A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward.

Nociceptin and its receptor are widely distributed throughout the brain in regions associated with reward behavior, yet how and when they act is unknown. Here, we dissected the role of a nociceptin peptide circuit in reward seeking. We generated a prepronociceptin (Pnoc)-Cre mouse line that revealed a unique subpopulation of paranigral ventral tegmental area (pnVTA) neurons enriched in prepronociceptin. Fiber photometry recordings during progressive ratio operant behavior revealed pnVTAPnoc neurons become most active when mice stop seeking natural rewards. Selective pnVTAPnoc neuron ablation, inhibition, and conditional VTA nociceptin receptor (NOPR) deletion increased operant responding, revealing that the pnVTAPnoc nucleus and VTA NOPR signaling are necessary for regulating reward motivation. Additionally, optogenetic and chemogenetic activation of this pnVTAPnoc nucleus caused avoidance and decreased motivation for rewards. These findings provide insight into neuromodulatory circuits that regulate motivated behaviors through identification of a previously unknown neuropeptide-containing pnVTA nucleus that limits motivation for rewards.

Vesiclepedia 2024: an extracellular vesicles and extracellular particles repository.

Vesiclepedia (http://www.microvesicles.org) is a free web-based compendium of DNA, RNA, proteins, lipids and metabolites that are detected or associated with extracellular vesicles (EVs) and extracellular particles (EPs). EVs are membranous vesicles that are secreted ubiquitously by cells from all domains of life from archaea to eukaryotes. In addition to EVs, it was reported recently that EPs like exomeres and supermeres are secreted by some mammalian cells. Both EVs and EPs contain proteins, nucleic acids, lipids and metabolites and has been proposed to be implicated in several key biological functions. Vesiclepedia catalogues proteins, DNA, RNA, lipids and metabolites from both published and unpublished studies. Currently, Vesiclepedia contains data obtained from 3533 EV studies, 50 550 RNA entries, 566 911 protein entries, 3839 lipid entries, 192 metabolite and 167 DNA entries. Quantitative data for 62 822 entries from 47 EV studies is available in Vesiclepedia. The datasets available in Vesiclepedia can be downloaded as tab-delimited files or accessible through the FunRich-based Vesiclepedia plugin.

UK clinicians' attitudes towards the application of molecular diagnostics to guide antibiotic use in ICU patients with pneumonias: a quantitative study.

BACKGROUND: Molecular diagnostic tests may improve antibiotic prescribing by enabling earlier tailoring of antimicrobial therapy. However, clinicians' trust and acceptance of these tests will determine their application in practice. OBJECTIVES: To examine ICU prescribers' views on the application of molecular diagnostics in patients with suspected hospital-acquired and ventilator-associated pneumonia (HAP/VAP). METHODS: Sixty-three ICU clinicians from five UK hospitals completed a cross-sectional questionnaire between May 2020 and July 2020 assessing attitudes towards using molecular diagnostics to inform initial agent choice and to help stop broad-spectrum antibiotics early. RESULTS: Attitudes towards using molecular diagnostics to inform initial treatment choices and to stop broad-spectrum antibiotics early were nuanced. Most (83%) were positive about molecular diagnostics, agreeing that using results to inform broad-spectrum antibiotic prescribing is good practice. However, many (58%) believed sick patients are often too unstable to risk stopping broad-spectrum antibiotics based on a negative result. CONCLUSIONS: Positive attitudes towards the application of molecular diagnostics to improve antibiotic stewardship were juxtapositioned against the perceived need to initiate and maintain broad-spectrum antibiotics to protect unstable patients.

Proteomic analysis of the small extracellular vesicles and soluble secretory proteins from cachexia inducing and non-inducing cancer cells.

