Early Burst Research Articles

Insulin-loaded liposomes packaged in alginate hydrogels promote the oral bioavailability of insulin.

Compared to subcutaneous injections, oral administration of insulin would be a preferred route of drug administration for diabetic patients. For oral delivery, both liposomes and alginate hydrogels face many challenges, including early burst release of the encapsulated drug and poor intestinal drug absorption. Also, adhesion to the intestinal mucosa remains weak, which all result in a low bioavailability of the payload. This study reports on an alginate hydrogel loaded with liposomes for oral insulin administration. Liposomes (Lip) loaded with arginine-insulin complexes (AINS) were incorporated into a hydrogel prepared from cysteine modified alginate (Cys-Alg) to form liposome-in-alginate hydrogels (AINS-Lip-Gel). An ex vivo study proves that intestinal permeation of AINS and AINS-Lip is approximately 2.0 and 6.0-fold, respectively, higher than that of free insulin. The hydrogel retarded early release of insulin (∼30%) from the liposomes and enhanced the intestinal mucosal retention. In vivo experiments revealed that the AINS-Lip-Gel released insulin in a controlled manner and possessed strong hypoglycemic effects. We conclude that liposome-in-alginate hydrogels loaded with AINS represent an attractive strategy for the oral delivery of insulin.

Hyaluronic Acid-Coated Chitosan/Gelatin Nanoparticles as a New Strategy for Topical Delivery of Metformin in Melanoma.

Metformin is a multipotential compound for treating diabetes II and controlling hormonal acne and skin cancer. This study was designed to enhance metformin skin penetration in melanoma using nanoparticles containing biocompatible polymers. Formulations with various concentrations of chitosan, hyaluronic acid, and sodium tripolyphosphate were fabricated using an ionic gelation technique tailored by the Box-Behnken design. The optimal formulation was selected based on the smallest particle size and the highest entrapment efficiency (EE%) and used in ex vivo skin penetration study. In vitro antiproliferation activity and apoptotic effects of formulations were evaluated using MTT and flow cytometric assays, respectively. The optimized formulation had an average size, zeta potential, EE%, and polydispersity index of 329 ± 6.30 nm, 21.94 ± 0.05 mV, 64.71 ± 6.12%, and 0.272 ± 0.010, respectively. The release profile of the optimized formulation displayed a biphasic trend, characterized by an early burst release, continued by a slow and sustained release compared to free metformin. The ex vivo skin absorption exhibited 1142.5 ± 156.3 μg/cm2 of metformin deposited in the skin layers for the optimized formulation compared to 603.2 ± 93.1 μg/cm2 for the free metformin. Differential scanning calorimetry confirmed the deformation of the drug from the crystal structure to an amorphous state. The attenuated total reflection Fourier transform infrared results approved no chemical interaction between the drug and other ingredients of the formulations. According to the MTT assay, metformin in nanoformulation exhibited a higher cytotoxic effect against melanoma cancer cells than free metformin (IC50: 3.94 ± 0.57 mM vs. 7.63 ± 0.26 mM, respectively, P < 0.001). The results proved that the optimized formulation of metformin could efficiently decrease cell proliferation by promoting apoptosis, thus providing a promising strategy for melanoma therapy.

Reconstructing the Assembly of Massive Galaxies. II. Galaxies Develop Massive and Dense Stellar Cores as They Evolve and Head toward Quiescence at Cosmic Noon

We use the spectral energy distribution fitting code Prospector to reconstruct the nonparametric star formation history (SFH) of massive () star-forming galaxies (SFGs) and quiescent galaxies (QGs) at redshift z obs ∼ 2 to investigate the joint evolution of star formation activity and structural properties. Compared to extended SFGs, compact SFGs are more likely to have experienced multiple star formation episodes, with the fractional mass formed during the older (≥1 Gyr) episode being larger, suggesting that high-redshift SFGs assembled their central regions earlier and then kept growing in central mass as they become more compact. The SFH of compact QGs does not significantly differ from the average for this category, and shows an early burst followed by a gradual decline of the star formation rate. The SFH of extended QGs, however, is similar to that of post-starburst galaxies, and their morphology is also frequently disturbed. Knowledge of the SFH also enables us to empirically reconstruct the structural evolution of individual galaxies. While the progenitor effect is clearly observed and accounted for in our analysis, it alone is insufficient to explain the observed structural evolution. We show that, as they evolve from star-forming phase to quiescence, galaxies grow massive dense stellar cores. Quenching begins at the center and then propagates outward to the rest of the structure. We discuss possible physical scenarios for the observed evolution and find that our empirical constraints are in good quantitative agreement with the model predictions from dissipative accretion of gas to the center followed by massive starbursts before final quiescence (wet compaction).

