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The severe greenhouse climate and seasonality of the early to mid-Late Triassic are thought to have limited terrestrial diversity at lower latitudes, but direct adaptations to these harsh conditions remain limited in vertebrates at the palaeoequator. Here, we present Ninumbeehan dookoodukah gen. et sp. nov., an early amphibian with specialized adaptations for seasonal estivation from the upper Jelm Formation of the Late Triassic of Wyoming, USA. Ninumbeehan are found in an association of vertebrate estivation burrows across a locally dense horizon, offering insights into the evolution and ecology of vertebrates amid the challenging conditions of low-latitude Late Triassic ecosystems. Estivation chambers were excavated within point bar deposits of an ephemeral river system, recording the cyclical signature of Triassic megamonsoons and documenting a vertebrate response to annual climate extremes across tens to hundreds of seasons. Phylogenetic analysis recovers Ninumbeehan within a group of temnospondyls characterized by fossorial adaptation, underscoring the widespread adoption of burrowing and estivation in total group Lissamphibia. Ninumbeehan hints at the pivotal role seasonal dynamics played in shaping amphibian evolution.

Current hypotheses of early tetrapod evolution posit close ecological and biogeographic ties to the extensive coal-producing wetlands of the Carboniferous palaeoequator with rapid replacement of archaic tetrapod groups by relatives of modern amniotes and lissamphibians in the late Carboniferous (about 307 million years ago). These hypotheses draw on a tetrapod fossil record that is almost entirely restricted to palaeoequatorial Pangea (Laurussia) 1,2 . Here we describe a new giant stem tetrapod, Gaiasia jennyae, from high-palaeolatitude (about 55° S) early Permian-aged (about 280 million years ago) deposits in Namibia that challenges this scenario. Gaiasia is represented by several large, semi-articulated skeletons characterized by a weakly ossified skull with a loosely articulated palate dominated by a broad diamond-shaped parasphenoid, a posteriorly projecting occiput, and enlarged, interlocking dentary and coronoid fangs. Phylogenetic analysis resolves Gaiasia within the tetrapod stem group as the sister taxon of the Carboniferous Colosteidae from Euramerica. Gaiasia is larger than all previously described digited stem tetrapods and provides evidence that continental tetrapods were well established in the cold-temperate latitudes of Gondwana during the final phases of the Carboniferous-Permian deglaciation. This points to a more global distribution of continental tetrapods during the Carboniferous-Permian transition and indicates that previous hypotheses of global tetrapod faunal turnover and dispersal at this time 2,3 must be reconsidered., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Lung cancer is the leading cause of cancer death worldwide. It may present as airway obstruction in a patient with endobronchial masses. Endobronchial brachytherapy (EBBT) has been shown to provide palliative therapy. It is the insertion of a radioactive material near the mass to reduce tumor size, thereby improving airway obstruction. This is the first case of EBBT done in our institution during the COVID-19 pandemic. A 53-year-old male, 60 kg, ASA Physical Status 2 for hypertension, smoker, malignancy, and previous pulmonary tuberculosis patient, presented with a cough and dyspnea. An endobronchial mass almost obstructing the right mainstem bronchus was seen on a computed tomography (CT) scan. He was diagnosed with squamous cell carcinoma of the lung and underwent radiotherapy and erlotinib chemotherapy. On repeat CT scan, there was no noted decrease in the size of the mass. EBBT was suggested, and a multi-disciplinary team was formed for the planned procedure. Pulmonology, radiation oncology, and anesthesiology teams were identified, and thorough planning was done prior to the actual procedure. Three fractions of EBBT were done under sedation using midazolam, fentanyl, and dexmedetomidine infusion. Lidocaine spray and transtracheal block were also performed as adjuncts prior to sedation. The procedure went as planned, and points for improvement were discussed for subsequent fractions. Due to persistent cough and discomfort from the catheter, additional ipratropium nebulization for minimization of secretions, and oral dextromethorphan for cough suppression were incorporated. After each fraction, the patient was monitored post-procedure for any side effects both from the radiotherapy and anesthetic technique. Qualitative reduction in mass size was noted in subsequent fractions. The patient was able to complete 3 fractions and was advised to follow-up after a month. EBBT is an emerging palliative and treatment modality for lung cancer, especially for intraluminal masses. Anesthetic considerations will depend on each case's characteristics such as airway anatomy, patient comfort and capacity, and procedural requirements. Conscious sedation with topical anesthesia is an adequate and appropriate anesthetic option, especially in cases where severe airway obstruction may compromise ventilation if airway reflexes are blunted. A multidisciplinary approach with different services and stakeholders is important for the proper planning, execution, and management of such patients., Competing Interests: All authors declared no conflicts of interest., (© 2024 Acta Medica Philippina.)

