[Palliative care and care for the elderly: Worlds to be reconciled around an ethic of vulnerability]. / Soins palliatifs et soins au grand âge : des univers à réconcilier autour d'une éthique de la vulnérabilité.

The ageing of Western societies is leading to a marked increase in mortality. Death and old age are now intertwined. This situation should be of particular concern to palliative care. But in reality, palliative care remains too inaccessible to the oldest sections of the population. Why this paradox? After reviewing the clinical and organisational reasons that are often given, we invite you to take a more global look, one that is both sociological and ethical.

Beneath the surface: DNA barcoding of shark fins in Singapore.

The global decline of shark populations, largely driven by overfishing to supply the shark fin trade, poses a significant threat to marine ecosystems. Southeast Asia, and particularly Singapore, is a key hub for the transit and trade of shark fins that contribute to the exploitation of these apex predators. Through the use of DNA barcoding techniques, this study aimed to determine what species of shark are involved in the Singapore shark fin trade. Fins were collected from markets, dried goods shops and traditional Chinese medicine halls throughout Singapore. In total, DNA was extracted from 684 fins collected in January 2024 and PCR amplification targeted a fragment of the mitochondrial COI gene for species identification. Results revealed fins from 24 species across 16 genera, with 19 species listed on CITES Appendices II, and 16 listed as threatened on the IUCN Red List (critically endangered = 2, endangered = 4, vulnerable = 10). The top five most frequently identified species were Carcharhinus falciformis, Galeorhinus galeus, Rhizoprionodon oligolinx, Sphyrna lewini and Rhizoprionodon acutus. Of these, four are listed on CITES Appendix II and four are listed as threatened on the IUCN Red List.

Shark Fin Sign in a Patient with Sepsis-induced Cardiomyopathy Associated with Retained Placenta: A Case Report and Review of the Literature.

Retained placenta can lead to septic shock; however, sepsis-induced cardiomyopathy (SICM) due to retained placenta has not been reported previously. This report presents a rare case of SICM following septic shock due to retained placenta after miscarriage in a 40-year-old woman, accompanied by the "shark fin sign" on an electrocardiogram, a pattern typically linked to myocardial ischemia. She experienced ventricular tachycardia and required venoarterial extracorporeal membrane oxygenation; however, she was successfully treated. We also reviewed previous cases of shark fin sign in patients without myocardial infarction. A review showed that half of the cases experienced lethal arrhythmias, even without myocardial infarction.

Intercorrelations of Chlorinated Paraffins, Dechloranes, and Legacy Persistent Organic Pollutants in 10 Species of Marine Mammals from Norway, in Light of Dietary Niche.

Short-, medium-, and long-chain chlorinated paraffins (CPs) (SCCPs, MCCPs, and LCCPs) and dechloranes are chemicals of emerging concern; however, little is known of their bioaccumulative potential compared to legacy contaminants in marine mammals. Here, we analyzed SCCPs, MCCPs, LCCPs, 7 dechloranes, 4 emerging brominated flame retardants, and 64 legacy contaminants, including polychlorinated biphenyls (PCBs), in the blubber of 46 individual marine mammals, representing 10 species, from Norway. Dietary niche was modeled based on stable isotopes of nitrogen and carbon in the skin/muscle to assess the contaminant accumulation in relation to diet. SCCPs and dechlorane-602 were strongly positively correlated with legacy contaminants and highest in killer (Orcinus orca) and sperm (Physeter macrocephalus) whales (median SCCPs: 160 ng/g lw; 230 ng/g lw and median dechlorane-602: 3.8 ng/g lw; 2.0 ng/g lw, respectively). In contrast, MCCPs and LCCPs were only weakly correlated to recalcitrant legacy contaminants and were highest in common minke whales (Balaenoptera acutorostrata; median MCCPs: 480 ng/g lw and LCCPs: 240 ng/g lw). The total contaminant load in all species was dominated by PCBs and legacy chlorinated pesticides (63-98%), and MCCPs dominated the total CP load (42-68%, except 11% in the long-finned pilot whale Globicephala melas). Surprisingly, we found no relation between contaminant concentrations and dietary niche, suggesting that other large species differences may be masking effects of diet such as lifespan or biotransformation and elimination capacities. CP and dechlorane concentrations were higher than in other marine mammals from the (sub)Arctic, and they were present in a killer whale neonate, indicating bioaccumulative properties and a potential for maternal transfer in these predominantly unregulated chemicals.