Cancer cachexia is a wasting syndrome characterised by the loss of fat and/or muscle mass in advanced cancer patients. It has been well-established that cancer cells themselves can induce cachexia via the release of several pro-cachectic and pro-inflammatory factors. However, it is unclear how this process is regulated and the key cachexins that are involved. In this study, we validated C26 and EL4 as cachexic and non-cachexic cell models, respectively. Treatment of adipocytes and myotubes with C26 conditioned medium induced lipolysis and atrophy, respectively. We profiled soluble secreted proteins (secretome) as well as small extracellular vesicles (sEVs) released from cachexia-inducing (C26) and non-inducing (EL4) cancer cells by label-free quantitative proteomics. A total of 1268 and 1022 proteins were identified in the secretome of C26 and EL4, respectively. Furthermore, proteomic analysis of sEVs derived from C26 and EL4 cancer cells revealed a distinct difference in the protein cargo. Functional enrichment analysis using FunRich highlighted the enrichment of proteins that are implicated in biological processes such as muscle atrophy, lipolysis, and inflammation in both the secretome and sEVs derived from C26 cancer cells. Overall, our characterisation of the proteomic profiles of the secretory factors and sEVs from cachexia-inducing and non-inducing cancer cells provides insights into tumour factors that promote weight loss by mediating protein and lipid loss in various organs and tissues. Further investigation of these proteins may assist in highlighting potential therapeutic targets and biomarkers of cancer cachexia.

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.

Investigation of heterocellular features of the mouse retinal neurovascular unit by 3D electron microscopy.

The retina has a complex structure with a diverse collection of component cells that work together to facilitate vision. The retinal capillaries supplying the nutritional requirements to the inner retina have an intricate system of neural, glial and vascular elements that interconnect to form the neurovascular unit (NVU). The retina has no autonomic nervous system and so relies on the NVU as an interdependent, physical and functional unit to alter blood flow appropriately to changes in the physiological environment. The importance of this is demonstrated by alterations in NVU function being apparent in the blinding disease diabetic retinopathy and other diseases of the retina. It is, therefore, imperative to understand the anatomy of the components of the NVU that underlie its functioning and in particular the nanoscale arrangements of its heterocellular components. However, information on this in three spatial dimensions is limited. In the present study, we utilised the technique of serial block-face scanning electron microscopy (SBF-SEM), and computational image reconstruction, to enable the first three-dimensional ultrastructural analysis of the NVU in mouse retinal capillaries. Mouse isolated retina was prepared for SBF-SEM and up to 150 serial scanning electron microscopy images (covering z-axes distances of 12-8 mm) of individual capillaries in the superficial plexus and NVU cellular components digitally aligned. Examination of the data in the x-, y- and z-planes was performed with the use of semi-automated computational image analysis tools including segmentation, 3D image reconstruction and quantitation of cell proximities. A prominent feature of the capillary arrangements in 3D was the extensive sheath-like coverage by singular pericytes. They appeared in close register to the basement membrane with which they interwove in a complex mesh-like appearance. Breaks in the basement membrane appeared to facilitate pericyte interactions with other NVU cell types. There were frequent, close (<10 nm) pericyte-endothelial interactions with direct contact points and peg-and-socket-like morphology. Macroglia typically intervened between neurons and capillary structures; however, regions were identified where neurons came into closer contact with the basement membrane. A software-generated analysis to assess the morphology of the different cellular components of the NVU, including quantifications of convexity, sphericity and cell-to-cell closeness, has enabled preliminary semi-quantitative characterisation of cell arrangements with neighbouring structures. This study presents new data on the nanoscale spatial characteristics of components of the murine retinal NVU in 3D that has implications for our understanding of structural integrity (e.g. pericyte-endothelial cell anchoring) and function (e.g. possible paracrine communication between macroglia and pericytes). It also serves as a platform to inform future studies examining changes in NVU characteristics with different biological and disease circumstances. All raw and processed image data have been deposited for public viewing.

MYT1L-associated neurodevelopmental disorder: description of 40 new cases and literature review of clinical and molecular aspects.

Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.

Effect of Commercial Gas Diffusion Layers on Catalyst Durability of Polymer Electrolyte Fuel Cells in Varied Cathode Gas Environment.

Gas diffusion layers (GDLs) play a crucial role in heat transfer and water management of cathode catalyst layers in polymer electrolyte fuel cells (PEFCs). Thermal and water gradients can accelerate electrocatalyst degradation and therefore the selection of GDLs can have a major influence on PEFC durability. Currently, the role of GDLs in electrocatalyst degradation is poorly studied. In this study, electrocatalyst accelerated stress test studies are performed on membrane electrode assemblies (MEAs) prepared using three most commonly used GDLs. The effect of GDLs on electrocatalyst degradation is evaluated in both nitrogen (non-reactive) and air (reactive) gas environments at 100% relative humidity. In situ electrochemical characterization and extensive physical characterization is performed to understand the subtle differences in electrocatalyst degradation and correlated to the use of different GDLs. Overall, no difference is observed in the electrocatalyst degradation due to GDLs based on polarization curves at the end of life. But interestingly, MEA with a cracked microporous layer (MPL) in the GDL exhibited a higher electrocatalyst loading loss, which resulted in a lower and more heterogeneous increase in the average electrocatalyst nanoparticle size.

