HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion.

Enhanced expression of the cold-shock protein RNA binding motif 3 (RBM3) is highly neuroprotective both in vitro and in vivo. Whilst upstream signalling pathways leading to RBM3 expression have been described, the precise molecular mechanism of RBM3 cold induction remains elusive. To identify temperature-dependent modulators of RBM3, we performed a genome-wide CRISPR-Cas9 knockout screen using RBM3-reporter human iPSC-derived neurons. We found that RBM3 mRNA and protein levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being the strongest positive regulator. Splicing analysis revealed that moderate hypothermia significantly represses the inclusion of a poison exon, which, when retained, targets the mRNA for nonsense-mediated decay. Importantly, we show that HNRNPH1 mediates this cold-dependent exon skipping via its thermosensitive interaction with a G-rich motif within the poison exon. Our study provides novel mechanistic insights into the regulation of RBM3 and provides further targets for neuroprotective therapeutic strategies.

Luminal transport through intact endoplasmic reticulum limits the magnitude of localized Ca2+ signals.

The endoplasmic reticulum (ER) forms an interconnected network of tubules stretching throughout the cell. Understanding how ER functionality relies on its structural organization is crucial for elucidating cellular vulnerability to ER perturbations, which have been implicated in several neuronal pathologies. One of the key functions of the ER is enabling Ca[Formula: see text] signaling by storing large quantities of this ion and releasing it into the cytoplasm in a spatiotemporally controlled manner. Through a combination of physical modeling and live-cell imaging, we demonstrate that alterations in ER shape significantly impact its ability to support efficient local Ca[Formula: see text] releases, due to hindered transport of luminal content within the ER. Our model reveals that rapid Ca[Formula: see text] release necessitates mobile luminal buffer proteins with moderate binding strength, moving through a well-connected network of ER tubules. These findings provide insight into the functional advantages of normal ER architecture, emphasizing its importance as a kinetically efficient intracellular Ca[Formula: see text] delivery system.

Predicting the target landscape of kinase inhibitors using 3D convolutional neural networks.

Many therapies in clinical trials are based on single drug-single target relationships. To further extend this concept to multi-target approaches using multi-targeted drugs, we developed a machine learning pipeline to unravel the target landscape of kinase inhibitors. This pipeline, which we call 3D-KINEssence, uses a new type of protein fingerprints (3D FP) based on the structure of kinases generated through a 3D convolutional neural network (3D-CNN). These 3D-CNN kinase fingerprints were matched to molecular Morgan fingerprints to predict the targets of each respective kinase inhibitor based on available bioactivity data. The performance of the pipeline was evaluated on two test sets: a sparse drug-target set where each drug is matched in most cases to a single target and also on a densely-covered drug-target set where each drug is matched to most if not all targets. This latter set is more challenging to train, given its non-exclusive character. Our model's root-mean-square error (RMSE) based on the two datasets was 0.68 and 0.8, respectively. These results indicate that 3D FP can predict the target landscape of kinase inhibitors at around 0.8 log units of bioactivity. Our strategy can be utilized in proteochemometric or chemogenomic workflows by consolidating the target landscape of kinase inhibitors.

Colonization, diversity, and seasonality of fishes at pelagic fish aggregating devices.

The pelagic zone of the ocean can be a challenging environment in which to conduct research and as a result we lack the robust baseline abundance and diversity data, compared to what is available in more accessible coastal habitats, to be able to track changes or stressors to the biota in this environment. Many large-scale fisheries target pelagic fish, and much of the information available on these species is based on fisheries-dependent data that may be biased towards hotspots and commercially valuable fishes. Here, a long-term video and visual fish survey was conducted on two subsurface moored fish aggregating devices (FADs) in the pelagic waters of the central Bahamas to determine the feasibility of using moored pelagic FADs as tools for collecting fish abundance and diversity data. A wide range of species was documented, including large migratory fish that are the focus of commercial and recreational fisheries, and smaller often overlooked species on which little abundance or seasonality information exists. We found that FADs colonize quickly and reach a peak stable (albeit seasonally cyclical) abundance and diversity within the first several months after deployment. Species richness was higher in video surveys, but abundance was higher in visual surveys, except for sharks. Our results highlight the need to tailor survey methods to fit the context and study objective, and provide further evidence for the importance of fisheries-independent data in monitoring pelagic species.

