Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is a worldwide public health concern for which no vaccine is available. Elucidation of the prefusion structure of the RSV F glycoprotein and its identification as the main target of neutralizing antibodies have provided new opportunities for development of an effective vaccine. Here, we describe the structure-based design of a self-assembling protein nanoparticle presenting a prefusion-stabilized variant of the F glycoprotein trimer (DS-Cav1) in a repetitive array on the nanoparticle exterior. The two-component nature of the nanoparticle scaffold enabled the production of highly ordered, monodisperse immunogens that display DS-Cav1 at controllable density. In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1. These results motivate continued development of this promising nanoparticle RSV vaccine candidate and establish computationally designed two-component nanoparticles as a robust and customizable platform for structure-based vaccine design.

Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes memory-associated gene regulatory networks.

The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy.

Argonaute NRDE-3 and MBT domain protein LIN-61 redundantly recruit an H3K9me3 HMT to prevent embryonic lethality and transposon expression.

The establishment and maintenance of chromatin domains shape the epigenetic memory of a cell, with the methylation of histone H3 lysine 9 (H3K9me) defining transcriptionally silent heterochromatin. We show here that the C. elegans SET-25 (SUV39/G9a) histone methyltransferase (HMT), which catalyzes H3K9me1, me2 and me3, can establish repressed chromatin domains de novo, unlike the SETDB1 homolog MET-2. Thus, SET-25 is needed to silence novel insertions of RNA or DNA transposons, and repress tissue-specific genes de novo during development. We identify two partially redundant pathways that recruit SET-25 to its targets. One pathway requires LIN-61 (L3MBTL2), which uses its four MBT domains to bind the H3K9me2 deposited by MET-2. The second pathway functions independently of MET-2 and involves the somatic Argonaute NRDE-3 and small RNAs. This pathway targets primarily highly conserved RNA and DNA transposons. These redundant SET-25 targeting pathways (MET-2-LIN-61-SET-25 and NRDE-3-SET-25) ensure repression of intact transposons and de novo insertions, while MET-2 can act alone to repress simple and satellite repeats. Removal of both pathways in the met-2;nrde-3 double mutant leads to the loss of somatic H3K9me2 and me3 and the synergistic derepression of transposons in embryos, strongly elevating embryonic lethality.

TRPS1 acts as a context-dependent regulator of mammary epithelial cell growth/differentiation and breast cancer development.

The GATA-type zinc finger transcription factor TRPS1 has been implicated in breast cancer. However, its precise role remains unclear, as both amplifications and inactivating mutations in TRPS1 have been reported. Here, we used in vitro and in vivo loss-of-function approaches to dissect the role of TRPS1 in mammary gland development and invasive lobular breast carcinoma, which is hallmarked by functional loss of E-cadherin. We show that TRPS1 is essential in mammary epithelial cells, since TRPS1-mediated suppression of interferon signaling promotes in vitro proliferation and lactogenic differentiation. Similarly, TRPS1 expression is indispensable for proliferation of mammary organoids and in vivo survival of luminal epithelial cells during mammary gland development. However, the consequences of TRPS1 loss are dependent on E-cadherin status, as combined inactivation of E-cadherin and TRPS1 causes persistent proliferation of mammary organoids and accelerated mammary tumor formation in mice. Together, our results demonstrate that TRPS1 can function as a context-dependent tumor suppressor in breast cancer, while being essential for growth and differentiation of normal mammary epithelial cells.

The role of tropical rainfall in driving range dynamics for a long-distance migratory bird.

Predicting how the range dynamics of migratory species will respond to climate change requires a mechanistic understanding of the factors that operate across the annual cycle to control the distribution and abundance of a species. Here, we use multiple lines of evidence to reveal that environmental conditions during the nonbreeding season influence range dynamics across the life cycle of a migratory songbird, the American redstart (Setophaga ruticilla). Using long-term data from the nonbreeding grounds and breeding origins estimated from stable hydrogen isotopes in tail feathers, we found that the relationship between annual survival and migration distance is mediated by precipitation, but only during dry years. A long-term drying trend throughout the Caribbean is associated with higher mortality for individuals from the northern portion of the species' breeding range, resulting in an approximate 500 km southward shift in breeding origins of this Jamaican population over the past 30 y. This shift in connectivity is mirrored by changes in the redstart's breeding distribution and abundance. These results demonstrate that the climatic effects on demographic processes originating during the tropical nonbreeding season are actively shaping range dynamics in a migratory bird.