Fibroin nanodisruptor with Ferroptosis-Autophagy synergism is potent for lung cancer treatment.

Chemotherapy agents for lung cancer often cause apoptotic resistance in cells, leading to suboptimal therapeutic outcomes. FIN56 can be a potential treatment for lung cancer as it induces non-apoptotic cell death, namely ferroptosis. However, a bottleneck exists in FIN56-induced ferroptosis treatment; specifically, FIN56 fails to induce sufficient oxidative stress and may even trigger the defense system against ferroptosis, resulting in poor therapeutic efficacy. To overcome this, this study proposed a strategy of co-delivering FIN56 and piperlongumine to enhance the ferroptosis treatment effect by increasing oxidative stress and connecting with the autophagy pathway. FIN56 and piperlongumine were encapsulated into silk fibroin-based nano-disruptors, named FP@SFN. Characterization results showed that the particle size of FP@SFN was in the nanometer range and the distribution was uniform. Both in vivo and in vitro studies demonstrated that FP@SFN could effectively eliminate A549 cells and inhibit subcutaneous lung cancer tumors. Notably, ferroptosis and autophagy were identified as the main cell death pathways through which the nano-disruptors increased oxidative stress and facilitated cell membrane rupture. In conclusion, nano-disruptors can effectively enhance the therapeutic effect of ferroptosis treatment for lung cancer through the ferroptosis-autophagy synergy mechanism, providing a reference for the development of related therapeutics.

Hydrodynamic pressure sensing for a biomimetic robotic fish caudal fin integrated with a resistive pressure sensor.

Micro-sensors, such as pressure and flow sensors, are usually adopted to attain actual fluid information around swimming biomimetic robotic fish for hydrodynamic analysis and control. However, most of the reported micro-sensors are mounted discretely on body surfaces of robotic fish and it is impossible to analyzed the hydrodynamics between the caudal fin and the fluid. In this work, a biomimetic caudal fin integrated with a resistive pressure sensor is designed and fabricated by laser machined conductive carbon fibre composites. To analyze the pressure exerted on the caudal fin during underwater oscillation, the pressure on the caudal fin is measured under different oscillating frequencies and angles. Then a model developed from Bernoulli equation indicates that the maximum pressure difference is linear to the quadratic power of the oscillating frequency and the maximum oscillating angle. The fluid disturbance generated by caudal fin oscillating increases with an increase of oscillating frequency, resulting in the decrease of the efficiency of converting the kinetic energy of the caudal fin oscillation into the pressure difference on both sides of the caudal fin. However, perhaps due to the longer stability time of the disturbed fluid, this conversion efficiency increases with the increase of the maximum oscillating angle. Additionally, the pressure variation of the caudal fin oscillating with continuous different oscillating angles is also demonstrated to be detected effectively. It is suggested that the caudal fin integrated with the pressure sensor could be used for sensing thein situflow field in real time and analyzing the hydrodynamics of biomimetic robotic fish.

The Missing Coronary: A Case Series of Inferior Wall Myocardial Infarction Due to Coronary Anomalies.

Coronary artery anomalies, while often asymptomatic, can sometimes present acutely in the context of myocardial infarction (MI). This case series highlights three unique instances of inferior wall MI precipitated by rare coronary anomalies. The first case involved a 40-year-old male with a congenital absence of the left circumflex artery, presenting with a "shark fin" ECG pattern in inferior leads. Urgent coronary angiography confirmed the anomaly and primary percutaneous coronary intervention (PCI) was performed on a superdominant right coronary artery (RCA). The second case details a 52-year-old male with a split RCA, initially undiagnosed due to apparently normal angiographic findings, later revealed to have a thrombotic occlusion of the posterior division. Careful re-evaluation and imaging from alternative angles facilitated successful PCI. The third case describes a 45-year-old male with an anomalous origin of the RCA from the left sinus of Valsalva, presenting difficulties during arterial engagement in PCI. A modified Judkins left catheter technique was employed to achieve selective cannulation and stent deployment. These cases underscore the importance of early recognition, accurate diagnosis, and innovative interventional strategies in managing acute MI due to congenital coronary anomalies.