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.

Knowledge About the Source of Emotion Predicts Emotion-Regulation Attempts, Strategies, and Perceived Emotion-Regulation Success.

People's ability to regulate emotions is crucial to healthy emotional functioning. One overlooked aspect in emotion-regulation research is that knowledge about the source of emotions can vary across situations and individuals, which could impact people's ability to regulate emotion. Using ecological momentary assessments (N = 396; 7 days; 5,466 observations), we measured adults' degree of knowledge about the source of their negative emotions. We used language processing to show that higher reported knowledge led to more concrete written descriptions of the source. We found that higher knowledge of the source predicted more emotion-regulation attempts; increased the use of emotion-regulation strategies that target the source (cognitive reappraisal, situation modification) versus strategies that do not (distraction, emotional eating); predicted greater perceived success in regulating emotions; and greater well-being. These patterns were evident both within and between persons. Our findings suggest that pinpointing the source of emotions might play an important role in emotion regulation.

Prophylactic immunization to Helicobacter pylori infection using spore vectored vaccines.

BACKGROUND: Helicobacter pylori infection remains a major public health threat leading to gastrointestinal illness and increased risk of gastric cancer. Mostly affecting populations in developing countries no vaccines are yet available and the disease is controlled by antimicrobials which, in turn, are driving the emergence of AMR. MATERIALS AND METHODS: We have engineered spores of Bacillus subtilis to display putative H. pylori protective antigens, urease subunit A (UreA) and subunit B (UreB) on the spore surface. Following oral dosing of mice with these spores, we evaluated immunity and colonization in animals challenged with H. pylori. RESULTS: Oral immunization with spores expressing either UreA or UreB showed antigen-specific mucosal responses (fecal sIgA) including seroconversion and hyperimmunity. Following challenge, colonization by H. pylori was significantly reduced by up to 1-log. CONCLUSIONS: This study demonstrates the utility of bacterial spores for mucosal vaccination to H. pylori infection. The heat stability and robustness of Bacillus spores coupled with their existing use as probiotics make them an attractive solution for either protection against H. pylori infection or potentially for therapy and control of active infection.

2023 International Olympic Committee's (IOC) consensus statement on Relative Energy Deficiency in Sport (REDs).

Relative Energy Deficiency in Sport (REDs) was first introduced in 2014 by the International Olympic Committee's expert writing panel, identifying a syndrome of deleterious health and performance outcomes experienced by female and male athletes exposed to low energy availability (LEA; inadequate energy intake in relation to exercise energy expenditure). Since the 2018 REDs consensus, there have been >170 original research publications advancing the field of REDs science, including emerging data demonstrating the growing role of low carbohydrate availability, further evidence of the interplay between mental health and REDs and more data elucidating the impact of LEA in males. Our knowledge of REDs signs and symptoms has resulted in updated Health and Performance Conceptual Models and the development of a novel Physiological Model. This Physiological Model is designed to demonstrate the complexity of either problematic or adaptable LEA exposure, coupled with individual moderating factors, leading to changes in health and performance outcomes. Guidelines for safe and effective body composition assessment to help prevent REDs are also outlined. A new REDs Clinical Assessment Tool-Version 2 is introduced to facilitate the detection and clinical diagnosis of REDs based on accumulated severity and risk stratification, with associated training and competition recommendations. Prevention and treatment principles of REDs are presented to encourage best practices for sports organisations and clinicians. Finally, methodological best practices for REDs research are outlined to stimulate future high-quality research to address important knowledge gaps.

Can a Blade-Stopping Mechanism on Circular Table Saws Reduce the Severity of Hand Injuries in Contact Scenarios? A Cadaveric Study.