Phenotypic traits evolution and morphological traits associated with echolocation calls in cryptic horseshoe bats (Rhinolophidae)

AbstractBats provide an excellent casestudy for studying evolution due to their remarkable flight and echolocation capabilities. In this study, we sought to understand the phenotypic evolution of key traits in Rhinolophidae (horseshoe bats) using phylogenetic comparative methods. We aimed to test the phylogenetic signals of traits, and evaluated the best‐fit evolutionary models given the data for each trait considering different traits may evolve under different models (i.e., Brownian Motion [BM], Ornstein‐Uhlenbeck [OU], and Early Burst [EB]) and reconstruct ancestral character states. We examined how phenotypic characters are associated with echolocation calls and minimum detectable prey size. We measured 34 traits of 10 Asian rhinolophids species (187 individuals). We found that the majority of traits showed a high phylogenetic signal based on Blomberg′s K and Pagel′s λ, but each trait may evolve under different evolutionary models. Sella traits were shown to evolve under stabilizing selection based on OU models, indicating sella traits have the tendency to move forward along the branches toward some medial value in equilibrium. Our findings highlight the importance of sella characters in association with echolocation call emissions in Rhinolophidae, as calls are important for spatial cognition and also influence dietary preferences. Minimum detectable prey size in Rhinolophidae was associated with call frequency, bandwidth, call duration, wingspan, and wing surface area. Ultimately, understanding trait evolution requires sensitivity due to the differential selective pressures which may apply to different characteristics.

Modeling the Evolution of Rates of Continuous Trait Evolution.

Rates of phenotypic evolution vary markedly across the tree of life, from the accelerated evolution apparent in adaptive radiations to the remarkable evolutionary stasis exhibited by so-called "living fossils". Such rate variation has important consequences for large-scale evolutionary dynamics, generating vast disparities in phenotypic diversity across space, time, and taxa. Despite this, most methods for estimating trait evolution rates assume rates vary deterministically with respect to some variable of interest or change infrequently during a clade's history. These assumptions may cause underfitting of trait evolution models and mislead hypothesis testing. Here, we develop a new trait evolution model that allows rates to vary gradually and stochastically across a clade. Further, we extend this model to accommodate generally decreasing or increasing rates over time, allowing for flexible modeling of "early/late bursts" of trait evolution. We implement a Bayesian method, termed "evolving rates" (evorates for short), to efficiently fit this model to comparative data. Through simulation, we demonstrate that evorates can reliably infer both how and in which lineages trait evolution rates varied during a clade's history. We apply this method to body size evolution in cetaceans, recovering substantial support for an overall slowdown in body size evolution over time with recent bursts among some oceanic dolphins and relative stasis among beaked whales of the genus Mesoplodon. These results unify and expand on previous research, demonstrating the empirical utility of evorates.

Effect of Polytomy on the Parameter Estimation and Goodness of Fit of Phylogenetic Linear Regression Models for Trait Evolution

Phylogenetic regression models for trait evolution incorporate phylogenetic trees for the analysis of comparative data, in order to study trait relationships among a group of related species. However, as such trees are estimated, it is unlikely that there will be no errors when describing the relationships among species. In particular, for polytomy trees, where the relationships within a particular clade of species are more/less certainly determined (hard/soft polytomy, respectively), results of comparative analyses obtained from models based on those phylogenetic trees may also be affected. In this study, through extensive simulations, the performances of several popular Gaussian process-based regression models (Brownian motion, BM; Ornstein–Uhlenbeck process, OU; early burst, EB), as well as branch-stretching models (Pagel’s λ,δ,κ), were evaluated by assessing their fit and parameter estimation performance when soft polytomies are presented on either the root or a clade with insufficient phylogenetic information. Comparisons of the models are conducted by either assessing the accuracy of the estimator of regression and model parameters, or using a measure of fit (AIC, r2, and mean square error). It is found that, although polytomy does not significantly impact the fit and parameter estimate within a specified model, distinguishable differences and effects may be observed among trees and models. In particular, Pagel λ model and the OU model yield more accurate estimates and provide better fitting effects than the other models (BM, EB, δ, κ). While correcting phylogeny is an essential step prior to analysis, users may also consider using more appropriate models when encountering the polytomy issue.

Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis.

Simple SummaryColorectal cancer (CRC) in adolescents and young adults (AYA) is rare. Genetic causes include autosomal recessive and dominant monogenic disorders due to pathogenic variants (PVs) in genes involved in DNA repair. However, the genetic etiology of the majority of AYA-CRC remains unidentified. In two teenage siblings with CRC, we show to our knowledge for the first time that AYA-CRC cases can be caused by digenic inheritance of each a heterozygous pathogenic variant (PV) in the mismatch-repair (MMR) gene PMS2 and the proofreading polymerase (PP) Pol δ gene POLD1. With the aim to elucidate how the constitutional polymerase proofreading defect and the high propensity to MMR deficiency (MMRd) interact, we performed a comprehensive tumor analysis of the two siblings’ tumors. Results indicate that tumorigenesis is initiated by MMRd and the inherited POLD1 PV contributes to fast tumor progression reflected by an ultra-high tumor mutational burden (TMB) and specific mutational signatures.Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant MLH1 and MSH2 alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of AYA-CRC cases remain unexplained. In two teenage siblings with multiple adenomas and CRC, we identified a maternally inherited heterozygous PMS2 exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited POLD1 variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (>100 Mut/Mb) and a large contribution of COSMIC signature SBS20 in both siblings’ CRCs, confirming their predisposition to AYA-CRC results from a high propensity for somatic MMR deficiency (MMRd) compounded by a constitutional Pol δ proofreading defect. COSMIC signature SBS20 as well as SBS26 in the index patient’s CRC were associated with an early mutation burst, suggesting MMRd was an early event in tumorigenesis. The somatic second hits in PMS2 were through loss of heterozygosity (LOH) in both tumors, suggesting PPd-independent acquisition of MMRd. Taken together, these patients represent the first cases of cancer predisposition due to heterozygous variants in PMS2 and POLD1. Analysis of their CRCs supports that POLD1-mutated tumors acquire hypermutation only with concurrent MMRd.

SDSS-IV MaNGA: The MaNGA Dwarf Galaxy Sample Presentation

We present the MaNGA Dwarf galaxy (MaNDala) Value Added Catalog (VAC), from the final release of the Sloan Digital Sky Survey-IV program. MaNDala consists of 136 randomly selected bright dwarf galaxies with M * < 109.1 M ⊙ and M g > −18.5, making it the largest integral field spectroscopy homogeneous sample of dwarf galaxies. We release a photometric analysis of the g, r, and z broadband imaging based on the DESI Legacy Imaging Surveys, as well as a spectroscopic analysis based on the Pipe3D SDSS-IV VAC. Our release includes the surface brightness (SB), geometric parameters, and color profiles, Sérsic fits as well as stellar population properties (such as stellar ages, metallicities, and star formation histories), and emission lines' fluxes within the FOV and the effective radii of the galaxies. We find that the majority of the MaNDala galaxies are star-forming late-type galaxies with 〈n Sersic,r〉 ∼ 1.6 that are centrals (central/satellite dichotomy). MaNDala covers a large range of SB values (we find 11 candidate ultra-diffuse galaxies and three compact ones), filling the gap between classical dwarfs and low-mass galaxies in the Kormendy Diagram and in the size–mass/luminosity relation, which seems to flatten at 108 < M */M ⊙ < 109 with 〈R e,r 〉 ∼ 2.7 kpc. A large fraction of MaNDala galaxies formed from an early low-metallicity burst of SF, but also from late SF events from more metal-enriched gas: half of the MaNDala galaxies assembled 50% of their mass at 〈z〉 > 2, while the last 20% was at 〈z〉 < 0.3. Finally, a bending of the sSFR-M * relation at M * ∼ 109 M ⊙ for the main-sequence galaxies seems to be supported by MaNDala.

Glaucoma through Animal's Eyes: Insights from the Evolution of Intraocular Pressure in Mammals and Birds.