Shark fin sign: A rare EKG finding in a patient with Takotsubo cardiomyopathy from influenza A infection.

This case demonstrated the rare "shark fin" ECG pattern, an ST-segment elevation typically seen in acute myocardial infarction. We reported a case of takotsubo cardiomyopathy secondary to influenza A infection with multiple organ failure, showing the shark fin sign and resulting in in-patient mortality and various complication.

Phylogenomics and pervasive genome-wide phylogenetic discordance among fin whales (Balaenoptera physalus).

Phylogenomics has the power to uncover complex phylogenetic scenarios across the genome. In most cases, no single topology is reflected across the entire genome as the phylogenetic signal differs among genomic regions due to processes, such as introgression and incomplete lineage sorting. Baleen whales are among the largest vertebrates on Earth with a high dispersal potential in a relatively unrestricted habitat, the oceans. The fin whale (Balaenoptera physalus) is one of the most enigmatic baleen whale species, currently divided into four subspecies. It has been a matter of debate whether phylogeographic patterns explain taxonomic variation in fin whales. Here we present a chromosome-level whole genome analysis of the phylogenetic relationships among fin whales from multiple ocean basins. First, we estimated concatenated and consensus phylogenies for both the mitochondrial and nuclear genomes. The consensus phylogenies based upon the autosomal genome uncovered monophyletic clades associated with each ocean basin, aligning with the current understanding of subspecies division. Nevertheless, discordances were detected in the phylogenies based on the Y chromosome, mitochondrial genome, autosomal genome and X chromosome. Furthermore, we detected signs of introgression and pervasive phylogenetic discordance across the autosomal genome. This complex phylogenetic scenario could be explained by a puzzle of introgressive events, not yet documented in fin whales. Similarly, incomplete lineage sorting and low phylogenetic signal could lead to such phylogenetic discordances. Our study reinforces the pitfalls of relying on concatenated or single locus phylogenies to determine taxonomic relationships below the species level by illustrating the underlying nuances which some phylogenetic approaches may fail to capture. We emphasize the significance of accurate taxonomic delineation in fin whales by exploring crucial information revealed through genome-wide assessments.

[Terminal palliative care at home: an analysis of the difficulties faced by private nurses in the Provence-Alpes-Côte d'Azur region]. / Prise en charge palliative terminale à domicile : analyse des difficultés des infirmiers libéraux dans la région Paca.

Many patients wish to receive end-of-life care at home. Liberal professionals are necessarily called upon to help in these situations. The issues most frequently raised are the management of specific symptoms, lack of knowledge of palliative care support structures, and a feeling of isolation among caregivers.

Incorporación de Tecnología Tridimensional mediante Tomografía Microcomputarizada en el Estudio de la Anatomía de Salmónidos: Una Evaluación de Utilidad

Los salmónidos, durante su desarrollo, pueden experimentar ocasionalmente deformaciones esqueléticas. Para su diagnóstico se emplean diversas metodologías, entre las que se incluyen radiografías, técnicas histológicas, diafanización con tinciones de alizarina y azul de alcián, así como el uso del microscopio electrónico de barrido (SEM), cada una con sus inherentes ventajas y desventajas. Este estudio tuvo como finalidad evaluar y comparar la eficacia de la tomografía microcomputarizada (Micro-CT) para el análisis anatómico, reconstruyendo tridimensionalmente las imágenes y contrastándolas con los resultados obtenidos mediante la técnica de diafanización. Se analizaron las aletas caudales de cinco ejemplares de salmón Oncorhynchus kisutch: dos sujetos a diafanización y tres procesados para análisis mediante Micro-CT utilizando el equipo BRUKER SkyScan 1272. La técnica de Micro-CT demostró superioridad en la resolución de las estructuras óseas, facilitando una exploración detallada de las variaciones morfológicas y la distribución de la densidad mineral. Este enfoque permitió identificar anomalías en la morfología y crecimiento de las últimas vértebras y lepidotriquias dorsales, así como una densidad incrementada en lepidotriquias dorsales malformadas. La mayor resolución proporcionada por la Micro-CT no solo potencia nuestra comprensión de la ontogenia piscícola y su adaptación a ambientes diversos, sino que además inaugura perspectivas innovadoras para el estudio de la evolución de las estrategias locomotoras y las respuestas adaptativas frente a cambios ambientales a través del tiempo.