The intensification of the stress response during resistance training (R T ) under hypoxia conditions could trigger unwanted effects that compromise muscle health and, therefore, the ability of the muscle to adapt to longer training periods. We examined the effect of acute moderate terrestrial hypoxia on metabolic, inflammation, antioxidant capacity and muscle atrophy biomarkers after a single R T session in a young male population. Twenty healthy volunteers allocated to the normoxia (N < 700 m asl) or moderate altitude (HH = 2320 m asl) group participated in this study. Before and throughout the 30 min following the R T session (3 × 10 reps, 90 s rest, 70% 1RM), venous blood samples were taken and analysed for circulating calcium, inorganic phosphate, cytokines (IL-6, IL-10 and TNF-α), total antioxidant capacity (TAC) and myostatin. Main results displayed a marked metabolic stress response after the R T in both conditions. A large to very large proportional increase in the adjusted to pre-exercise change of inflammatory and anti-inflammatory markers favoured HH (serum TNF-α [ES = 1.10; p = 0.024] and IL-10 [ES = 1.31; p = 0.009]). The exercise produced a similar moderate increment of myostatin in both groups, followed by a moderate non-significant reduction in HH throughout the recovery (ES =  - 0.72; p = 0.21). The R T slightly increased the antioxidant response regardless of the environmental condition. These results revealed no clear impact of R T under acute hypoxia on the metabolic, TAC and muscle atrophy biomarkers. However, a coordinated pro/anti-inflammatory response balances the potentiated effect of R T on systemic inflammation., (© 2023. The Author(s).)

Introduction: Cytomegalovirus (CMV) is a common herpesvirus with a high prevalence worldwide. After the acute infection phase, CMV can remain latent in several tissues. CD8 T cells in the lungs and salivary glands mainly control its reactivation control. White adipose tissue (WAT) contains a significant population of memory T cells reactive to viral antigens, but CMV specificity has mainly been studied in mouse WAT. Therefore, we obtained blood, omental WAT (oWAT), subcutaneous WAT (sWAT), and liver samples from 11 obese donors to characterize the human WAT adaptive immune landscape from a phenotypic and immune receptor specificity perspective., Methods: We performed high-throughput sequencing of the T cell receptor (TCR) locus to analyze tissue and blood TCR repertoires of the 11 donors. The presence of TCRs specific to CMV epitopes was tested through ELISpot assays. Moreover, phenotypic characterization of T cells was carried out through flow cytometry., Results: High-throughput sequencing analyses revealed that tissue TCR repertoires in oWAT, sWAT, and liver samples were less diverse and dominated by hyperexpanded clones when compared to blood samples. Additionally, we predicted the presence of TCRs specific to viral epitopes, particularly from CMV, which was confirmed by ELISpot assays. Remarkably, we found that oWAT has a higher proportion of CMV-reactive T cells than blood or sWAT. Finally, flow cytometry analyses indicated that most WAT-infiltrated lymphocytes were tissue-resident effector memory CD8 T cells., Discussion: Overall, these findings postulate human oWAT as a major reservoir of CMV-specific T cells, presumably for latent viral reactivation control. This study enhances our understanding of the adaptive immune response in human WAT and highlights its potential role in antiviral defense., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Redruello-Romero, Benitez-Cantos, Lopez-Perez, García-Rubio, Tamayo, Pérez-Bartivas, Moreno-SanJuan, Ruiz-Palmero, Puentes-Pardo, Vilchez, López-Nevot, García, Cano, León and Carazo.)

The potential use of agomelatine as an alternative treatment for colorectal cancer is evaluated in this work. The effect of agomelatine was studied in an in vitro model using two cell lines with different p53 statuses (HCT-116, wild-type p53, and HCT-116 p53 null) and an in vivo xenograft model. The inhibitory effects of agomelatine and melatonin were stronger in the cells harboring the wild-type p53, although in both cell lines, the effect of agomelatine was greater than that of the melatonin. In vivo, only agomelatine was able to reduce the volumes of tumors generated by the HCT-116-p53-null cells. Both treatments induced changes in the rhythmicity of the circadian-clock genes in vitro, albeit with some differences. Agomelatine and melatonin regulated the rhythmicity of Per1-3, Cry1, Sirt1, and Prx1 in the HCT-116 cells. In these cells, agomelatine also regulated Bmal1 and Nr1d2, while melatonin changed the rhythmicity of Clock. In the HCT-116-p53-null cells, agomelatine regulated Per1-3, Cry1, Clock, Nr1d2, Sirt1, and Prx1; however, melatonin only induced changes in Clock, Bmal1, and Sirt1. The differences found in the regulation of the clock genes may explain the greater oncostatic effect of agomelatine in CRC.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a protein involved in multiple physiological processes. Elevated PARP-1 expression has been found in several tumours, being associated with stemness and tumorigenesis. In colorectal cancer (CRC), some controversy among studies has been described. In this study, we analysed the expression of PARP-1 and cancer stem cell (CSC) markers in CRC patients with different p53 status. In addition, we used an in vitro model to evaluate the influence of PARP-1 in CSC phenotype regarding p53. In CRC patients, PARP-1 expression correlated with the differentiation grade, but this association was only maintained for tumours harbouring wild-type p53. Additionally, in those tumours, PARP-1 and CSC markers were positively correlated. In mutated p53 tumours, no associations were found, but PARP-1 was an independent factor for survival. According to our in vitro model, PARP-1 regulates CSC phenotype depending on p53 status. PARP-1 overexpression in a wild type p53 context increases CSC markers and sphere forming ability. By contrast, those features were reduced in mutated p53 cells. These results could implicate that patients with elevated PARP-1 expression and wild type p53 could benefit from PARP-1 inhibition therapies, meanwhile it could have adverse effects for those carrying mutated p53 tumours.