PURPOSE: Table saws are commonly used woodworking tools that carry a substantial risk of injury. Blade-stopping technology has been developed and has the potential to reduce the frequency and severity of injury. This study aimed to evaluate this technology on human tissue and characterize the resulting injuries. METHODS: Twenty-seven fresh, frozen cadaveric specimen hands were used. Three scenarios were tested, with the specimen (1) moving forward ("forward"); (2) moving backward, such as in a kickback scenario ("reverse"); and (3) dropped from above the saw blade ("top"). Each scenario was tested at both slow (0.001 m/sec) and fast (forward: 0.6 m/sec; reverse: 0.5 m/sec; top: 2.4 m/sec) approach speeds. The severity of the injuries was characterized by anatomic evaluation and confirmed with radiographic evaluation. Injuries were classified as no laceration, superficial soft tissue injury, deep soft tissue injury, and bony injury. RESULTS: For the slow approach speed, the brake cartridge engaged in 100% of the trials for all 3 scenarios, and 100% of the specimens sustained no injuries. Forward testing at a fast approach speed revealed the brake cartridge engaged in 89% of the trials (injuries: 4 superficial, 2 deep, 3 bony). Reverse testing at a fast approach speed revealed the brake cartridge engaged in 11% of trials (injuries: 1 superficial, 8 bony). Top testing at a fast approach speed revealed the brake cartridge engaged in 89% of the trials (injuries: 9 bony). CONCLUSIONS: Modern blade-stopping technology did not prevent all traumatic hand injuries in fast approach speed scenarios, but it reduced the incidence and severity of injuries. The technology was more effective at low approach speed scenarios. CLINICAL RELEVANCE: The findings of this study provide information to help understand the factors that can prevent or reduce the severity of contact injuries (hand, finger, or thumb) for operators of table saws.

Extracranial medulloepithelioma: a review of the literature.

PURPOSE: Medulloepithelioma is a rare, malignant tumor that typically arises in the periventricular region of the cerebral hemispheres or the ciliary body of the eye. Even rarer still is the extracranial manifestation of medulloepithelioma with only 12 cases reported to date. Our purpose is to report a case of an intradural, extra-medullary medulloepithelioma and review the limited literature about diagnosis and treatment of this extremely rare pathology. METHODS: PubMed was queried using search terms "peripheral medulloepithelioma" and "pre-sacral medulloepithelioma." Medulloepitheliomas which were intraocular or occurred in reproductive organs were excluded. Patients' age, sex, the symptomatic period prior to diagnosis, primary tumor site, stage, treatment regimen, pathologic description, and survival outcomes were collected. RESULTS: We present a case of extracranial medulloepithelioma in an 8-year-old male. Morphology of the neoplasm was representative of medulloepithelioma but there was no amplification of C19MC. Additionally, the neoplasm stained positive for CD99. Twelve other cases of extracranial medulloepithelioma were found in literature review. CONCLUSIONS: The rarity of extracranial medulloepithelioma makes for a challenging diagnosis. Designing an optimal treatment strategy is difficult because of a scarcity of cases and wide variety in locations and treatments. Our case provides an example of treatment including resection, intense induction chemotherapy, consolidation with high-dose chemotherapy and stem cell rescue, craniospinal proton radiation therapy, and metronomic chemotherapy.

Investigating the behaviour of Atlantic salmon (Salmo salar L.) post-smolts during their early marine migration through the Clyde Marine Region.

It is thought that survival during migration is particularly poor for Atlantic salmon post-smolts immediately after entry into sea and particularly in the estuarine environment. Nonetheless, there is currently a lack of information on Atlantic salmon post-smolt movement behaviour in estuaries in the UK. This study used acoustic tagging to estimate loss rates and compare the behaviour of Atlantic salmon post-smolts migrating from two distinctly different rivers draining into the Clyde Estuary, the River Endrick (n = 145) and the Gryffe (n = 102). Contrary to most literature, post-smolts undertook rapid migrations through the estuary, potentially decreasing their exposure to predators/anthropogenic stressors and reducing their estimated loss rates (river: 1%-3% km-1 ; estuary: 0.20%-0.60% km-1 ). The low loss rates in the estuary occurred despite post-smolts engaging in passive reversal movements with the tide upon entering the estuary, possibly allowing them more time to adapt to the increased salinity. Atlantic salmon post-smolts from both the rivers used similar migration pathways exiting into the coastal marine zone during ebbing tide. This study provides novel information on the timing and migratory routes of Atlantic salmon post-smolts in the Clyde Estuary that can ultimately be used to inform management decisions on how to assess and reduce the potential impacts of current natural and anthropogenic stressors. Temporal repeatability of this study over multiple years is required to determine if there is variation in the factors driving the migratory patterns and loss rates of smolts in this system.