SUMMARY: During their development, some species of salmonids may occasionally experience skeletal deformations. Several methodologies are currently being used for the diagnosis of such malformations, among which X-rays, histological techniques, diaphanization coupled either with Alizarin Red or Alcian Blue stains, as well as Scanning Electron Microscopy (SEM) can be mentioned. Each one of those methods presents inherent advantages and disadvantages. The purpose of this study was twofold: Firstly, to evaluate and compare the effectiveness of microcomputed tomography (Micro-CT) technology for anatomical analysis, three-dimensionally reconstructing the obtained images; and secondly, to contrast those images with the results obtained through the diaphanization technique. The caudal fins of five specimens of the Oncorhynchus kisutch salmon were analyzed: Two specimens were subjected to diaphanization and three were processed for Micro-CT analysis, using the BRUKER SkyScan 1272 equipment. The Micro-CT technology demonstrated superiority in the resolution of bone structures, facilitating a detailed exploration of morphological variations, as well as the distribution of mineral density. This experimental approach allowed us to identify anomalies in the morphology and growth of the last vertebrae and dorsal lepidotrichiae, as well as an increased mineral density in the malformed dorsal lepidotrichiae. The higher resolution provided by Micro-CT not only enhances our understanding of the fish ontogeny and its adaptation to diverse environments, but also opens innovative perspectives for the study of the evolution of locomotor strategies and adaptive responses to environmental changes.

Relationship between skin and body condition in three species of baleen whales.

The assessment of free-ranging cetacean health through the study of skin conditions using photographs has gained prominence in recent years. However, little attention has been given to the relationships between cetacean skin conditions, species, and body condition. To explore this relationship among baleen whale species along the northwestern coast of Spain, we employed a non-invasive method involving photograph analysis. In this study, we examined skin conditions (including injuries, epizoites and ectoparasites, pigmentation disorders, skin lesions, and anatomical malformations) and body condition (overall physical contours and form, as an indicator of nutritional status and health) in 3 species of whales (blue, fin, and minke whales). This methodology facilitated the identification of 29 subcategories of distinct skin conditions and an assessment of body condition over a 5 yr period (2017 to 2021). In our study, we present evidence linking hypopigmentation, protruding pieces of tissue, and tattoo-like lesions to 'Poor' body condition in the 3 baleen whale species. Fin whales exhibited a higher susceptibility to mottling (prevalence = 17.7%), while blue whales were more prone to starbursts (prevalence = 90.5%). Additionally, we found a significant relationship between skin condition diversity and individual body condition. Our findings contribute valuable information to the broader understanding of the health status of baleen whales. Further investigations are necessary to delve into the etiology of the documented skin conditions and their potential implications for individual survival. This study serves as a foundation for ongoing research aimed at advancing our comprehension of these findings.

Disruption of the creb3l1 gene causes defects in caudal fin regeneration and patterning in zebrafish Danio rerio.