Mammalian life depends on two distinct pathways of DNA damage tolerance.

DNA damage threatens genomic integrity and instigates stem cell failure. To bypass genotoxic lesions during replication, cells employ DNA damage tolerance (DDT), which is regulated via PCNA ubiquitination and REV1. DDT is conserved in all domains of life, yet its relevance in mammals remains unclear. Here, we show that inactivation of both PCNA-ubiquitination and REV1 results in embryonic and adult lethality, and the accumulation of DNA damage in hematopoietic stem and progenitor cells (HSPCs) that ultimately resulted in their depletion. Our results reveal the crucial relevance of DDT in the maintenance of stem cell compartments and mammalian life in unperturbed conditions.

Modulation of TMEM16B channel activity by the calcium-activated chloride channel regulator 4 (CLCA4) in human cells.

The Ca2+-activated Cl- channel regulator CLCA1 potentiates the activity of the Ca2+-activated Cl- channel (CaCC) TMEM16A by directly engaging the channel at the cell surface, inhibiting its reinternalization and increasing Ca2+-dependent Cl- current (ICaCC) density. We now present evidence of functional pairing between two other CLCA and TMEM16 protein family members, namely CLCA4 and the CaCC TMEM16B. Similar to CLCA1, (i) CLCA4 is a self-cleaving metalloprotease, and the N-terminal portion (N-CLCA4) is secreted; (ii) the von Willebrand factor type A (VWA) domain in N-CLCA4 is sufficient to potentiate ICaCC in HEK293T cells; and (iii) this is mediated by the metal ion-dependent adhesion site motif within VWA. The results indicate that, despite the conserved regulatory mechanism and homology between CLCA1 and CLCA4, CLCA4-dependent ICaCC are carried by TMEM16B, rather than TMEM16A. Our findings show specificity in CLCA/TMEM16 interactions and suggest broad physiological and pathophysiological links between these two protein families.

Genomic underpinnings of head and body shape in Arctic charr ecomorph pairs.

Across its Holarctic range, Arctic charr (Salvelinus alpinus) populations have diverged into distinct trophic specialists across independent replicate lakes. The major aspect of divergence between ecomorphs is in head shape and body shape, which are ecomorphological traits reflecting niche use. However, whether the genomic underpinnings of these parallel divergences are consistent across replicates was unknown but key for resolving the substrate of parallel evolution. We investigated the genomic basis of head shape and body shape morphology across four benthivore-planktivore ecomorph pairs of Arctic charr in Scotland. Through genome-wide association analyses, we found genomic regions associated with head shape (89 SNPs) or body shape (180 SNPs) separately and 50 of these SNPs were strongly associated with both body and head shape morphology. For each trait separately, only a small number of SNPs were shared across all ecomorph pairs (3 SNPs for head shape and 10 SNPs for body shape). Signs of selection on the associated genomic regions varied across pairs, consistent with evolutionary demography differing considerably across lakes. Using a comprehensive database of salmonid QTLs newly augmented and mapped to a charr genome, we found several of the head- and body-shape-associated SNPs were within or near morphology QTLs from other salmonid species, reflecting a shared genetic basis for these phenotypes across species. Overall, our results demonstrate how parallel ecotype divergences can have both population-specific and deeply shared genomic underpinnings across replicates, influenced by differences in their environments and demographic histories.

Pleistocene diversification of unifoliolate-leaved Lupinus (Leguminosae: Papilionoideae) in Florida.