Breast cancer (BC) is the most widespread tumor in women and the second type of most common cancer worldwide. Despite all the technical and medical advances in existing therapies, between 30 and 50% of patients with BC will develop metastasis, which contributes to the failure of existing treatments. This situation urges the need to find more effective prevention and treatment strategies like the use of plant-based nutraceutical compounds. In this context, we purified three Narrow Leafed Lupin (NLL) β-conglutins isoforms using affinity-chromatography and evaluated their effectiveness in terms of viability, proliferation, apoptosis, stemness properties, and mechanism of action on both BC cell lines and a healthy one. NLL β-conglutins proteins have very promising effects at the molecular level on BC cells at very low concentrations, emerging as a potential natural cytotoxic agent and preserving the viability of healthy cells. These proteins could act through a dual mechanism involving tumorigenic and stemness-related genes such as SIRT1 and FoxO1, depending on the state of p53. More studies must be carried out to completely understand the underlying mechanisms of action of these nutraceutical compounds in BC in vitro and in vivo, and their potential use for the inhibition of other cancer cell types.

Among living tetrapods, many lineages have converged on a snake-like body plan, where extreme axial elongation is accompanied by reduction or loss of paired limbs. However, when and how this adaptive body plan first evolved in amniotes remains poorly understood. Here, we provide insights into this question by reporting on a new taxon of molgophid recumbirostran, Nagini mazonense gen. et sp. nov., from the Francis Creek Shale (309-307 million years ago) of Illinois, United States, that exhibits extreme axial elongation and corresponding limb reduction. The molgophid lacks entirely the forelimb and pectoral girdle, thus representing the earliest occurrence of complete loss of a limb in a taxon recovered phylogenetically within amniotes. This forelimb-first limb reduction is consistent with the pattern of limb reduction that is seen in modern snakes and contrasts with the hindlimb-first reduction process found in many other tetrapod groups. Our findings suggest that a snake-like limb-reduction mechanism may be operating more broadly across the amniote tree., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Scientific practices stemming from colonialism, whereby middle- and low-income countries supply data for high-income countries and the contributions of local expertise are devalued, are still prevalent today in the field of palaeontology. In response to these unjust practices, countries such as Mexico and Brazil adopted protective laws and regulations during the twentieth century to preserve their palaeontological heritage. However, scientific colonialism is still reflected in many publications describing fossil specimens recovered from these countries. Here, we present examples of 'palaeontological colonialism' from publications on Jurassic-Cretaceous fossils from NE Mexico and NE Brazil spanning the last three decades. Common issues that we identified in these publications are the absence of both fieldwork and export permit declarations and the lack of local experts among authorships. In Mexico, access to many fossil specimens is restricted on account of these specimens being housed in private collections, whereas a high number of studies on Brazilian fossils are based on specimens illegally reposited in foreign collections, particularly in Germany and Japan. Finally, we outline and discuss the wider academic and social impacts of these research practices, and propose exhaustive recommendations to scientists, journals, museums, research institutions and government and funding agencies in order to overcome these practices., Competing Interests: We declare we have no competing interests., (© 2022 The Authors.)

Colorectal cancer (CRC) is one of the most common tumours in developed countries. Although its incidence and mortality rates have decreased, its prognosis has not changed, and a high percentage of patients with CRC develop relapse (metachronous metastasis, MM, or local recurrence, LR) during their disease. The identification of these patients is very important for their correct management, but the lack of prognostic markers makes it difficult. Given the connection between circadian disruption and cancer development and progression, we aimed to analyse the prognostic significance of core circadian proteins in CRC. We measured the expression of PER1-3, CRY1-2, BMAL1 and NR1D2 in a cohort of CRC patients by immunohistochemistry (IHC) and analysed their prognostic potential in this disease. A low expression of PER2 and BMAL1 was significantly associated with metastasis at the moment of disease diagnosis, whereas a high expression of CRY1 appeared as an independent prognostic factor of MM development. A high expression of NR1D2 appeared as an independent prognostic factor of LR development after disease diagnosis. Moreover, patients with a low expression of BMAL1 and a high expression of CRY1 showed lower OS and DFS at five years. Although these markers need to be validated in larger and different ethnic cohorts, the simplicity of IHC makes these proteins candidates for personalizing CRC treatment.

Heme oxygenase-1 (HO-1) is an antioxidant protein implicated in tumor progression, metastasis, and resistance to therapy. Elevated HO-1 expression is associated with stemness in several types of cancer, although this aspect has not yet been studied in colorectal cancer (CRC). Using an in vitro model, we demonstrated that HO-1 overexpression regulates stemness and resistance to 5-FU treatment, regardless of p53. In samples from CRC patients, HO-1 and endothelin converting enzyme-1 (ECE-1) expression correlated significantly, and p53 had no influence on this result. Carbon monoxide (CO) activated the ECE-1/endothelin-1 (ET-1) pathway, which could account for the protumoral effects of HO-1 in p53 wild-type cells, as demonstrated after treatment with bosentan (an antagonist of both ETRA and ETRB endothelin-1 receptors). Surprisingly, in cells with a non-active p53 or a mutated p53 with gain-of-function, ECE-1-produced ET-1 acted as a protective molecule, since treatment with bosentan led to increased efficiency for spheres formation and percentage of cancer stem cells (CSCs) markers. In these cells, HO-1 could activate or inactivate certain unknown routes that could induce these contrary responses after treatment with bosentan in our cell model. However more research is warranted to confirm these results. Patients carrying tumors with a high expression of both HO-1 and ECE-1 and a non-wild-type p53 should be considered for HO-1 based-therapies instead of ET-1 antagonists-based ones.