BACKGROUND: The gene cAMP-Responsive Element Binding protein 3-like-1 (CREB3L1) has been implicated in bone development in mice, with CREB3L1 knock-out mice exhibiting fragile bones, and in humans, with CREB3L1 mutations linked to osteogenesis imperfecta. However, the mechanism through which Creb3l1 regulates bone development is not fully understood. RESULTS: To probe the role of Creb3l1 in organismal physiology, we used CRISPR-Cas9 genome editing to generate a Danio rerio (zebrafish) model of Creb3l1 deficiency. In contrast to mammalian phenotypes, the Creb3l1 deficient fish do not display abnormalities in osteogenesis, except for a decrease in the bifurcation pattern of caudal fin. Both, skeletal morphology and overall bone density appear normal in the mutant fish. However, the regeneration of caudal fin postamputation is significantly affected, with decreased overall regenerate and mineralized bone area. Moreover, the mutant fish exhibit a severe patterning defect during regeneration, with a significant decrease in bifurcation complexity of the fin rays and distalization of the bifurcation sites. Analysis of genes implicated in bone development showed aberrant patterning of shha and ptch2 in Creb3l1 deficient fish, linking Creb3l1 with Sonic Hedgehog signaling during fin regeneration. CONCLUSIONS: Our results uncover a novel role for Creb3l1 in regulating tissue growth and patterning during regeneration.

Appendage-resident epithelial cells expedite wound healing response in adult zebrafish.

Adult zebrafish are able to heal large-sized cutaneous wounds in hours with little to no scarring. This rapid re-epithelialization is crucial for preventing infection and jumpstarting the subsequent regeneration of damaged tissues. Despite significant progress in understanding this process, it remains unclear how vast numbers of epithelial cells are orchestrated on an organismic scale to ensure the timely closure of millimeter-sized wounds. Here, we report an unexpected role of adult zebrafish appendages (fins) in accelerating the re-epithelialization process. Through whole-body monitoring of single-cell dynamics in live animals, we found that fin-resident epithelial cells (FECs) are highly mobile and migrate to cover wounds in nearby body regions. Upon injury, FECs readily undergo organ-level mobilization, allowing for coverage of body surfaces of up to 4.78 mm2 in less than 8 h. Intriguingly, long-term fate-tracking experiments revealed that the migratory FECs are not short-lived at the wound site; instead, the cells can persist on the body surface for more than a year. Our experiments on "fin-less" and "fin-gaining" individuals demonstrated that the fin structures are not only capable of promoting rapid re-epithelialization but are also necessary for the process. We further found that fin-enriched extracellular matrix laminins promote the active migration of FECs by facilitating lamellipodia formation. These findings lead us to conclude that appendage structures in regenerative vertebrates, such as fins, may possess a previously unrecognized function beyond serving as locomotor organs. The appendages may also act as a massive reservoir of healing cells, which speed up wound closure and tissue repair.

Design of stochastic computational Levenberg Marquardt backpropagation-based technique to investigate temperature distribution of longitudinal moving porous fin.

The improvement of thermal exchange is of utmost interest in a wide range of engineering areas. The current study focuses on thermal evaluation involving natural radiation and convection in a fractionally arranged moving longitudinal fin model placed under a magnetic field. We implement the Levenberg Marquardt backpropagation (LMB) algorithm for investigating an innovative use of stochastic numerical computation for analyzing the efficiency of the temperature distribution in a porous moving longitudinal fin. The datasets for LMB have been created using a shooting approach for dynamic systems with varying ranges of different parameters. The validation, testing, and training processes are used to simulate networks using the LMB approach for diverse scenarios of moving porous fin models. The reliability of results is assessed based on the regression measures, absolute error, error histograms, mean square error, and other metrics for fuller numerical modeling of the suggested LMB to investigate the thermal efficiency and effectiveness of porous moving fin.

Numerical Study on the Hydrodynamic Performance of a Flexible Caudal Fin with Different Trailing-Edge Shapes.

This paper presents a three-dimensional fluid-structure-coupled simulation of a flexible caudal fin with different trailing-edge shapes. The influences of caudal-fin shape on hydrodynamic performance are investigated by comparing the results of a simplified model of a square caudal fin with forked and deeply forked caudal fins under a wider range of non-dimensional flapping frequency, 0.6 < f* < 1.5, where f* is the ratio of flapping frequency to the natural frequency of each caudal fin, i.e., f* = f/fn. The leading edge of each caudal fin is forced to oscillate vertically in a water tank with zero free-stream conditions. The numerical results show that the amount of forking in the geometry of the caudal fin has significant effects on its hydrodynamic performance. A comparison of thrust coefficients shows that the square caudal fin has a greater thrust coefficient in the non-dimensional frequency range of 0.6 < f* < 1.2, while the deeply forked caudal fin generates higher thrust when 1.2 < f* < 1.5. In terms of propulsive efficiency, the square caudal fin is more efficient when 0.6 < f* < 0.9, while the propulsive efficiency of a deeply forked caudal fin is significantly enhanced when 0.9 < f* < 1.5. Based on our results, the deeply forked caudal fin has greater thrust coefficients and a higher propulsive efficiency in a higher frequency range than the natural frequency of each caudal fin. The thrust characteristics and flow fields around each caudal fin are investigated in detail.