The importance and prevalence of recent ice-age and post-glacial speciation and species diversification during the Pleistocene across many organismal groups and physiographic settings are well established. However, the extent to which Pleistocene diversification can be attributed to climatic oscillations and their effects on distribution ranges and population structure remains debatable. In this study, we use morphologic, geographic and genetic (RADseq) data to document Pleistocene speciation and intra-specific diversification of the unifoliolate-leaved clade of Florida Lupinus, a small group of species largely restricted to inland and coastal sand ridges across the Florida peninsula and panhandle. Phylogenetic and demographic analyses alongside morphological and geographic evidence suggest that recent speciation and intra-specific divergence within this clade were driven by a combination of non-adaptive allopatric divergence caused by edaphic niche conservatism and opportunities presented by the emergence of new post-glacial sand ridge habitats. These results highlight the central importance of even modest geographic isolation and short periods of allopatric divergence following range expansion in the emergence of new taxa and add to the growing evidence that Pleistocene climatic oscillations may contribute to rapid diversification in a myriad of physiographic settings. Furthermore, our results shed new light on long-standing taxonomic debate surrounding the number of species in the Florida unifoliate Lupinus clade providing support for recognition of five species and a set of intra-specific variants. The important conservation implications for the narrowly restricted, highly endangered species Lupinus aridorum, which we show to be genetically distinct from its sister species Lupinus westianus, are discussed.

Tcf1 is essential for initiation of oncogenic Notch1-driven chromatin topology in T-ALL.

NOTCH1 is a well-established lineage specifier for T cells and among the most frequently mutated genes throughout all subclasses of T cell acute lymphoblastic leukemia (T-ALL). How oncogenic NOTCH1 signaling launches a leukemia-prone chromatin landscape during T-ALL initiation is unknown. Here we demonstrate an essential role for the high-mobility-group transcription factor Tcf1 in orchestrating chromatin accessibility and topology, allowing aberrant Notch1 signaling to convey its oncogenic function. Although essential, Tcf1 is not sufficient to initiate leukemia. The formation of a leukemia-prone epigenetic landscape at the distal Notch1-regulated Myc enhancer, which is fundamental to this disease, is Tcf1-dependent and occurs within the earliest progenitor stage even before cells adopt a T lymphocyte or leukemic fate. Moreover, we discovered a unique evolutionarily conserved Tcf1-regulated enhancer element in the distal Myc-enhancer, which is important for the transition of preleukemic cells to full-blown disease.

Review of Nutrition Guidelines and Evidence on Diet and Survival Outcomes for Cancer Survivors: Call for Integrating Nutrition into Oncology Care.

Several organizations have published nutrition guidelines for cancer survivors during and after treatment. This review compared nutrition guidelines for cancer survivors published in the United States for the topics that are covered in the guidelines and evaluated the evidence that these guidelines are based upon. A team of researchers, patient stakeholders, and healthcare providers collectively identified 5 nutrition guidelines for cancer survivors in the United States: the 2022 American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors, the 2018 American Institute for Cancer Research Cancer Nutrition Guide, the 2022 National Cancer Institute Physician Data Query and Eating Hints, the 2024 National Comprehensive Cancer Network Guidelines for Cancer Survivors, and the 2020 American Society for Clinical Oncology Guidelines. The 5 guidelines cover a comprehensive list of nutrition topics but overall promote to follow those recommendations for cancer prevention. This review also evaluated the current evidence from meta-analyses on dietary patterns and intakes of foods and nutrients in relation to survival outcomes among cancer survivors. Although the evidence on dietary patterns is strong, the evidence on most dietary factors is still limited and the current research was primarily conducted among breast and colorectal cancer survivors. Although nutrition recommendations are available for cancer survivors, practical strategies need to be implemented to integrate nutrition into oncology care and help cancer survivors follow these recommendations. Further research is warranted to provide additional evidence on the role of nutrition in the health outcomes of cancer survivors and guide the development of evidence-based nutrition recommendations. The protocol is registered in PROSPERO: CRD42023429240.

Treatments for Morton's neuroma.