Glaucoma, an eye disorder caused by elevated intraocular pressure (IOP), is the leading cause of irreversible blindness in humans. Understanding how IOP levels have evolved across animal species could shed light on the nature of human vulnerability to glaucoma. Here, we studied the evolution of IOP in mammals and birds and explored its life history correlates. We conducted a systematic review, to create a dataset of species-specific IOP levels and reconstructed the ancestral states of IOP using three models of evolution (Brownian, Early burst, and Ornstein-Uhlenbeck (OU)) to understand the evolution of glaucoma. Furthermore, we tested the association between life history traits (e.g., body mass, blood pressure, diet, longevity, and habitat) and IOP using phylogenetic generalized least squares (PGLS). IOP in mammals and birds evolved under the OU model, suggesting stabilizing selection toward an optimal value. Larger mammals had higher IOPs and aquatic birds had higher IOPs; no other measured life history traits, the type of tonometer used, or whether the animal was sedated when measuring IOP explained the significant variation in IOP in this dataset. Elevated IOP, which could result from physiological and anatomical processes, evolved multiple times in mammals and birds. However, we do not understand how species with high IOP avoid glaucoma. While we found very few associations between life history traits and IOP, we suggest that more detailed studies may help identify mechanisms by which IOP is decoupled from glaucoma. Importantly, species with higher IOPs (cetaceans, pinnipeds, and rhinoceros) could be good model systems for studying glaucoma-resistant adaptations.

Association between early stage N2 sleep spindle burst characteristics and vigilance groups: an observational study on patients from a tertiary sleep centre

Objective. Obstructive sleep apnoea (OSA) is associated with impaired vigilance. This paper examines the hypothesis that sleep spindle (Sp) characteristics during nocturnal sleep can be mapped to vigilance deficits measured by the psychomotor vigilance task (PVT) in patients with OSA. Approach. The PVT was performed prior to In-laboratory Polysomnography for 250 patients. PVT outcomes were clustered into three vigilance groups (VGs). Spindles were scored manually for a Training Cohort of 55 patients, (9491 Sps) across different blocks of NREM sleep (SBs) and validated in a Test Cohort (25 patients, 4867 Sps). We proposed a novel set of Sp features including a spindle burst index (SBI), which quantifies the burst characteristics of spindles and constructed models mapping them to VGs. We also explored the performance of conventional Sp features (such as Sp number and density) in our modelling approach. Main results. In the Training Cohort, we observed statistically significant differences in the SBI across VGs and SBs independent of OSA severity (1st stage N2 SBI; p = <0.001 across VGs). In the Test Cohort, a Model based on the proposed SBI predicted VG membership with 88% accuracy. A model based on conventional Sp features mapped to VGs with 80% accuracy, and a model using mixed burst and conventional features reached an accuracy of 88%. Significance. Spindle features measured during diagnostic In-laboratory polysomnography measurements can be mapped to PVT outcomes. The novel SBI proved useful for exploring the relationship between PVT outcomes and sleep. Further studies in larger populations are needed to verify these conclusions.

Microphysics of Relativistic Collisionless Electron-ion-positron Shocks

We perform particle-in-cell simulations to elucidate the microphysics of relativistic weakly magnetized shocks loaded with electron-positron pairs. Various external magnetizations σ ≲ 10−4 and pair-loading factors Z ± ≲ 10 are studied, where Z ± is the number of loaded electrons and positrons per ion. We find the following: (1) The shock becomes mediated by the ion Larmor gyration in the mean field when σ exceeds a critical value σ L that decreases with Z ±. At σ ≲ σ L the shock is mediated by particle scattering in the self-generated microturbulent fields, the strength and scale of which decrease with Z ±, leading to lower σ L. (2) The energy fraction carried by the post-shock pairs is robustly in the range between 20% and 50% of the upstream ion energy. The mean energy per post-shock electron scales as . (3) Pair loading suppresses nonthermal ion acceleration at magnetizations as low as σ ≈ 5 × 10−6. The ions then become essentially thermal with mean energy , while electrons form a nonthermal tail, extending from to . When σ = 0, particle acceleration is enhanced by the formation of intense magnetic cavities that populate the precursor during the late stages of shock evolution. Here, the maximum energy of the nonthermal ions and electrons keeps growing over the duration of the simulation. Alongside the simulations, we develop theoretical estimates consistent with the numerical results. Our findings have important implications for models of early gamma-ray burst afterglows.