Anti-growth and pro-apoptotic effects of dasatinib on human oral cancer cells through multi-targeted mechanisms.

Dasatinib is an inhibitor of Src that has anti-tumour effects on many haematological and solid cancers. However, the anti-tumour effects of dasatinib on human oral cancers remain unclear. In this study, we investigated the effects of dasatinib on different types of human oral cancer cells: the non-tumorigenic YD-8 and YD-38 and the tumorigenic YD-10B and HSC-3 cells. Strikingly, dasatinib at 10 µM strongly suppressed the growth and induced apoptosis of YD-38 cells and inhibited the phosphorylation of Src, EGFR, STAT-3, STAT-5, PKB and ERK-1/2. In contrast, knockdown of Src blocked the phosphorylation of EGFR, STAT-5, PKB and ERK-1/2, but not STAT-3, in YD-38 cells. Dasatinib induced activation of the intrinsic caspase pathway, which was inhibited by z-VAD-fmk, a pan-caspase inhibitor. Dasatinib also decreased Mcl-1 expression and S6 phosphorylation while increased GRP78 expression and eIF-2α phosphorylation in YD-38 cells. In addition, to its direct effects on YD-38 cells, dasatinib also exhibited anti-angiogenic properties. Dasatinib-treated YD-38 or HUVEC showed reduced HIF-1α expression and stability. Dasatinib alone or conditioned media from dasatinib-treated YD-38 cells inhibited HUVEC tube formation on Matrigel without affecting HUVEC viability. Importantly, dasatinib's anti-growth, anti-angiogenic and pro-apoptotic effects were additionally seen in tumorigenic HSC-3 cells. Together, these results demonstrate that dasatinib has strong anti-growth, anti-angiogenic and pro-apoptotic effects on human oral cancer cells, which are mediated through the regulation of multiple targets, including Src, EGFR, STAT-3, STAT-5, PKB, ERK-1/2, S6, eIF-2α, GRP78, caspase-9/3, Mcl-1 and HIF-1α.

The relationship between antihypertensive medications and mood disorders: analysis of linked healthcare data for 1.8 million patients.

BACKGROUND: Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists (AAs) and calcium channel blockers, were associated with reduced risk of new-onset major depressive disorder (MDD) or bipolar disorder (BD). METHOD: Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by a receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n = 538 730) included patients with no previous history of mood disorder, whereas the other (n = 262 278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression. RESULTS: For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For AA monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95% CI 1.04-1.31). Beta blockers' association was stronger (HR 2.68; 95% CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against BD, particularly AAs (HR 0.46; 95% CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD. CONCLUSIONS: There was no evidence that antihypertensive medications prevented new episodes of MDD but AAs may represent a novel treatment avenue for BD.

Response to a COVID-19 Outbreak on a University Campus - Indiana, August 2020.

Institutions of higher education adopted different approaches for the fall semester 2020 in response to the coronavirus disease 2019 (COVID-19) pandemic. Approximately 45% of colleges and universities implemented online instruction, more than one fourth (27%) provided in-person instruction, and 21% used a hybrid model (1). Although CDC has published COVID-19 guidance for institutions of higher education (2-4), little has been published regarding the response to COVID-19 outbreaks on college and university campuses (5). In August 2020, an Indiana university with approximately 12,000 students (including 8,000 undergraduate students, 85% of whom lived on campus) implemented various public health measures to reduce transmission of SARS-CoV-2, the virus that causes COVID-19. Despite these measures, the university experienced an outbreak involving 371 cases during the first few weeks of the fall semester. The majority of cases occurred among undergraduate students living off campus, and several large off-campus gatherings were identified as common sources of exposure. Rather than sending students home, the university switched from in-person to online instruction for undergraduate students and instituted a series of campus restrictions for 2 weeks, during which testing, contact tracing, and isolation and quarantine programs were substantially enhanced, along with educational efforts highlighting the need for strict adherence to the mitigation measures. After 2 weeks, the university implemented a phased return to in-person instruction (with 85% of classes offered in person) and resumption of student life activities. This report describes the outbreak and the data-driven, targeted interventions and rapid escalation of testing, tracing, and isolation measures that enabled the medium-sized university to resume in-person instruction and campus activities. These strategies might prove useful to other colleges and universities responding to campus outbreaks.

