that targeting p75NTR could be a promising strategy to limit the memory and cognitive deficits that accompany sleep loss.SIGNIFICANCE STATEMENT The lack of sufficient sleep is a major health concern in today's world. Sleep deprivation (SD) affects cognitive functions such as memory. We have investigated how associative memory mechanisms, synaptic tagging and capture (STC), was impaired in SD mice at cellular and behavioral level. Interestingly, mutant male mice that lacked the p75 neurotrophin receptor (p75NTR) were seen to be resistant to the SD-induced impairments in hippocampal synaptic plasticity and STC. Additionally, we elucidated the molecular pathways responsible for this rescue of plasticity in the mutant mice. Our study has thus identified p75NTR as a promising target to limit the cognitive deficits associated with SD.