Exploring the wound healing potential of Lobostemon fruticosus using in vitro and in vivo bioassays.

ETHNOPHARMACOLOGICAL RELEVANCE: Lobostemon fruticosus (L.) H.Buek is a perennial and woody shrub of the Boraginaceae family, found in the Cape region of South Africa. The leaves and twigs are used to treat dermatological conditions such as wounds, burns, ringworm, erysipelas and eczema. Anti-inflammatory, antibacterial, antiviral and anti-proliferative activities of L. fruticosus have been reported. However, there is a void in research which reports on the wound healing properties of this plant. AIM OF THE STUDY: Aligned with the traditional use of L. fruticosus, our study aimed to use in vitro and in vivo bioassays to confirm the wound healing potential of the plant. MATERIALS AND METHODS: An aqueous methanol extract (80% v/v) of L. fruticosus was prepared using a sample collected from the Western Cape Province of South Africa and chromatographically profiled by ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay was performed to determine the non-toxic concentrations of the extract for subsequent use in the in vitro scratch assay. Both the human keratinocyte (HaCaT) and fibroblast (BJ-5ta) cell lines were employed in the in vitro scratch assay. The in vivo caudal fin amputation assay was used to assess the wound healing potential of L. fruticosus, by monitoring fin regeneration in zebrafish larvae treated with the plant extract at various concentrations. RESULTS: Six major compounds were tentatively identified in the L. fruticosus extract namely; globoidnan A, globoidnan B, rutin, rabdosiin, sagerinic acid and rosmarinic acid. The potentially toxic pyrrolizidine alkaloids were also identified and quantitatively confirmed to be present at a low concentration of 119.58 ppm (m/m). Treatment of HaCaT and BJ-5ta cells with the plant extract in the scratch assay resulted in an increase in cell migration, which translates to accelerated wound closure. After 24 hr treatment with 100 µg/mL of extract, wound closure was recorded to be 91.1 ± 5.7% and 94.1 ± 1.3% for the HaCaT and BJ-5ta cells, respectively, while the untreated (medium) controls showed 72.3 ± 3.3% and 73.0 ± 4.3% for the two cell lines, respectively. Complete wound closure was observed between 24 and 36 hr, while the untreated control group did not achieve 100% wound closure by the end of the observation period (48 hr). In vivo, the crude extract at 100 µg/mL accelerated zebrafish caudal fin regeneration achieving 100.5 ± 3.8% regeneration compared to 68.3 ± 6.6% in the untreated control at two days post amputation. CONCLUSIONS: The study affirms the wound healing properties, as well as low toxicity of L. fruticosus using both in vitro and in vivo assays, which supports the traditional medicinal use. Other in vitro assays that target different mechanisms involved in wound healing should be investigated to support the current findings.

Adult caudal fin shape is imprinted in the embryonic fin fold.