Suppression of Proliferation of Human Glioblastoma Cells by Combined Phosphodiesterase and Multidrug Resistance-Associated Protein 1 Inhibition.

The paucity of currently available therapies for glioblastoma multiforme requires novel approaches to the treatment of this brain tumour. Disrupting cyclic nucleotide-signalling through phosphodiesterase (PDE) inhibition may be a promising way of suppressing glioblastoma growth. Here, we examined the effects of 28 PDE inhibitors, covering all the major PDE classes, on the proliferation of the human U87MG, A172 and T98G glioblastoma cells. The PDE10A inhibitors PF-2545920, PQ10 and papaverine, the PDE3/4 inhibitor trequinsin and the putative PDE5 inhibitor MY-5445 potently decreased glioblastoma cell proliferation. The synergistic suppression of glioblastoma cell proliferation was achieved by combining PF-2545920 and MY-5445. Furthermore, a co-incubation with drugs that block the activity of the multidrug resistance-associated protein 1 (MRP1) augmented these effects. In particular, a combination comprising the MRP1 inhibitor reversan, PF-2545920 and MY-5445, all at low micromolar concentrations, afforded nearly complete inhibition of glioblastoma cell growth. Thus, the potent suppression of glioblastoma cell viability may be achieved by combining MRP1 inhibitors with PDE inhibitors at a lower toxicity than that of the standard chemotherapeutic agents, thereby providing a new combination therapy for this challenging malignancy.

Notes on age determination, size and age structure, longevity and growth of co-occurring macrourid fishes.

Nineteen species of the deep-water fish family Macrouridae inhabit the Mid-Atlantic Ridge (MAR) of the North Atlantic. Size and age structure, longevity and length at age were explored for seven of the more abundant species: Coryphaenoides armatus, Coryphaenoides brevibarbis, Coryphaenoides carapinus, Coryphaenoides guentheri, Coryphaenoides mediterraneus, Coryphaenoides rupestris and Macrourus berglax. The otoliths from these species had growth increments resembling those accepted as annuli in other deep-water species for which validation experiments have been conducted. Based on the counts of these growth increments, age estimates were derived as the basis for studies of age structure, growth and longevity. All the species appeared to have relatively low growth rates, but the interspecific variation in longevity illustrates that there is a considerable variation within the family and among species inhabiting the same deep-sea environment. Most of the species likely complete full life cycles on the MAR, but it is probable that both the youngest and the largest-oldest individuals of some of the species were not sampled adequately.

Evidence for seasonal cycles in deep-sea fish abundances: A great migration in the deep SE Atlantic?

Animal migrations are of global ecological significance, providing mechanisms for the transport of nutrients and energy between distant locations. In much of the deep sea (>200 m water depth), the export of nutrients from the surface ocean provides a crucial but seasonally variable energy source to seafloor ecosystems. Seasonal faunal migrations have been hypothesized to occur on the deep seafloor as a result, but have not been documented. Here, we analyse a 7.5-year record of photographic data from the Deep-ocean Environmental Long-term Observatory Systems seafloor observatories to determine whether there was evidence of seasonal (intra-annual) migratory behaviours in a deep-sea fish assemblage on the West African margin and, if so, identify potential cues for the behaviour. Our findings demonstrate a correlation between intra-annual changes in demersal fish abundance at 1,400 m depth and satellite-derived estimates of primary production off the coast of Angola. Highest fish abundances were observed in late November with a smaller peak in June, occurring approximately 4 months after corresponding peaks in primary production. Observed changes in fish abundance occurred too rapidly to be explained by recruitment or mortality, and must therefore have a behavioural driver. Given the recurrent patterns observed, and the established importance of bottom-up trophic structuring in deep-sea ecosystems, we hypothesize that a large fraction of the fish assemblage may conduct seasonal migrations in this region, and propose seasonal variability in surface ocean primary production as a plausible cause. Such trophic control could lead to changes in the abundance of fishes across the seafloor by affecting secondary production of prey species and/or carrion availability for example. In summary, we present the first evidence for seasonally recurring patterns in deep-sea demersal fish abundances over a 7-year period, and demonstrate a previously unobserved level of dynamism in the deep sea, potentially mirroring the great migrations so well characterized in terrestrial systems.