Type 2 diabetes (T2D) is a rising global health problem mainly caused by obesity and a sedentary lifestyle. In healthy individuals, white adipose tissue (WAT) has a relevant homeostatic role in glucose metabolism, energy storage, and endocrine signaling. Mast cells contribute to these functions promoting WAT angiogenesis and adipogenesis. In patients with T2D, inflammation dramatically impacts WAT functioning, which results in the recruitment of several leukocytes, including monocytes, that enhance this inflammation. Accordingly, the macrophages population rises as the WAT inflammation increases during the T2D status worsening. Since mast cell progenitors cannot arrive at WAT, the amount of WAT mast cells depends on how the new microenvironment affects progenitor and differentiated mast cells. Here, we employed a flow cytometry-based approach to analyze the number of mast cells from omental white adipose tissue (o-WAT) and subcutaneous white adipose tissue (s-WAT) in a cohort of 100 patients with obesity. Additionally, we measured the number of mast cell progenitors in a subcohort of 15 patients. The cohort was divided in three groups: non-T2D, pre-T2D, and T2D. Importantly, patients with T2D have a mild condition (HbA1c <7%). The number of mast cells and mast cell progenitors was lower in patients with T2D in both o-WAT and s-WAT in comparison to subjects from the pre-T2D and non-T2D groups. In the case of mast cells in o-WAT, there were statistically significant differences between non-T2D and T2D groups (p = 0.0031), together with pre-T2D and T2D groups (p=0.0097). However, in s-WAT, the differences are only between non-T2D and T2D groups (p=0.047). These differences have been obtained with patients with a mild T2D condition. Therefore, little changes in T2D status have a huge impact on the number of mast cells in WAT, especially in o-WAT. Due to the importance of mast cells in WAT physiology, their decrease can reduce the capacity of WAT, especially o-WAT, to store lipids and cause hypoxic cell deaths that will trigger inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lopez-Perez, Redruello-Romero, Garcia-Rubio, Arana, Garcia-Escudero, Tamayo, Puentes-Pardo, Moreno-SanJuan, Salmeron, Blanco, Galvez, Leon and Carazo.)

Immobilization of enzymes has been extensively required in a wide variety of industrial applications as a way to ensure functionality and the potential of enzyme recycling after use. In particular, enzyme immobilization on magnetic nanoparticles (MNPs) could offer reusability by means of magnetic recovery and concentration, along with increased stability and robust activity of the enzyme under different physicochemical conditions. In the present work, microbial α-amylase (AmyKS) and xylanase (XAn11) were both immobilized on different types of MNPs [MamC-mediated biomimetic MNPs (BMNPs) and inorganic MNPs] by using two different strategies (electrostatic interaction and covalent bond). AmyKS immobilization was successful using electrostatic interaction with BMNPs. Instead, the best strategy to immobilize XAn11 was using MNPs through the hetero-crosslinker 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N -hydroxysuccinimide (NHS). The immobilization protocols were optimized by varying glutaraldehyde (GA) concentration, enzyme quantity, and reaction time. Under optimal conditions, 92% of AmyKS and 87% of XAn11 were immobilized on BMNPs and MNPs-E/N, respectively (here referred as AmyKS-BMNPs and XAn11-MNPs nanoassemblies). The results show that the immobilization of the enzymes did not extensively alter their functionality and increased enzyme stability compared to that of the free enzyme upon storage at 4 and 20 °C. Interestingly, the immobilized amylase and xylanase were reused for 15 and 8 cycles, respectively, without significant loss of activity upon magnetic recovery of the nanoassemblies. The results suggest the great potential of these nanoassemblies in bioindustry applications., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Heme oxygenase 1 (HO-1) is the rate-limiting enzyme of heme oxidative degradation, generating carbon monoxide (CO), free iron, and biliverdin. HO-1, a stress inducible enzyme, is considered as an anti-oxidative and cytoprotective agent. As many studies suggest, HO-1 is highly expressed in the gastrointestinal tract where it is involved in the response to inflammatory processes, which may lead to several diseases such as pancreatitis, diabetes, fatty liver disease, inflammatory bowel disease, and cancer. In this review, we highlight the pivotal role of HO-1 and its downstream effectors in the development of disorders and their beneficial effects on the maintenance of the gastrointestinal tract health. We also examine clinical trials involving the therapeutic targets derived from HO-1 system for the most common diseases of the digestive system.

Recent efforts have led to the development of extremely sophisticated methods for incorporating tree-wide data and accommodating uncertainty when estimating the temporal patterns of phylogenetic trees, but assignment of prior constraints on node age remains the most important factor. This depends largely on understanding substantive disagreements between specialists (paleontologists, geologists, and comparative anatomists), which are often opaque to phylogeneticists and molecular biologists who rely on these data as downstream users. This often leads to misunderstandings of how the uncertainty associated with node age minima arises, leading to inappropriate treatments of that uncertainty by phylogeneticists. In order to promote dialogue on this subject, we here review factors (phylogeny, preservational megabiases, spatial and temporal patterns in the tetrapod fossil record) that complicate assignment of prior node age constraints for deep divergences in the tetrapod tree, focusing on the origin of crown-group Amniota, crown-group Amphibia, and crown-group Tetrapoda. We find that node priors for amphibians and tetrapods show high phylogenetic lability and different phylogenetic treatments identifying disparate taxa as the earliest representatives of these crown groups. This corresponds partially to the well-known problem of lissamphibian origins but increasingly reflects deeper instabilities in early tetrapod phylogeny. Conversely, differences in phylogenetic treatment do not affect our ability to recognize the earliest crown-group amniotes but do affect how diverse we understand the earliest amniote faunas to be. Preservational megabiases and spatiotemporal heterogeneity of the early tetrapod fossil record present unrecognized challenges in reliably estimating the ages of tetrapod nodes; the tetrapod record throughout the relevant interval is spatially restricted and disrupted by several major intervals of minimal sampling coincident with the emergence of all three crown groups. Going forward, researchers attempting to calibrate the ages for these nodes, and other similar deep nodes in the metazoan fossil record, should consciously consider major phylogenetic uncertainty, preservational megabias, and spatiotemporal heterogeneity, preferably examining the impact of working hypotheses from multiple research groups. We emphasize a need for major tetrapod collection effort outside of classic European and North American sections, particularly from the southern hemisphere, and suggest that such sampling may dramatically change our timelines of tetrapod evolution., (Copyright © 2020 Pardo, Lennie and Anderson.)