Vitamin B6 levels do not correlate with severity of neuropathy in chronic idiopathic axonal polyneuropathy.

Pyridoxine (vitamin B6) toxicity is known to cause a length-dependent, sensory predominant axonal polyneuropathy. There is debate regarding the threshold at which intake levels can cause neurological symptoms through pyridoxine toxicity. We asked if elevated plasma vitamin B6 levels were related to outcome measures in a well-characterized cohort of patients with chronic idiopathic axonal polyneuropathy (CIAP). We included 261 patients enrolled in the Peripheral Neuropathy Research Registry who had a complete dataset including a plasma vitamin B6 value. Patients with vitamin B6 deficiency (0-4.9 µg/L) were excluded. We performed a chi-square test for independence and analyzed the logistic relation of elevated plasma B6 level to nerve conduction studies (NCS), neurological examination findings, and patient-reported symptoms controlling for age and time elapsed since neuropathy symptom onset. Plasma B6 level was not related to neuropathy severity. There was no logistic relation of elevated plasma B6 level to NCS results, examination features including toe strength, vibration sense, and deep tendon reflexes, or patient-reported numbness or pain intensity. This study suggests that moderately elevated plasma B6 levels, even in the 100 to 200 µg/L range, are not associated with significantly worse neuropathy signs or symptoms. Although standard supplementation of B6 does not appear to have a major negative affect on CIAP, this study does not directly answer whether stopping supplementation will have a beneficial effect. Very few patients in the study had vitamin B6 levels >300 µg/L, suggesting that screening for vitamin B6 toxicity may be left to the discretion of the physician.

Tidal evolution of the Moon from a high-obliquity, high-angular-momentum Earth.

In the giant-impact hypothesis for lunar origin, the Moon accreted from an equatorial circum-terrestrial disk; however, the current lunar orbital inclination of five degrees requires a subsequent dynamical process that is still unclear. In addition, the giant-impact theory has been challenged by the Moon's unexpectedly Earth-like isotopic composition. Here we show that tidal dissipation due to lunar obliquity was an important effect during the Moon's tidal evolution, and the lunar inclination in the past must have been very large, defying theoretical explanations. We present a tidal evolution model starting with the Moon in an equatorial orbit around an initially fast-spinning, high-obliquity Earth, which is a probable outcome of giant impacts. Using numerical modelling, we show that the solar perturbations on the Moon's orbit naturally induce a large lunar inclination and remove angular momentum from the Earth-Moon system. Our tidal evolution model supports recent high-angular-momentum, giant-impact scenarios to explain the Moon's isotopic composition and provides a new pathway to reach Earth's climatically favourable low obliquity.

Socially Distanced Intercellular Communication: Mechanisms for Extracellular Vesicle Cargo Delivery.

Extracellular vesicles (EVs) are increasingly being recognised as players in intercellular communication within the human body. EVs are nano-sized vesicles that are secreted by virtually all cells, primarily arising from either the plasma membrane or the endocytic system. They contain a wide range of proteins and nucleic acids in their lumen, as well as cell surface proteins on their exterior. The proteins and nucleic acids within are the 'cargo' that EVs deliver into the cytosol of recipient cells to elicit a response or phenotypic change. For delivery to occur, the cargo needs to cross two lipid bilayers; one that makes up the vesicle itself, and the other of the recipient cell. Exactly how this process works is a topic that is poorly understood, despite being pivotal for their function. Furthermore, extracellular vesicles have therapeutic potential as drug delivery vehicles. Therefore, understanding their delivery mechanism and harnessing its action for drug delivery is of great importance. This chapter will focus on the proposed mechanisms for cargo delivery and discuss existing evidence for cargo delivery from EVs into the cytosol of recipient cells.