BACKGROUND: Morton's neuroma (MN) is a painful neuropathy resulting from a benign enlargement of the common plantar digital nerve that occurs commonly in the third webspace and, less often, in the second webspace of the foot. Symptoms include burning or shooting pain in the webspace that extends to the toes, or the sensation of walking on a pebble. These impact on weight-bearing activities and quality of life. OBJECTIVES: To assess the benefits and harms of interventions for MN. SEARCH METHODS: On 11 July 2022, we searched CENTRAL, CINAHL Plus EBSCOhost, ClinicalTrials.gov, Cochrane Neuromuscular Specialised Register, Embase Ovid, MEDLINE Ovid, and WHO ICTRP. We checked the bibliographies of identified randomised trials and systematic reviews and contacted trial authors as needed. SELECTION CRITERIA: We included all randomised, parallel-group trials (RCTs) of any intervention compared with placebo, control, or another intervention for MN. We included trials where allocation occurred at the level of the individual or the foot (clustered data). We included trials that confirmed MN through symptoms, a clinical test, and an ultrasound scan (USS) or magnetic resonance imaging (MRI). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We assessed bias using Cochrane's risk of bias 2 tool (RoB 2) and assessed the certainty of the evidence using the GRADE framework. MAIN RESULTS: We included six RCTs involving 373 participants with MN. We judged risk of bias as having 'some concerns' across most outcomes. No studies had a low risk of bias across all domains. Post-intervention time points reported were: three months to less than 12 months from baseline (nonsurgical outcomes), and 12 months or longer from baseline (surgical outcomes). The primary outcome was pain, and secondary outcomes were function, satisfaction or health-related quality of life (HRQoL), and adverse events (AE). Nonsurgical treatments Corticosteroid and local anaesthetic injection (CS+LA) versus local anaesthetic injection (LA) Two RCTs compared CS+LA versus LA. At three to six months: • CS+LA may result in little to no difference in pain (mean difference (MD) -6.31 mm, 95% confidence interval (CI) -14.23 to 1.61; P = 0.12, I2 = 0%; 2 studies, 157 participants; low-certainty evidence). (Assessed via a pain visual analogue scale (VAS; 0 to 100 mm); a lower score indicated less pain.) • CS+LA may result in little to no difference in function when compared with LA (standardised mean difference (SMD) -0.30, 95% CI -0.61 to 0.02; P = 0.06, I2 = 0%; 2 studies, 157 participants; low-certainty evidence). (Function was measured using: the American Orthopaedic Foot and Ankle Society Lesser Toe Metatarsophalangeal-lnterphalangeal Scale (AOFAS; 0 to 100 points) - we transformed the scale so that a lower score indicated improved function - and the Manchester Foot Pain and Disability Schedule (MFPDS; 0 to 100 points), where a lower score indicated improved function.) • CS+LA probably results in little to no difference in HRQoL when compared to LA (MD 0.07, 95% CI -0.03 to 0.17; P = 0.19; 1 study, 122 participants; moderate-certainty evidence), and CS+LA may not increase satisfaction (risk ratio (RR) 1.08, 95% CI 0.63 to 1.85; P = 0.78; 1 study, 35 participants; low-certainty evidence). (Assessed using the EuroQol five dimension instrument (EQ-5D; 0-1 point); a higher score indicated improved HRQoL.) • The evidence is very uncertain about the effects of CS+LA on AE when compared with LA (RR 9.84, 95% CI 1.28 to 75.56; P = 0.03, I2 = 0%; 2 studies, 157 participants; very low-certainty evidence). Adverse events for CS+LA included mild skin atrophy (3.9%), hypopigmentation of the skin (3.9%) and plantar fat pad atrophy (2.6%); no adverse events were observed with LA. Ultrasound-guided (UG) CS+LA versus non-ultrasound-guided (NUG) CS+LA Two RCTs compared UG CS+LA versus NUG CS+LA. At six months: • UG CS+LA probably reduces pain when compared with NUG CS+LA (MD -15.01 mm, 95% CI -27.88 to -2.14; P = 0.02, I2 = 0%; 2 studies, 116 feet; moderate-certainty evidence). (Assessed with a pain VAS.) • UG CS+LA probably increases function when compared with NUG CS+LA (SMD -0.47, 95% CI -0.84 to -0.10; P = 0.01, I2 = 0%; 2 studies, 116 feet; moderate-certainty evidence). We do not know of any established minimum clinical important difference (MCID) for the scales that assessed function, specifically, the MFPDS and the Manchester-Oxford Foot Questionnaire (MOXFQ; 0 to 100 points; a lower score indicated improved function.) • UG CS+LA may increase satisfaction compared with NUG CS+LA (risk ratio (RR) 1.71, 95% CI 1.19 to 2.44; P = 0.003, I2 = 15%; 2 studies, 114 feet; low-certainty evidence). • HRQoL was not measured. • UG CS+LA may result in little to no difference in AE when compared with NUG CS+LA (RR 0.42, 95% CI 0.12 to 1.39; P = 0.15, I2 = 0%; 2 studies, 116 feet; low-certainty evidence). AE included depigmentation or fat atrophy for UG CS+LA (4.9%) and NUG CS+LA (12.7%). Surgical treatments Plantar incision neurectomy (PN) versus dorsal incision neurectomy (DN) One study compared PN versus DN. At 34 months (mean; range 28 to 42 months), PN may result in little to no difference for satisfaction (RR 1.06, 95% CI 0.87 to 1.28; P = 0.58; 1 study, 73 participants; low-certainty evidence), or for AE (RR 0.95, 95% CI 0.32 to 2.85; P = 0.93; 1 study, 75 participants; low-certainty evidence) compared with DN. AE for PN included hypertrophic scaring (11.4%), foreign body reaction (2.9%); AE for DN included missed nerve (2.5%), artery resected (2.5%), wound infection (2.5%), postoperative dehiscence (2.5%), deep vein thrombosis (2.5%) and reoperation with plantar incision due to intolerable pain (5%). The data reported for pain and function were not suitable for analysis. HRQoL was not measured. AUTHORS' CONCLUSIONS: Although there are many interventions for MN, few have been assessed in RCTs. There is low-certainty evidence that CS+LA may result in little to no difference in pain or function, and moderate-certainty evidence that UG CS+LA probably reduces pain and increases function for people with MN. Future trials should improve methodology to increase certainty of the evidence, and use optimal sample sizes to decrease imprecision.

Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel.

Epigenetic regulators play key roles in cancer and are increasingly being targeted for treatment. However, for many, little is known about mechanisms of resistance to the inhibition of these regulators. We have generated a model of resistance to inhibitors of protein arginine methyltransferase 5 (PRMT5). This study was conducted in KrasG12D;Tp53-null lung adenocarcinoma (LUAD) cell lines. Resistance to PRMT5 inhibitors (PRMT5i) arose rapidly, and barcoding experiments showed that this resulted from a drug-induced transcriptional state switch, not selection of a preexisting population. This resistant state is both stable and conserved across variants arising from distinct LUAD lines. Moreover, it brought with it vulnerabilities to other chemotherapeutics, especially the taxane paclitaxel. This paclitaxel sensitivity depended on the presence of stathmin 2 (STMN2), a microtubule regulator that is specifically expressed in the resistant state. Remarkably, STMN2 was also essential for resistance to PRMT5 inhibition. Thus, a single gene is required for both acquisition of resistance to PRMT5i and collateral sensitivity to paclitaxel in our LUAD cells. Accordingly, the combination of PRMT5i and paclitaxel yielded potent and synergistic killing of the murine LUAD cells. Importantly, the synergy between PRMT5i and paclitaxel also extended to human cancer cell lines. Finally, analysis of The Cancer Genome Atlas patient data showed that high STMN2 levels correlate with complete regression of tumors in response to taxane treatment. Collectively, this study reveals a recurring mechanism of PRMT5i resistance in LUAD and identifies collateral sensitivities that have potential clinical relevance.

When inflammation is not just inflammation-A review of systemic diseases of the nose and sinuses part 2: Granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis.