The transition from water to land by the earliest tetrapods in the Devonian Period is seen as one of the greatest steps in evolution. However, little is understood concerning changes in brain morphology over this transition. Here, we determine the brain-braincase relationship in fishes and basal lissamphibians as a proxy to elucidate the changes that occurred over the fish-tetrapod transition. We investigate six basal extant sarcopterygians spanning coelacanths to salamanders ( Latimeria chalumnae, Neoceratodus, Protopterus aethiopicus, P. dolloi, Cynops, Ambystoma mexicanum ) using micro-CT and MRI and quantify the brain-braincase relationship in these extant taxa. Our results show that regions of lowest brain-endocast disparity are associated with regions of bony reinforcement directly adjacent to masticatory musculature for the mandible except in Neoceratodus and Latimeria . In Latimeria this deviation from the trend can be accounted for by the possession of an intracranial joint and basicranial muscles, whereas in Neoceratodus difference is attributed to dermal bones contributing to the overall neurocranial reinforcement. Besides Neoceratodus and Latimeria, regions of low brain-endocast disparity occur where there is less reinforcement away from high mandibular muscle mass, where the trigeminal nerve complex exits the braincase and where endolymphatic sacs occupy space between the brain and braincase wall. Despite basal tetrapods possessing reduced adductor muscle mass and a different biting mechanism to piscine sarcopterygians, regions of the neurocranium lacking osteological reinforcement in the basal tetrapods Lethiscus and Brachydectes broadly correspond to regions of high brain-endocast disparity seen in extant taxa., Competing Interests: The authors declare no competing financial or non-financial interests., (© 2020 The Authors.)

Pancreatic cancer is one of the most lethal cancers worldwide due to its symptoms, early metastasis, and chemoresistance. Thus, the mechanisms contributing to pancreatic cancer progression require further exploration. Circadian rhythms are the daily oscillations of multiple biological processes regulated by an endogenous clock. Several evidences suggest that the circadian clock may play an important role in the cell cycle, cell proliferation and apoptosis. In addition, timing of chemotherapy or radiation treatment can influence the efficacy and toxicity treatment. Here, we revisit the studies on circadian clock as an emerging target for therapy in pancreatic cancer. We highlight those potential circadian genes regulators that are commonly affected in pancreatic cancer according to most recent reports., (Copyright © 2020 García-Costela, Escudero-Feliú, Puentes-Pardo, San Juán, Morales-Santana, Ríos-Arrabal, Carazo and León.)

An increasing concern for natural resources preservation and environmental safety is the removal of heavy metals from contaminated water. It is essential to develop simple procedures that use ecofriendly materials with high removal capacities. In this context, we have synthesized a new hybrid material in which eggshell membranes (ESMs) act as nucleation sites for magnetite nanoparticles (MNPs) precipitation in the presence of an external magnetic field. As a result, ESM was transformed into a magnetic biomaterial (MESM) in order to combine the Pb adsorption abilities of both MNPs and ESM and to facilitate collection of the bioadsorbant using an external magnetic field. This green co-precipitation method produced long strands of bead-like 50 nm superparamagnetic MNPs decorating the ESM fibers. When MESM were incubated in Pb(NO 3 ) 2 solutions, the hybrid material displayed a 2.5-fold increase in binding constant with respect to that of ESM alone, and a 10-fold increased capacity to remove Pb ions from aqueous solution. The manufactured MESMs present a maximum loading capacity of 0.066 ± 0.009 mg Pb/mg MNPs at 25 °C, which is increased up to 0.15 ± 0.05 mg Pb/mg MNPs at 45 °C. Moreover, the MESM system is very stable, since incubation in 1% HCl solution resulted in rapid Pb desorption, while MNP release from the MESM during the same period was negligible. Altogether, these results suggest that MESM could be utilized as an efficient nanoremediation agent for separation/removal of heavy metal ions or other charged pollutants from contaminated waters, with facile recovery for recycling., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Inc.)