A Multifaceted Evaluation of a COVID-19 Contact Tracing Program in King County, Washington.

CONTEXT: Despite the massive scale of COVID-19 case investigation and contact tracing (CI/CT) programs operating worldwide, the evidence supporting the intervention's public health impact is limited. OBJECTIVE: To evaluate the Public Health-Seattle & King County (PHSKC) CI/CT program, including its reach, timeliness, effect on isolation and quarantine (I&Q) adherence, and potential to mitigate pandemic-related hardships. DESIGN: This program evaluation used descriptive statistics to analyze surveillance records, case and contact interviews, referral records, and survey data provided by a sample of cases who had recently ended isolation. SETTING: The PHSKC is one of the largest governmental local health departments in the United States. It serves more than 2.2 million people who reside in Seattle and 38 other municipalities. PARTICIPANTS: King County residents who were diagnosed with COVID-19 between July 2020 and June 2021. INTERVENTION: The PHSKC integrated COVID-19 CI/CT with prevention education and service provision. RESULTS: The PHSKC CI/CT team interviewed 42 900 cases (82% of cases eligible for CI/CT), a mean of 6.1 days after symptom onset and 3.4 days after SARS-CoV-2 testing. Cases disclosed the names and addresses of 10 817 unique worksites (mean = 0.8/interview) and 11 432 other recently visited locations (mean = 0.5/interview) and provided contact information for 62 987 household members (mean = 2.7/interview) and 14 398 nonhousehold contacts (mean = 0.3/interview). The CI/CT team helped arrange COVID-19 testing for 5650 contacts, facilitated grocery delivery for 7253 households, and referred 9127 households for financial assistance. End of I&Q Survey participants (n = 304, 54% of sampled) reported self-notifying an average of 4 nonhousehold contacts and 69% agreed that the information and referrals provided by the CI/CT team helped them stay in isolation. CONCLUSIONS: In the 12-month evaluation period, CI/CT reached 42 611 households and identified thousands of exposure venues. The timing of CI/CT relative to infectiousness and difficulty eliciting nonhousehold contacts may have attenuated the intervention's effect. Through promotion of I&Q guidance and services, CI/CT can help mitigate pandemic-related hardships.

The role of social exposure in predicting weight bias and weight bias internalisation: an international study.

BACKGROUND: Whilst the consequences of weight bias and weight bias internalisation (WBI) have been explored, less is known about the factors contributing to their development. Some research has explored the role of social exposure in weight bias and WBI but has been limited in its definition of exposure and focused solely on western countries. The present study therefore aimed to assess the role of social exposure defined in terms of both population and personal exposure in predicting weight bias and WBI, in an international sample. METHODS: Participants (N = 1041) from 33 countries, aged 18-85 years completed online measures of demographics, weight bias, WBI, and population and personal social exposure. Population exposure was defined using national obesity prevalence data from the World Health Organisation to classify countries as low (obesity rates ≤19.9%; n = 162), medium (20.0-29.9%; n = 672) or high prevalence (≥30%; n = 192). Personal exposure was defined in terms of personal contact and health and attractiveness normalisation. RESULTS: Using regression analysis, greater weight bias was significantly predicted by being younger, male, less educated, and personal exposure in terms of normalisation beliefs that thinner body types are healthier and more attractive, greater daily exposure and overall exposure to thinner friends. The strongest predictors of weight bias (adj R2 = 13%) were gender (ß = -0.24, p < .001), and personal exposure in terms of normalisation beliefs that thinner body types are more attractive (ß = -0.13, p = .001). The strongest predictors of WBI (adj R2 = 6%) were attractiveness normalisation (ß = -0.23, p < 0.001) and participants' perceived body shape (ß = -0.27, p < 0.001). Population exposure did not predict either weight bias or WBI. CONCLUSIONS: Personal exposure is more important than population exposure in predicting both weight bias and WBI. Findings hold implications for improving the wellbeing and lived experiences of those living with overweight and obesity.

The impact of body diversity vs thin-idealistic media messaging on health outcomes: an experimental study.