As migrações dos animais são importantes para a ecologia global pois fornecem mecanismos para o transporte de nutrientes e energia entre diferentes locais. Em grande parte do oceano profundo (>200 m de profundidade), a exportação de nutrientes da superfície para os ecossistemas do fundo marinho é uma fonte de energia crucial, mas que varia entre estações. Consequentemente, calcula-se que ocorram migrações sazonais de animais no fundo marinho, mas tal nunca foi reportado. Neste estudo, nós analisamos dados fotográficos do observatório do fundo marinho DELOS colhidos ao longo de 7.5 anos, para determinar se existem indícios de comportamentos migratórios sazonais (intra-anuais) na comunidade de peixes de profundidade na costa oeste africana ao largo de Angola e, se se confirmar, tentar identificar o que desencadeia este comportamento. Os resultados obtidos mostram que há uma correlação entre as alterações intra-anuais da densidade de peixes demersais a 1,400 m de profundidade e as estimativas de produção primária obtidas por satélite. A densidade de peixes atinge o seu máximo no final de Novembro, com um pico menos acentuado em Junho, aproximadamente quatro meses após os respectivos picos de produção primária na superfície. As alterações na densidade de peixe ocorreram de uma forma tão rápida que não podem ser explicadas por recrutamento ou mortalidade, e como tal devem só podem ser geradas por uma alteração do comportamento. Dado a recorrência do padrão observado, e importância da estrutura trófica fundo-topo em ecossistemas do oceano profundo, nós colocamos a hipótese de que uma fracção grande da comunidade de peixes faz migrações sazonais nesta região, e propomos que a variação sazonal da produção primária na superfície esteja na sua origem. Este controlo trófico poderá levar a alterações na densidade de peixes no fundo marinho via, por exemplo, a produção secundária de presas e/ou disponibilidade de corpos em processo de decomposição. Resumindo, nós apresentamos aqui a primeira evidência de padrões sazonais recorrentes na densidade de peixes demersais de profundidade ao longo de um período de sete anos, e provamos existir um nível de dinamismo nunca dantes observado no oceano profundo, que poderá espelhar as grandes migrações comummente observadas em sistemas terrestres.

Genome to phenome tools: In vivo and in vitro transfection of Crassostrea virginica hemocytes.

The sequencing of the Crassostrea virginica genome has brought back the interest for gene delivery and editing methodologies. Here, we report the expression in oyster hemocytes of two heterologous expression vectors under the CMV promoter delivered with dendrimers. Expression was monitored using confocal microscopy, flow cytometry, and immunofluorescence assay. C. virginica hemocytes were able to express the green fluorescence protein and Crassostrea gigas vascular endothelial growth factor under CMV viral promoter both in vivo and in vitro. These results provide the bases for interrogating the genome and adapting genome editing methodologies.

The TICking clock of EGFR therapy resistance in glioblastoma: Target Independence or target Compensation.

Targeted therapy against driver mutations responsible for cancer progression has been shown to be effective in many tumor types. For glioblastoma (GBM), the epidermal growth factor receptor (EGFR) gene is the most frequently mutated oncogenic driver and has therefore been considered an attractive target for therapy. However, so far responses to EGFR-pathway inhibitors have been disappointing. We performed an exhaustive analysis of the mechanisms that might account for therapy resistance against EGFR inhibition. We define two major mechanisms of resistance and propose modalities to overcome them. The first resistance mechanism concerns target independence. In this case, cells have lost expression of the EGFR protein and experience no negative impact of EGFR targeting. Loss of extrachromosomally encoded EGFR as present in double minute DNA is a frequent mechanism for this type of drug resistance. The second mechanism concerns target compensation. In this case, cells will counteract EGFR inhibition by activation of compensatory pathways that render them independent of EGFR signaling. Compensatory pathway candidates are platelet-derived growth factor ß (PDGFß), Insulin-like growth factor 1 (IGFR1) and cMET and their downstream targets, all not commonly mutated at the time of diagnosis alongside EGFR mutation. Given that both mechanisms make cells independent of EGFR expression, other means have to be found to eradicate drug resistant cells. To this end we suggest rational strategies which include the use of multi-target therapies that hit truncation mutations (mechanism 1) or multi-target therapies to co-inhibit compensatory proteins (mechanism 2).