The Carboniferous-Permian transition (CPT) was Earth's last pre-Quaternary icehouse-greenhouse transition, recording major shifts in late Palaeozoic climate regimes and increased continental seasonality over approximately 40 Myr. Its parallels to Quaternary climate change have inspired recent investigations into the impacts of purported rainforest collapse on palaeotropical vertebrate diversity, but little is known about how the protracted spatial dynamics of this transition impacted the emergence of modern tetrapod lineages. Here, we apply ecological ordinance analyses on a dataset of 286 CPT fossil vertebrate localities binned across four physiographic regions forming a palaeoequatorial transect. Our results clarify the spatiotemporal expansion of land-living vertebrates, demonstrating that the reduction of tropical wetlands accommodated emerging dryland-adapted amniote faunas from a western Pangaean epicentre. We call this west-east lag the 'Vaughn-Olson model': CPT climatic transitions were regionally diachronous with delayed proliferation of amniote-dominated dryland assemblages in the east. By combining our ecological analyses with a phylogenetic approach, we demonstrate that this pattern also applies to some co-occurring total-group amphibians, suggesting that there was pervasive selection for such dryland adaptations across the crown tetrapod tree, in contrast with stem tetrapods and 'fishes'.

Earliest Pennsylvanian (Bashkirian) vertebrate fossil assemblages of the Joggins Formation (Cumberland Group) of Nova Scotia, Canada, have long been noted for the unique representation of the earliest known crown amniotes, but the overall vertebrate fauna remains poorly understood. The vast majority of Joggins vertebrates have historically been assigned to the Microsauria, a group originally established by Dawson specifically to accommodate the abundant, diminutive fossils of the Joggins Formation. As the Microsauria concept has evolved, some Joggins taxa (e.g. the eureptile Hylonomus lyelli ) have been removed from the group, but many of the Joggins 'microsaurs' remain unrevised, obscuring the true diversity of the earliest Pennsylvanian tetrapod fauna. Here we amend part of this problem by revisiting the morphology of Dawson's 'microsaur' Hylerpeton longidentatum . This taxon, represented by the anterior half of a left hemimandible, is here reinterpreted as a plesiomorphic aïstopod and assigned to a new genus, Andersonerpeton . A. longidentatum shows a surprisingly primitive anatomy of the lower jaw, retaining a parasymphyseal fang pair on the dentary, an adsymphyseal bone bearing a denticle field, fangs on all coronoids and parasymphyseal foramina, as well as a prearticular which extends far anterior along the coronoid series. However, several aïstopod characters can also be seen, including a lack of sculpturing on the dentary and a reduced number of recurved, weakly socketed teeth. The anatomy of A. longidentatum corroborates recent phylogenetic work which has placed the origin of aïstopods within the Devonian fin-to-limb transition but preserves a mosaic of characteristics suggesting an even earlier divergence. The presence of an aïstopod in the Joggins fauna expands the taxonomic diversity of the Joggins fauna and suggests that Joggins may preserve a more typical Carboniferous fauna than previously thought., Competing Interests: All authors declare no competing interests.

The vertebrate fossil record of the earliest Carboniferous is notoriously poorly sampled, obscuring a critical interval in vertebrate evolution and diversity. Recent studies of diversity across the Devonian-Carboniferous boundary have proposed a vertebrate mass extinction at the end-Devonian, and recent phylogenies suggest that the origin of the actinopterygian crown may have occurred in the earliest Carboniferous, as part of a broader recovery fauna. However, the data necessary to test this are limited. Here, we describe a partial actinopterygian skull, including diagnostic elements of the posterior braincase, from the Tournaisian Horton Bluff Formation of Blue Beach, Nova Scotia. The braincase surprisingly shows a confluence of characters common in Devonian taxa but absent in Mississippian forms, such as an open spiracular groove; lateral dorsal aortae that pass through open broadly separated, parallel grooves in the ventral otoccipital region, posterior to the articulation of the first infrapharyngobranchial and an intertemporal-supratemporal complex. Phylogenetic analysis places it deep within the actinopterygian stem, among Devonian moythomasiids and mimiids, suggesting more phylogenetically inclusive survivorship of stem group actinopterygians across the end-Devonian mass extinction. With a high lineage survivorship in tetrapods and lungfish across the Devonian-Carboniferous boundary and high vertebrate diversity at Tournaisian localities, this hints at a more gradual turnover between Devonian and Carboniferous vertebrate faunas., Competing Interests: The authors declare no competing interests.

The origin of the limbless caecilians remains a lasting question in vertebrate evolution. Molecular phylogenies and morphology support that caecilians are the sister taxon of batrachians (frogs and salamanders), from which they diverged no later than the early Permian. Although recent efforts have discovered new, early members of the batrachian lineage, the record of pre-Cretaceous caecilians is limited to a single species, Eocaecilia micropodia The position of Eocaecilia within tetrapod phylogeny is controversial, as it already acquired the specialized morphology that characterizes modern caecilians by the Jurassic. Here, we report on a small amphibian from the Upper Triassic of Colorado, United States, with a mélange of caecilian synapomorphies and general lissamphibian plesiomorphies. We evaluated its relationships by designing an inclusive phylogenetic analysis that broadly incorporates definitive members of the modern lissamphibian orders and a diversity of extinct temnospondyl amphibians, including stereospondyls. Our results place the taxon confidently within lissamphibians but demonstrate that the diversity of Permian and Triassic stereospondyls also falls within this group. This hypothesis of caecilian origins closes a substantial morphologic and temporal gap and explains the appeal of morphology-based polyphyly hypotheses for the origins of Lissamphibia while reconciling molecular support for the group's monophyly. Stem caecilian morphology reveals a previously unrecognized stepwise acquisition of typical caecilian cranial apomorphies during the Triassic. A major implication is that many Paleozoic total group lissamphibians (i.e., higher temnospondyls, including the stereospondyl subclade) fall within crown Lissamphibia, which must have originated before 315 million years ago., Competing Interests: The authors declare no conflict of interest.