Synthesis and In Vitro/Ex Vivo Characterizations of Ceftriaxone-Loaded Sodium Alginate/poly(vinyl alcohol) Clay Reinforced Nanocomposites: Possible Applications in Wound Healing

(1) Background: Nanocomposite films are widely applied in the pharmaceutical industry (e.g., nanodrug delivery systems—NDDS). Indeed, these nanomaterials can be produced at a large industrial scale and display valuable properties (e.g., antibacterial, renewability, biodegradability, bioavailability, safety, tissue-specific targeting, and biocompatibility), which can enhance the activity of conventional marketed drugs. (2) Aim: To fabricate and investigate the in vitro properties of the antibiotic ceftriaxone sodium (CTX) once encapsulated into sodium alginate (SA)/poly(vinyl alcohol)PVA-clay reinforced nanocomposite films. (3) Methods: Different ratios of the polymers (i.e., SA, PVA) and CTX drug were used for the synthesis of nanocomposite films by solvent casting technique. Montmorillonite (MMT), modified organically, was added as a nanofiller to increase their thermal and mechanical strength. The prepared samples were physically characterized by thermogravimetric analysis (TGA), X-ray diffraction (XRD), scanning electronic microscopy (SEM), and energy-dispersive X-ray analysis (EDX). The physicochemical behavior (i.e., swelling, erosion, dissolution/drug release behavior and rat skin permeation) was also assessed. Comparisons were made with the currently marketed free CTX dosage form. (4) Results: TGA of the nanoformulation showed increased thermostability. XRD revealed its semi-crystalline nature. SEM depicted a homogeneous drug-loaded SA/PVA nanocomposite with an average size ranging between 300 and 500 nm. EDX confirmed the elemental composition and uniform distribution of mixing components. The water entrapment efficiency study showed that the highest swelling and erosion ratio is encountered with the nanoformulations S100(3) and S100D15(3). Ex vivo permeation revealed a bi-step discharge mode with an early burst liberation chased by continued drug discharge of devised nanoparticles (NPs). The dissolution studies of the drug-loaded polymer nanocomposites elicited sustained pH-dependent drug release. The cumulative drug release was the highest (90.93%) with S100D15(3). (5) Conclusion: S100D15(3) was the finest formulation. To the best of our knowledge, we also pioneered the use of solvent casting for the preparation of such nanoformulations. Polymers and reinforcing agent, concentrations and pH were rate-deterring features for the preparation of the optimized formulation. Thus, CTX-loaded SA/PVA-MMT reinforced nanocomposite appeared as a promising nanodrug delivery system (NDDS) based on its in vitro physicochemical properties.

Early oxidative burst and anthocyanin-mediated antioxidant defense mechanism impart resistance against Sclerotinia sclerotiorum in Indian mustard

The current study builds on our prior findings that anthocyanin buildup around the pathogen inoculation site confers resistance to S. sclerotiorum resistance in Indian mustard. However, the mechanism by which anthocyanin accumulation confers resistance is largely unknown. To better understand this mechanism, we compared the disease responses and biochemical profiling of two contrasting and wild type genotypes of Indian mustard [Sclerotinia stem rot-resistant RH 1222–28 (WR) and susceptible Varuna (WS)], as well as two anthocyanin contrasting mutants [anthocyanin-more (PM) and anthocyanin-devoid (AM) mutant] during different infection phases. Regardless of the inoculation time, disease examination revealed that WR and PM had considerably (P ≤ 0.05) lower mean lesion length (MLL) and rate of lesion expansion than WS and AM. Compared to WS and AM, biochemical results showed that WR and PM responses to infection were earlier, more timely regulated, and more robust. In the resistant WR and PM, hydrogen peroxide (H2O2) and superoxide anions (O2−1) accumulated rapidly and peaked during the early infection stage (2 days after inoculation; DAI), whereas in the susceptible WS and AM, accumulation was stronger and more intense in the later infection stage (8 DAI). Compared to the susceptible genotype (WS), the resistant genotype (WR) had significantly higher anthocyanin accumulation, a lower rate of lipid peroxidation, and a strong, efficient, and timely regulated antioxidant system that limited pathogen colonization and disease development. The anthocyanin-rich mutant (PM) is more resistant to ROS-induced oxidative damage. It has a slower rate of lesion development than the anthocyanin-deficient (AM) mutant, which has lower anthocyanin accumulation and higher oxidative stress with weak antioxidative potential, resulting in significantly (P ≤ 0.05) longer stem lesion length and rate of lesion expansion. These findings imply that during distinct infection phases of S. sclerotiorum, a well-coordinated oxidants/antioxidants system in terms of intensity and timing regulates Sclerotinia stem rot resistance/susceptibility. Overall, anthocyanin accumulation around the pathogen infection site appears to play a critical role in altering the ROS producing and scavenging machinery in Indian mustard, which contributes to resistance to S. sclerotiorum.