BACKGROUND: Chronic rhinosinusitis is a very common condition. Granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (eGPA) are systemic diseases which can contribute to the development of chronic rhinosinusitis in select patients. OBJECTIVE: Characterize the presenting features, diagnostic criteria, workup, and management of granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis as they are encountered in otolaryngology clinics. METHODS: Full length manuscripts published 2000 or later were reviewed. A separate search was conducted for each disease. Pertinent clinical features related to sinonasal manifestations of GPA and eGPA were collected and reported in this review. RESULTS: 467 references were discovered during literature review process. In total, 42 references for GPA and 35 references for eGPA were included in this review. CONCLUSION: GPA and eGPA are vasculitis syndromes which commonly present in the context of multisystem disease. For GPA, pulmonary and renal disease are common; for eGPA a history of asthma is nearly ubiquitous. Sinonasal disease is a very common feature for both disease processes and may precede the development of systemic symptoms in many patients. Clinical work up and diagnosis is complex and generally requires multidisciplinary care. Treatment primarily consists of immunosuppressive agents, and a number of steroids, steroid sparing agents, and biologics have been shown to be effective. The role of sinus surgery includes tissue biopsy for diagnosis, functional surgery for symptom management in select cases, and reconstruction of cosmetic and functional defects.

When inflammation is not just inflammation-A review of systemic diseases of the nose and sinuses part 1: IgG4-related disease and sarcoidosis.

BACKGROUND: Chronic rhinosinusitis is a very common condition. IgG4-related disease (IgG4-RD) and sarcoidosis are systemic diseases which can contribute to the development of chronic rhinosinusitis in select patients. OBJECTIVE: Characterize the presenting features, diagnostic criteria, workup, and management of sinonasal IgG4-RD and sarcoidosis as they are encountered in otolaryngology clinics. METHODS: Full length manuscripts published 2000 or later were reviewed. A separate search was conducted for each disease. Pertinent clinical features related to sinonasal manifestations of IgG4-RD and sarcoidosis were collected and reported in this review. RESULTS: 404 references were discovered during literature review process. In total, 42 references for IgG4-RD and 34 references for sarcoidosis were included in this review. CONCLUSION: IgG4-RD and sarcoidosis are autoimmune inflammatory conditions that can affect many systems of the body. For both disease entities, sinonasal disease is a less common presentation which can lead to delayed diagnosis. Sinonasal IgG4-RD commonly presents in the setting of multisystem disease. All with other clinical features, biopsy plays a key role in the diagnosis for both diseases. Treatment for IgG4-RD consists primarily of steroids and rituximab which can lead to excellent and durable remission. A variety of immunosuppressive agents are used in the management of sarcoidosis. Surgery for IgG4-RD is primarily utilized for tissue biopsy, although resection or debulking may be considered. For sarcoidosis, surgery can be used for tissue biopsy and functional sinus surgery can offer symptomatic relief in many patients.

The Suppression of the Epithelial to Mesenchymal Transition in Prostate Cancer through the Targeting of MYO6 Using MiR-145-5p.

Aberrant expression of miR-145-5p has been observed in prostate cancer where is has been suggested to play a tumor suppressor role. In other cancers, miR-145-5p acts as an inhibitor of epithelial-to-mesenchymal transition (EMT), a key molecular process for tumor progression. However, the interaction between miR-145-5p and EMT remains to be elucidated in prostate cancer. In this paper the link between miR-145-5p and EMT in prostate cancer was investigated using a combination of in silico and in vitro analyses. miR-145-5p expression was significantly lower in prostate cancer cell lines compared to normal prostate cells. Bioinformatic analysis of The Cancer Genome Atlas prostate adenocarcinoma (TCGA PRAD) data showed significant downregulation of miR-145-5p in prostate cancer, correlating with disease progression. Functional enrichment analysis significantly associated miR-145-5p and its target genes with EMT. MYO6, an EMT-associated gene, was identified and validated as a novel target of miR-145-5p in prostate cancer cells. In vitro manipulation of miR-145-5p levels significantly altered cell proliferation, clonogenicity, migration and expression of EMT-associated markers. Additional TCGA PRAD analysis suggested miR-145-5p tumor expression may be useful predictor of disease recurrence. In summary, this is the first study to report that miR-145-5p may inhibit EMT by targeting MYO6 in prostate cancer cells. The findings suggest miR-145-5p could be a useful diagnostic and prognostic biomarker for prostate cancer.