Phylogenetic analysis of early tetrapod evolution has resulted in a consensus across diverse data sets in which the tetrapod stem group is a relatively homogenous collection of medium- to large-sized animals showing a progressive loss of 'fish' characters as they become increasingly terrestrial, whereas the crown group demonstrates marked morphological diversity and disparity. The oldest fossil attributed to the tetrapod crown group is the highly specialized aïstopod Lethiscus stocki, which shows a small size, extreme axial elongation, loss of limbs, spool-shaped vertebral centra, and a skull with reduced centres of ossification, in common with an otherwise disparate group of small animals known as lepospondyls. Here we use micro-computed tomography of the only known specimen of Lethiscus to provide new information that strongly challenges this consensus. Digital dissection reveals extremely primitive cranial morphology, including a spiracular notch, a large remnant of the notochord within the braincase, an open ventral cranial fissure, an anteriorly restricted parasphenoid element, and Meckelian ossifications. The braincase is elongate and lies atop a dorsally projecting septum of the parasphenoid bone, similar to stem tetrapods such as embolomeres. This morphology is consistent in a second aïstopod, Coloraderpeton, although the details differ. Phylogenetic analysis, including critical new braincase data, places aïstopods deep on the tetrapod stem, whereas another major lepospondyl lineage is displaced into the amniotes. These results show that stem group tetrapods were much more diverse in their body plans than previously thought. Our study requires a change in commonly used calibration dates for molecular analyses, and emphasizes the importance of character sampling for early tetrapod evolutionary relationships.

Lysorophians are a group of early tetrapods with extremely elongate trunks, reduced limbs, and highly reduced skulls. Since the first discovery of this group, general similarities in outward appearance between lysorophians and some modern lissamphibian orders (specifically Urodela and Gymnophiona) have been recognized, and sometimes been the basis for hypotheses of lissamphibian origins. We studied the morphology of the skull, with particular emphasis on the neurocranium, of a partial growth series of the lysorophian Brachydectes newberryi using x-ray micro-computed tomography (μCT). Our study reveals similarities between the braincase of Brachydectes and brachystelechid recumbirostrans, corroborating prior work suggesting a close relationship between these taxa. We also describe the morphology of the epipterygoid, stapes, and quadrate in this taxon for the first time. Contra the proposals of some workers, we find no evidence of expected lissamphibian synapomorphies in the skull morphology in Brachydectes newberryi, and instead recognize a number of derived amniote characteristics within the braincase and suspensorium. Morphology previously considered indicative of taxonomic diversity within Lysorophia may reflect ontogenetic rather than taxonomic variation. The highly divergent morphology of lysorophians represents a refinement of morphological and functional trends within recumbirostrans, and is analogous to morphology observed in many modern fossorial reptiles., Competing Interests: The authors have declared that no competing interests exist.

Recumbirostran 'microsaurs,' a group of early tetrapods from the Late Carboniferous and Early Permian, are the earliest known example of adaptation to head-first burrowing in the tetrapod fossil record. However, understanding of the diversity of fossorial adaptation within the Recumbirostra has been hindered by poor anatomical knowledge of the more divergent forms within the group. Here we report the results of μCT study of Quasicaecilia texana, a poorly-known recumbirostran with a unique, broad, shovel-like snout. The organization of the skull roof and braincase of Quasicaecilia is found to be more in line with that of other recumbirostrans than previously described, despite differences in overall shape. The braincase is found to be broadly comparable to Carrolla craddocki, with a large presphenoid that encompasses much of the interorbital septum and the columella ethmoidalis, and a single compound ossification encompassing the sphenoid, otic, and occipital regions. The recumbirostran braincase conserves general structure and topology of braincase regions and cranial nerve foramina, but it is highly variable in the number of ossifications and their extent, likely associated with the reliance on braincase ossifications to resist compression during sediment compaction and mechanical manipulation by epaxial and hypaxial musculature. Expansion of the deep ventral neck musculature in Quasicaecilia, autapomorphic among recumbirostrans, may reflect unique biomechanical function, and underscores the importance of future attention to the role of the cervical musculature in contextualizing the origin and evolution of fossoriality in recumbirostrans.

The Early Permian recumbirostran lepospondyl Rhynchonkos stovalli has been identified as a possible close relative of caecilians due to general similarities in skull shape as well as similar robustness of the braincase, a hypothesis that implies the polyphyly of extant lissamphibians. In order to better assess this phylogenetic hypothesis, we studied the morphology of the holotype and three specimens previously attributed to R. stovalli. With the use of micro-computed x-ray tomography (μCT) we are able to completely describe the external and internal cranial morphology of these specimens, dramatically revising our knowledge of R. stovalli and recognizing two new taxa, Aletrimyti gaskillae gen et sp. n. and Dvellacanus carrolli gen et sp. n. The braincases of R. stovalli, A. gaskillae, and D. carrolli are described in detail, demonstrating detailed braincase morphology and new information on the recumbirostran supraoccipital bone. All three taxa show fossorial adaptations in the braincase, sutural articulations of skull roof bones, and in the lower jaw, but variation in cranial morphology between these three taxa may reflect different modes of head-first burrowing behaviors and capabilities. We revisit the homology of the supraoccipital, median anterior bone, and temporal bone of recumbirostrans, and discuss implications of alternate interpretations of the homology of these elements. Finally, we evaluate the characteristics previously used to unite Rhynchonkos stovalli with caecilians in light of these new data. These proposed similarities are more ambiguous than previous descriptions suggest, and result from the composite nature of previous descriptions, ambiguities in external morphology, and functional convergence between recumbirostrans and caecilians for head-first burrowing.