The recent rise in body dissatisfaction and weight bias has led to a call to the media to increase the diversity of their imagery, in efforts to challenge the thin-ideal. Therefore, this study aimed to evaluate the effects of both body diversity and thin-ideal interventions on health outcomes. Female participants (n = 160) were randomly allocated into an intervention group: body diversity; thin-ideal; control. They completed measures of body satisfaction, body compassion, internalisation of the thin-ideal, weight bias and behavioural intentions at baseline and post-intervention. The results showed significant differences between groups for weight bias and intentions to eat healthily. Specifically, those in the body diversity intervention group reported a greater reduction in weight bias compared to the other conditions. Further, those in the thin-ideal intervention group reported a greater increase in intentions to eat healthily compared to the other conditions. There were no differences between groups for body satisfaction, body compassion, internalisation of the thin-ideal and behavioural intentions to exercise and manage weight. In conclusion, exposure to body diversity images reduced weight bias whereas exposure to the thin-ideal promoted intentions towards healthy eating. These findings therefore offer empirical evidence for the impact of using different types of imagery to change different health outcomes.

Running on empty? Freshwater feeding by spawning anadromous alewife Alosa pseudoharengus.

Anadromous alewife Alosa pseudoharengus (n = 202; mean ± s.d. fork length = 231 ± 14 mm) were captured from 10 May to 27 June 2018 in an upper watershed lake on the Isthmus of Chignecto, Canada (45°57'N, 64°14'W). Thirty individuals (mean ± s.d. fork length = 250 ± 12 mm) were captured in an adjacent estuary downstream of a tide gate on 25 April 2018. Comparing estuarine to freshwater specimens, mean gonad mass and gonadosomatic indices in males and females decreased approximately 40% and 60%, and 31% and 50%, respectively. Individuals were characterized as pre-spawners in the estuary and spawners in the lake. Males maintained similar body condition throughout the spawning run whereas female condition decreased 9.4% between the estuary and lake. Stomach fullness decreased comparing estuarine and freshwater specimens, yet 93% of stomachs examined from individuals captured in the lake contained prey. Most males fed throughout all spawning stages (3%-17% empty stomachs), while all females fed during pre- and post-spawning stages and some fasted during spawning (11% empty stomachs). Cumulative prey curve never reached an asymptote, either weekly or for the entire sampling period, so freshwater diet may not have been completely described. Calanoid copepods (79.3%IA ) were a diet staple, with the secondary prey of mayfly nymphs (O. Ephemeroptera) consumed more by females (13.6%IA ) than males (6.2%IA ). PERMANOVA and PERMDISP analyses revealed significant dietary differences in freshwater were weekly and not due to dispersion effects, thus most likely due to feeding on various development stages of insect species. Our results challenge the long-held paradigm that anadromous A. pseudoharengus fast during the spawning migration.

Size-Exclusion Chromatography Separation Reveals That Vesicular and Non-Vesicular Small RNA Profiles Differ in Cell Free Urine.

Urinary extracellular vesicles (EVs) and their RNA cargo are a novel source of biomarkers for various diseases. We aimed to identify the optimal method for isolating small (<200 nm) EVs from human urine prior to small RNA analysis. EVs from filtered healthy volunteer urine were concentrated using three methods: ultracentrifugation (UC); a precipitation-based kit (PR); and ultrafiltration (UF). EVs were further purified by size-exclusion chromatography (SEC). EV preparations were analysed with transmission electron microscopy (TEM), Western blotting, nanoparticle tracking analysis (NTA) and an Agilent Bioanalyzer Small RNA kit. UF yielded the highest number of particles both before and after SEC. Small RNA analysis from UF-concentrated urine identified two major peaks at 10-40 nucleotides (nt) and 40-80 nt. In contrast, EV preparations obtained after UC, PR or SEC combined with any concentrating method, contained predominantly 40-80 nt sized small RNA. Protein fractions from UF+SEC contained small RNA of 10-40 nt in size (consistent with miRNAs). These data indicate that most of the microRNA-sized RNAs in filtered urine are not associated with small-sized EVs, and highlights the importance of removing non-vesicular proteins and RNA from urine EV preparations prior to small RNA analysis.

Successful management of suspected acorn (Quercus petraea) toxicity in a dog.

