Advances in surface design and biomedical applications of magnetic nanoparticles.

Despite significant efforts by scientists in the development of advanced nanotechnology materials for smart diagnosis devices and drug delivery systems, the success of clinical trials remains largely elusive. In order to address this biomedical challenge, magnetic nanoparticles (MNPs) have gained attention as a promising candidate due to their theranostic properties, which allow the simultaneous treatment and diagnosis of a disease. Moreover, MNPs have advantageous characteristics such as a larger surface area, high surface-to-volume ratio, enhanced mobility, mass transference and, more notably, easy manipulation under external magnetic fields. Besides, certain magnetic particle types based on the magnetite (Fe3O4) phase have already been FDA-approved, demonstrating biocompatible and low toxicity. Typically, surface modification and/or functional group conjugation are required to prevent oxidation and particle aggregation. A wide range of inorganic and organic molecules have been utilized to coat the surface of MNPs, including surfactants, antibodies, synthetic and natural polymers, silica, metals, and various other substances. Furthermore, various strategies have been developed for the synthesis and surface functionalization of MNPs to enhance their colloidal stability, biocompatibility, good response to an external magnetic field, etc. Both uncoated MNPs and those coated with inorganic and organic compounds exhibit versatility, making them suitable for a range of applications such as drug delivery systems (DDS), magnetic hyperthermia, fluorescent biological labels, biodetection and magnetic resonance imaging (MRI). Thus, this review provides an update of recently published MNPs works, providing a current discussion regarding their strategies of synthesis and surface modifications, biomedical applications, and perspectives.

Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology

Cutaneous squamous cell carcinoma (CSCC) accounts for ∼20%-25% of all skin tumors. Its precise incidence is often challenging to determine due to limited statistics and its incorporation with mucosal forms. While most cases have a favorable prognosis, challenges arise in patients presenting with locally advanced or metastatic forms, mainly appearing in immunocompromised patients, solid organ transplantation recipients, or those facing social difficulties. Traditionally, chemotherapy and targeted therapy were the mainstays for advanced cases, but recent approvals of immunotherapeutic agents like cemiplimab and pembrolizumab have revolutionized treatment options. These guidelines, developed by the Italian Association of Medical Oncologists (AIOM) using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, aim to guide clinicians in diagnosing, treating, and monitoring patients with CSCC, covering key aspects from primitive tumors to advanced stages, selected by a panel of experts selected by AIOM and other national scientific societies. The incorporation of these guidelines into clinical practice is expected to enhance patient care and address the evolving landscape of CSCC management.

Guidelines for the diagnosis and treatment of cutaneous squamous cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.

Cutaneous squamous cell carcinoma (CSCC) accounts for ∼20%-25% of all skin tumors. Its precise incidence is often challenging to determine due to limited statistics and its incorporation with mucosal forms. While most cases have a favorable prognosis, challenges arise in patients presenting with locally advanced or metastatic forms, mainly appearing in immunocompromised patients, solid organ transplantation recipients, or those facing social difficulties. Traditionally, chemotherapy and targeted therapy were the mainstays for advanced cases, but recent approvals of immunotherapeutic agents like cemiplimab and pembrolizumab have revolutionized treatment options. These guidelines, developed by the Italian Association of Medical Oncologists (AIOM) using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, aim to guide clinicians in diagnosing, treating, and monitoring patients with CSCC, covering key aspects from primitive tumors to advanced stages, selected by a panel of experts selected by AIOM and other national scientific societies. The incorporation of these guidelines into clinical practice is expected to enhance patient care and address the evolving landscape of CSCC management.

Guidelines for the diagnosis and treatment of basal cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology.

Basal cell carcinoma (BCC) is the most common form of cancer, with a high impact on the public health burden and social costs. Despite the overall prognosis for patients with BCC being excellent, if lesions are allowed to progress, or in a small subset of cases harboring an intrinsically aggressive biological behavior, it can result in local spread and significant morbidity, and conventional treatments (surgery and radiotherapy) may be challenging. When a BCC is not amenable to either surgery or radiotherapy with a reasonable curative intent, or when metastatic spread occurs, systemic treatments with Hedgehog inhibitors are available. These guidelines were developed, applying the GRADE approach, on behalf of the Italian Association of Medical Oncologists (AIOM) to assist clinicians in treating patients with BCC. They contain recommendations with regard to the diagnosis, treatment and follow-up, from primitive tumors to those locally advanced or metastatic, addressing the aspects of BCC management considered as priorities by a panel of experts selected by AIOM and other national scientific societies. The use of these guidelines in everyday clinical practice should improve patient care.