Genome and transcriptome mechanisms driving cephalopod evolution

Cephalopods are known for their large nervous systems, complex behaviors and morphological innovations. To investigate the genomic underpinnings of these features, we assembled the chromosomes of the Boston market squid, Doryteuthis (Loligo) pealeii, and the California two-spot octopus, Octopus bimaculoides, and compared them with those of the Hawaiian bobtail squid, Euprymna scolopes. The genomes of the soft-bodied (coleoid) cephalopods are highly rearranged relative to other extant molluscs, indicating an intense, early burst of genome restructuring. The coleoid genomes feature multi-megabase, tandem arrays of genes associated with brain development and cephalopod-specific innovations. We find that a known coleoid hallmark, extensive A-to-I mRNA editing, displays two fundamentally distinct patterns: one exclusive to the nervous system and concentrated in genic sequences, the other widespread and directed toward repetitive elements. We conclude that coleoid novelty is mediated in part by substantial genome reorganization, gene family expansion, and tissue-dependent mRNA editing.

Abscisic Acid-Defensive Player in Flax Response to Fusarium culmorum Infection.

Fusarium culmorum is a ubiquitous soil pathogen with a wide host range. In flax (Linum ussitatissimum), it causes foot and root rot and accumulation of mycotoxins in flax products. Fungal infections lead to huge losses in the flax industry. Moreover, due to mycotoxin accumulation, flax products constitute a potential threat to the consumers. We discovered that the defense against this pathogen in flax is based on early oxidative burst among others. In flax plants infected with F. culmorum, the most affected genes are connected with ROS production and processing, callose synthesis and ABA production. We hypothesize that ABA triggers defense mechanism in flax and is a significant player in a successful response to infection.

Early Origins of Divergent Patterns of Morphological Evolution on the Mammal and Reptile Stem-Lineages.

The origin of amniotes 320 million years ago signaled independence from water in vertebrates and was closely followed by divergences within the mammal and reptile stem lineages (Synapsida and Reptilia). Early members of both groups had highly similar morphologies, being superficially “lizard-like” forms with many plesiomorphies. However, the extent to which they might have exhibited divergent patterns of evolutionary change, with the potential to explain the large biological differences between their living members, is unresolved. We use a new, comprehensive phylogenetic dataset to quantify variation in rates and constraints of morphological evolution among Carboniferous–early Permian amniotes. We find evidence for an early burst of evolutionary rates, resulting in the early origins of morphologically distinctive subgroups that mostly persisted through the Cisuralian. Rates declined substantially through time, especially in reptiles. Early reptile evolution was also more constrained compared with early synapsids, exploring a more limited character state space. Postcranial innovation in particular was important in early synapsids, potentially related to their early origins of large body size. In contrast, early reptiles predominantly varied the temporal region, suggesting disparity in skull and jaw kinematics, and foreshadowing the variability of cranial biomechanics seen in reptiles today. Our results demonstrate that synapsids and reptiles underwent an early divergence of macroevolutionary patterns. This laid the foundation for subsequent evolutionary events and may be critical in understanding the substantial differences between mammals and reptiles today. Potential explanations include an early divergence of developmental processes or of ecological factors, warranting cross-disciplinary investigation. [Amniote; body size; constraint; phylogeny; rate.]