A 7-year-old neutered male Labrador retriever dog was referred to a tertiary care veterinary hospital because of gastrointestinal signs and icterus. The dog developed a hepatopathy and acute kidney injury after ingesting acorns (Quercus petraea) 4 days prior to referral. The dog required hospitalization in an intensive care unit but made a full clinical recovery and was discharged after 6 days. This report documents that dogs can be affected by this toxicity and highlights the need for veterinarians to consider acorns as a potential cause of acute hepatotoxicity and renal injury. To the authors' knowledge, this is the first reported case of acorn toxicity in a dog.

Prise en charge réussie d'une toxicité présumée par des glands ( Quercus petraea ) chez un chien. Un chien labrador retriever mâle stérilisé âgé de 7 ans a été référé à un hôpital vétérinaire de soins tertiaires en raison de signes gastro-intestinaux et d'ictère. Le chien a développé une hépatopathie et une lésion rénale aiguë après avoir ingéré des glands (Quercus petraea) 4 jours avant d'être référé. Le chien a dû être hospitalisé dans une unité de soins intensifs mais s'est complètement rétabli et a obtenu son congé après 6 jours. Ce rapport documente que les chiens peuvent être affectés par cette toxicité et souligne la nécessité pour les vétérinaires de considérer les glands comme une cause potentielle d'hépatotoxicité aiguë et de lésions rénales. À la connaissance des auteurs, il s'agit du premier cas signalé de toxicité par des glands chez un chien.(Traduit par Dr Serge Messier).

Unconventional secretion of annexins and galectins.

Eukaryotic cells have a highly evolved system of protein secretion, and dysfunction in this pathway is associated with many diseases including cancer, infection, metabolic disease and neurological disorders. Most proteins are secreted using the conventional endoplasmic reticulum (ER)/Golgi network and as such, this pathway is well-characterised. However, several cytosolic proteins have now been documented as secreted by unconventional transport pathways. This review focuses on two of these proteins families: annexins and galectins. The extracellular functions of these proteins are well documented, as are associations of their perturbed secretion with several diseases. However, the mechanisms and regulation of their secretion remain poorly characterised, and are discussed in this review. This review is part of a Special Issues of SCDB on 'unconventional protein secretion' edited by Walter Nickel and Catherine Rabouille.

The Genetic Legacy of Zoroastrianism in Iran and India: Insights into Population Structure, Gene Flow, and Selection.

Zoroastrianism is one of the oldest extant religions in the world, originating in Persia (present-day Iran) during the second millennium BCE. Historical records indicate that migrants from Persia brought Zoroastrianism to India, but there is debate over the timing of these migrations. Here we present genome-wide autosomal, Y chromosome, and mitochondrial DNA data from Iranian and Indian Zoroastrians and neighboring modern-day Indian and Iranian populations and conduct a comprehensive genome-wide genetic analysis in these groups. Using powerful haplotype-based techniques, we find that Zoroastrians in Iran and India have increased genetic homogeneity relative to other sampled groups in their respective countries, consistent with their current practices of endogamy. Despite this, we infer that Indian Zoroastrians (Parsis) intermixed with local groups sometime after their arrival in India, dating this mixture to 690-1390 CE and providing strong evidence that Iranian Zoroastrian ancestry was maintained primarily through the male line. By making use of the rich information in DNA from ancient human remains, we also highlight admixture in the ancestors of Iranian Zoroastrians dated to 570 BCE-746 CE, older than admixture seen in any other sampled Iranian group, consistent with a long-standing isolation of Zoroastrians from outside groups. Finally, we report results, and challenges, from a genome-wide scan to identify genomic regions showing signatures of positive selection in present-day Zoroastrians that might correlate to the prevalence of particular diseases among these communities.

Transbilayer phospholipid movement facilitates the translocation of annexin across membranes.

Annexins are cytosolic phospholipid-binding proteins that can be found on the outer leaflet of the plasma membrane. The extracellular functions of annexin include modulating fibrinolysis activity and cell migration. Despite having well-described extracellular functions, the mechanism of annexin transport from the cytoplasmic inner leaflet to the extracellular outer leaflet of the plasma membrane remains unclear. Here, we show that the transbilayer movement of phospholipids facilitates the transport of annexins A2 and A5 across membranes in cells and in liposomes. We identified TMEM16F (also known as anoctamin-6, ANO6) as a lipid scramblase required for transport of these annexins to the outer leaflet of the plasma membrane. This work reveals a mechanism for annexin translocation across membranes which depends on plasma membrane phospholipid remodelling.