Migration patterns and navigation cues of Atlantic salmon post-smolts migrating from 12 rivers through the coastal zones around the Irish Sea.

The freshwater phase of the first seaward migration of juvenile Atlantic salmon (Salmo salar) is relatively well understood when compared with our understanding of the marine phase of their migration. In 2021, 1008 wild and 60 ranched Atlantic salmon smolts were tagged with acoustic transmitters in 12 rivers in England, Scotland, Northern Ireland and Ireland. Large marine receiver arrays were deployed in the Irish Sea at two locations: at the transition of the Irish Sea into the North Atlantic between Ireland and Scotland, and between southern Scotland and Northern Ireland, to examine the early phase of the marine migration of Atlantic salmon smolts. After leaving their natal rivers' post-smolt migration through the Irish Sea was rapid with minimum speeds ranging from 14.03 to 38.56 km.day-1 for Atlantic salmon smolts that entered the Irish Sea directly from their natal river, to 9.69-39.94 km.day-1 for Atlantic salmon smolts that entered the Irish Sea directly from their natal estuary. Population minimum migration success through the study area was strongly correlated with the distance of travel, populations further away from the point of entry to the open North Atlantic exhibited lower migration success. Post-smolts from different populations experienced different water temperatures on entering the North Atlantic. This was largely driven by the timing of their migration and may have significant consequences for feeding and ultimately survivorship. The influence of water currents on post-smolt movement was investigated using data from previously constructed numerical hydrodynamic models. Modeled water current data in the northern Irish Sea showed that post-smolts had a strong preference for migrating when the current direction was at around 283° (west-north-west) but did not migrate when exposed to strong currents in other directions. This is the most favorable direction for onward passage from the Irish Sea to the continental shelf edge current, a known accumulation point for migrating post-smolts. These results strongly indicate that post-smolts migrating through the coastal marine environment are: (1) not simply migrating by current following (2) engage in active directional swimming (3) have an intrinsic sense of their migration direction and (4) can use cues other than water current direction to orientate during this part of their migration.

Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland, and Ireland.

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea.

Pathogenic alleles in microtubule, secretory granule and extracellular matrix-related genes in familial keratoconus.

Keratoconus is a common corneal defect with a complex genetic basis. By whole exome sequencing of affected members from 11 multiplex families of European ancestry, we identified 23 rare, heterozygous, potentially pathogenic variants in 8 genes. These include nonsynonymous single amino acid substitutions in HSPG2, EML6 and CENPF in two families each, and in NBEAL2, LRP1B, PIK3CG and MRGPRD in three families each; ITGAX had nonsynonymous single amino acid substitutions in two families and an indel with a base substitution producing a nonsense allele in the third family. Only HSPG2, EML6 and CENPF have been associated with ocular phenotypes previously. With the exception of MRGPRD and ITGAX, we detected the transcript and encoded protein of the remaining genes in the cornea and corneal cell cultures. Cultured stromal cells showed cytoplasmic punctate staining of NBEAL2, staining of the fibrillar cytoskeletal network by EML6, while CENPF localized to the basal body of primary cilia. We inhibited the expression of HSPG2, EML6, NBEAL2 and CENPF in stromal cell cultures and assayed for the expression of COL1A1 as a readout of corneal matrix production. An upregulation in COL1A1 after siRNA inhibition indicated their functional link to stromal cell biology. For ITGAX, encoding a leukocyte integrin, we assayed its level in the sera of 3 affected families compared with 10 unrelated controls to detect an increase in all affecteds. Our study identified genes that regulate the cytoskeleton, protein trafficking and secretion, barrier tissue function and response to injury and inflammation, as being relevant to keratoconus.

Erratum: Strong constraints on aerosol-cloud interactions from volcanic eruptions.

This corrects the article DOI: 10.1038/nature22974.