Appendage shape is formed during development (and re-formed during regeneration) according to spatial and temporal cues that orchestrate local cellular morphogenesis. The caudal fin is the primary appendage used for propulsion in most fish species, and exhibits a range of distinct morphologies adapted for different swimming strategies, however the molecular mechanisms responsible for generating these diverse shapes remain mostly unknown. In zebrafish, caudal fins display a forked shape, with longer supportive bony rays at the periphery and shortest rays at the center. Here, we show that a premature, transient pulse of sonic hedgehog a (shha) overexpression during late embryonic development results in excess proliferation and growth of the central rays, causing the adult caudal fin to grow into a triangular, truncate shape. Both global and regional ectopic shha overexpression are sufficient to alter fin shape, and forked shape may be rescued by subsequent treatment with an antagonist of the canonical Shh pathway. The induced truncate fins show a decreased fin ray number and fail to form the hypural diastema that normally separates the dorsal and ventral fin lobes. While forked fins regenerate their original forked morphology, truncate fins regenerate truncate, suggesting that positional memory of the fin rays can be permanently altered by a transient treatment during embryogenesis. Ray finned fish have evolved a wide spectrum of caudal fin morphologies, ranging from truncate to forked, and the current work offers insights into the developmental mechanisms that may underlie this shape diversity.

Lack of Nuclear Localization of the Creb3l1 Transcription Factor Causes Defects in Caudal Fin Bifurcation in Zebrafish Danio rerio.

INTRODUCTION: The formation of normal bone and bone healing requires the cAMP-responsive element binding protein 3-like-1 (Creb3l1) transmembrane transcription factor, as deletion of the murine CREB3L1 results in osteopenic animals with limited capacity to repair bone after a fracture. Creb3l1 undergoes regulated intramembrane proteolysis (RIP) to release the N-terminal transcription activating (TA) fragment that enters the nucleus and regulates the expression of target genes. METHODS: To expand our understanding of Creb3l1's role in skeletal development and skeletal patterning, we aimed to generate animals expressing only the TA fragment of Creb3l1 lacking the transmembrane domain and thereby not regulated through RIP. However, the CRISPR/Cas9-mediated genome editing in zebrafish Danio rerio caused a frameshift mutation that added 56 random amino acids at the C-terminus of the TA fragment (TA+), making it unable to enter the nucleus. Thus, TA+ does not regulate transcription, and the creb3l1TA+/TA+ fish do not mediate creb3l1-dependent transcription. RESULTS: We document that the creb3l1TA+/TA+ fish exhibit defects in the patterning of caudal fin lepidotrichia, with significantly distalized points of proximal bifurcation and decreased secondary bifurcations. Moreover, using the caudal fin amputation model, we show that creb3l1TA+/TA+ fish have decreased regeneration and that their regenerates replicate the distalization and bifurcation defects observed in intact fins of creb3l1TA+/TA+ animals. These defects correlate with altered expression of the shha and ptch2 components of the Sonic Hedgehog signaling pathway in creb3l1TA+/TA+ regenerates. CONCLUSION: Together, our results uncover a previously unknown intersection between Creb3l1 and the Sonic Hedgehog pathway and document a novel role of Creb3l1 in tissue patterning.

Reducing Off-State and Leakage Currents by Dielectric Permittivity-Graded Stacked Gate Oxides on Trigate FinFETs: A TCAD Study.

Since its invention in the 1960s, one of the most significant evolutions of metal-oxide semiconductor field effect transistors (MOSFETs) would be the 3D version that makes the semiconducting channel vertically wrapped by conformal gate electrodes, also recognized as FinFET. During recent decades, the width of fin (Wfin) and the neighboring gate oxide width (tox) in FinFETs has shrunk from about 150 nm to a few nanometers. However, both widths seem to have been leveling off in recent years, owing to the limitation of lithography precision. Here, we show that by adapting the Penn model and Maxwell-Garnett mixing formula for a dielectric constant (κ) calculation for nanolaminate structures, FinFETs with two- and three-stage κ-graded stacked combinations of gate dielectrics with SiO2, Si3N4, Al2O3, HfO2, La2O3, and TiO2 perform better against the same structures with their single-layer dielectrics counterparts. Based on this, FinFETs simulated with κ-graded gate oxides achieved an off-state drain current (IOFF) reduced down to 6.45 × 10-15 A for the Al2O3: TiO2 combination and a gate leakage current (IG) reaching down to 2.04 × 10-11 A for the Al2O3: HfO2: La2O3 combination. While our findings push the individual dielectric laminates to the sub 1 nm limit, the effects of dielectric permittivity matching and κ-grading for gate oxides remain to have the potential to shed light on the next generation of nanoelectronics for higher integration and lower power consumption opportunities.