A recent discovery in membrane research is the ability of styrene-maleic acid (SMA) copolymers to solubilize membranes in the form of nanodisks allowing extraction and purification of membrane proteins from their native environment in a single detergent-free step. This has important implications for membrane research because it allows isolation as well as characterization of proteins and lipids in a near-native environment. Here, we aimed to unravel the molecular mode of action of SMA copolymers by performing systematic studies using model membranes of varying compositions and employing complementary biophysical approaches. We found that the SMA copolymer is a highly efficient membrane-solubilizing agent and that lipid bilayer properties such as fluidity, thickness, lateral pressure profile, and charge density all play distinct roles in the kinetics of solubilization. More specifically, relatively thin membranes, decreased lateral chain pressure, low charge density at the membrane surface, and increased salt concentration promote the speed and yield of vesicle solubilization. Experiments using a native membrane lipid extract showed that the SMA copolymer does not discriminate between different lipids and thus retains the native lipid composition in the solubilized particles. A model is proposed for the mode of action of SMA copolymers in which membrane solubilization is mainly driven by the hydrophobic effect and is further favored by physical properties of the polymer such as its relatively small cross-sectional area and rigid pendant groups. These results may be helpful for development of novel applications for this new type of solubilizing agent, and for optimization of the SMA technology for solubilization of the wide variety of cell membranes found in nature., (Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Complete, exceptionally-preserved skulls of the Permian lungfish Persephonichthys chthonica gen. et sp. nov. are described. Persephonichthys chthonica is unique among post-Devonian lungfishes in preserving portions of the neurocranium, permitting description of the braincase of a stem-ceratodontiform for the first time. The completeness of P. chthonica permits robust phylogenetic analysis of the relationships of the extant lungfish lineage within the Devonian lungfish diversification for the first time. New analyses of the relationships of this new species within two published matrices using both maximum parsimony and Bayesian inference robustly place P. chthonica and modern lungfishes within dipterid-grade dipnoans rather than within a clade containing Late Devonian 'phaneropleurids' and common Late Paleozoic lungfishes such as Sagenodus. Monophyly of post-Devonian lungfishes is not supported and the Carboniferous-Permian taxon Sagenodus is found to be incidental to the origins of modern lungfishes, suggesting widespread convergence in Late Paleozoic lungfishes. Morphology of the skull, hyoid arch, and pectoral girdle suggests a deviation in feeding mechanics from that of Devonian lungfishes towards the more dynamic gape cycle and more effective buccal pumping seen in modern lungfishes. Similar anatomy observed previously in 'Rhinodipterus' kimberyensis likely represents an intermediate state between the strict durophagy observed in most Devonian lungfishes and the more dynamic buccal pump seen in Persephonichthys and modern lungfishes, rather than adaptation to air-breathing exclusively.

A study was made of 14 thoracotomized dogs under i.v. sodium thiopental anesthesia; the effects of 1.5 mg/kg intravenous ATP on sinus node automatism and atrio-ventricular conduction were investigated. In 7 dogs (group A) ATP was administered under control conditions and following successive intravenous administrations of atropine (1 mg/kg), aminophylline (5 mg/kg) and propranolol (0.6 mg/kg). The remaining 7 dogs (group B) received ATP following atropine (1 mg/kg), isoproterenol (0.4 microgram/kg/min.), and aminophylline (5 mg/kg). An analysis was made of the percentage variations in cardiac cycle length during spontaneous rhythm and of the AH interval during atrial pacing at a fixed rate. In group A the negative dromotropic and chronotropic effects of ATP under control conditions decreased in 5 cases following atropine, although the average decrease was not statistically significant. On adding aminophylline, a statistically significant decrease was observed in the effects of ATP, and following propranolol the drop in negative chronotropic effect of ATP provoked by aminophylline was maintained. In group B, and following prior atropinization, the negative chronotropic and dromotropic effects of ATP were maintained in the presence of isoproterenol. As in group A, aminophylline significantly reduced the effects of ATP. To conclude: in the thoracotomized dog under sodium thiopental anesthesia, 1) atropine does not prevent the negative chronotropic and dromotropic actions of ATP, although the effect of the latter is decreased in a large percentage of cases; 2) sympathetic beta stimulation following prior atropinization does not prevent ATP action; 3) aminophylline in the atropinized dog noticeably reduces the effects of ATP, and 4) this action of aminophylline is effective in the presence of sympathetic beta stimulation.

Polyglactin and nylon suture material were compared in microsurgical anastomosis of oviduct of rabbits with regard to the histologic reaction, adhesion formation, and nidation index. Thirty days after surgery, the tissue inflammatory response was very similar in both groups. At 90 days, polyglactin had been totally absorbed in 80% of the cases, and no inflammatory reaction persisted at the site of the suture. At this time, multinucleated giant cell reaction to nylon sutures was persistent but minimal. The results reveal no significant functional differences between oviduct reanastomosed with nylon versus polyglactin suture. No significant difference in subsequent fertility due to suture selection was demonstrated.