Ontogenetic niche shifts in the Mesozoic bird Confuciusornis sanctus

Paleontological evidence reveals that the rapid growth characteristic of living birds evolved close to the origin of the crown-group Neornithes, as more stemward birds experienced protracted growth until becoming fully grown.1 Research on Mesozoic confuciusornithids, the earliest divergence of fully beaked birds, has revealed a complex life cycle in which these birds experienced multiple growth phases.2-4 Such a life-history pattern calls for the exploration of the role that ontogenetic niche shifts may have played in size-structuring confuciusornithid populations.5,6 Here, by analyzing the skeletal morphometrics of a dense sample of fossil individuals of Confuciusornis sanctus (n= 171, all fledged), we show that the youngest individuals of this confuciusornithid species experienced a precocious burst of beak growth, probably facilitating access to novel food resources that helped them meet the high energetic demands of their initial growth spurt. Such an early burst of facial (i.e., snout) growth resembles that of young crocodilians.7 However, in these reptiles, facial growth slows down soon thereafter, and the matching of snout scaling between mid-sized and larger individuals instigates demographic competence and the dispersion of the former.8 In contrast, our results reveal that beak growth in C.sanctus continued steadily. We hypothesized that the protracted facial growth of older individuals led to ontogenetic niche shifts by dietary segregation among size classes within populations. Our study thus confirms that the life cycle of C.sanctus was notably different from that of modern birds, and it reveals that beak size allometry may have facilitated population cohesiveness between coinhabiting age classes.

The Impacts of PLGA/PEG Triblock Copolymers with Variable Molecular Weights on the Sustained Release of Buprenorphine.

Current in-situ injectable implants of buprenorphine (BP) such as Sublocade® consist of N-methyl-2-pyrrolidone (NMP)-dissolved PLGA. To control the initial burst release of Sublocade® during the first 24 hours after injection, we here used a BP in-situ forming composite (ISFC) employing different molecular weights of PLGA-PEG-PLGA triblock. The triblock was synthesized by Ring-Opening Polymerization (ROP) using PEG molecules with weights of 1500, 3000, and 4000 Da via the melting method. The specifications of the triblocks were evaluated by 1H-NMR, FTIR, GPC, and DSC. The sol-gel, gel-precipitate temperatures, in-vitro release, and composites' morphology, degradation, and toxicity were assessed for determining the features of ISFC 1500, ISFC 3000, and ISFC 4000 formulations. ROP was performed successfully via the melting method. The yields of all polymerization reactions were greater than 83.4%. The PEG 1500 triblock showed both sol-gel and gel-precipitate temperatures, but PEG 3000 and 4000 only showed a sol-precipitate temperature. The values of initial burst release of BP from ISFC 1500, ISFC 3000, and ISFC 4000 were 6.52 ± 0.22%, 12.39 ± 0.61%, and 15.80 ± 0.98%, respectively. BP release from the ISFCs wascompleted over three weeks for ISFC 1500 and 10 days for ISFC 3000 and ISFC 4000. The composites containing PEG 3000 and PEG 4000 were more spongy and porous than PEG 1500. The ISFC 1500 delivered a higher cell viability (95.17 ± 1.15%) compared with ISFC 3000 (86.37 ± 2.25%) and ISFC 4000 (79.70 ± 3.77%). These results indicated that ISFC 1500 wasbiocompatible and delivered suitable early initial burst reactions compared with ISFC 3000 and 4000 and might be a good candidate for preparing sustained-release formulation of BP.

Interleukin-29 profiles in COVID-19 patients: Survival is associated with IL-29 levels.

Interleukin-29 profiles in COVID-19 patients: Survival is associated with IL-29 levels.

Analytic modelling of synchrotron self-Compton spectra: Application to GRB 190114C

ABSTRACT Observations of TeV emission from early gamma-ray burst (GRB) afterglows revealed the long sought for inverse Compton (IC) upscattering of the lower energy synchrotron. However, it turned out that the long hoped for ability to easily interpret the synchrotron self-Compton (SSC) spectra didn’t materialize. The TeV emission is in the Klein–Nishina (KN) regime and the simple Thomson regime SSC spectrum is modified, complicating the scene. We describe here a methodology to obtain an analytic approximation to an observed spectrum and infer the conditions at the emitting region. The methodology is general and can be used in any such source. As a test case we apply it to the observations of GRB 190114C. We find that the procedure of fitting the model parameters using the analytic SSC spectrum suffers from some generic problems. However, at the same time, it conveniently gives a useful insight into the conditions that shape the spectrum. Once we introduce a correction to the standard KN approximation, the best-fitting solution is consistent with the one found in detailed numerical simulations. As in the numerical analysis, we find a family of solutions that provide a good approximation to the data and satisfy roughly B ∝ Γ−3 between the magnetic field and the bulk Lorentz factor, and we provide a tentative explanation why such a family arises.