An in silico analysis of Ibuprofen enantiomers in high concentrations of sodium chloride with SARS-CoV-2 main protease.

2020 will be remembered worldwide for the outbreak of Coronavirus disease (COVID-19), which quickly spread until it was declared as a global pandemic. The main protease (Mpro) of SARS-CoV-2, a key enzyme in coronavirus, represents an attractive pharmacological target for inhibition of SARS-CoV-2 replication. Here, we evaluated whether the anti-inflammatory drug Ibuprofen, may act as a potential SARS-CoV-2 Mpro inhibitor, using an in silico study. From molecular dynamics (MD) simulations, we also evaluated the influence of ionic strength on the affinity and stability of the Ibuprofen-Mpro complexes. The docking analysis shows that R(-)Ibuprofen and S(+)Ibuprofen isomers can interact with multiple key residues of the main protease, through hydrophobic interactions and hydrogen bonds, with favourable binding energies (-6.2 and -5.7 kcal/mol, respectively). MM-GBSA and MM-PBSA calculations confirm the affinity of these complexes, in terms of binding energies. It also demonstrates that the ionic strength modifies significantly their binding affinities. Different structural parameters calculated from the MD simulations (120 ns) reveal that these complexes are conformational stable in the different conditions analysed. In this context, the results suggest that the condition 2 (0.25 NaCl) bind more tightly the Ibuprofen to Mpro than the others conditions. From the frustration analysis, we could characterize two important regions (Cys44-Pro52 and Linker loop) of this protein involved in the interaction with Ibuprofen. In conclusion, our findings allow us to propose that racemic mixtures of the Ibuprofen enantiomers might be a potential treatment option against SARS-CoV-2 Mpro. However, further research is necessary to determinate their possible medicinal use.Communicated by Ramaswamy H. Sarma.

Effects of locally applied Insulin-like Growth Factor-I on osseointegration.

BACKGROUND: The aim of this study was to assess the effect of local application of IGF-I on osseointegration of dental implants placed in osteoporotic bones. MATERIAL AND METHODS: 16 rabbits were randomly distributed into two groups: eight animals were ovariectomized and fed a low-calcium diet for six weeks, in order to induce experimental osteoporosis, and the others were sham-operated and fed a standard diet. A titanium implant was inserted into the tibiae in both groups. In half of the rabbits, 4 µg of IGF-I was applied into the ostectomy, prior to the implant insertion. A total of 32 implants were placed. Animals were sacrificed two weeks after surgery and decalcified samples were processed for Bone-To-Implant Contact (BIC) and Bone Area Density (BAD) measurements. Analysis of variance (ANOVA) was used for statistical evaluation. P<0.05 was considered to be significant. RESULTS: Ovariectomy induced statistically significant lower BAD values (p=0.008) and a tendency towards lower BIC values when compared osteoporotic and healthy groups. The administration of 4 µg of IGF-I did not produce statistically significant differences neither on BIC nor on BAD values, neither in the osteoporotic animals nor in healthy. CONCLUSIONS: Within the limitations of this experimental study, local administration of 4 µg of IGF-I was not able to induce any changes in the osseointegration process two weeks after surgery, neither in healthy rabbits nor in the osteoporotic group.

Effects of long-term administration of Lactobacillus reuteri DSM-17938 on circulating levels of 5-HT and BDNF in adults with functional constipation.

Accumulated evidence shows that some probiotic strains ameliorate functional constipation (FC) via the modulation of specific gastrointestinal peptide pathways. The aims of this study were to investigate: (1) the effects of long-term administration of Lactobacillus reuteri (LR) DSM 17938 on the serum levels of serotonin (5-HT) and brain-derived neurotrophic factor (BDNF); (2) the possible link between 5-HT, BDNF, and specific constipation-related symptoms; (3) whether genetic variability at the 5-HTT gene-linked polymorphic region (5-HTTLPR) and BDNF Val66Met loci could be associated with serum 5-HT and BDNF variations. LR DSM 17938 was administered to 56 FC patients for 105 days in a randomised, double-blind manner. The fasting blood samples were collected during the randomisation visit (V1), at day 15 (induction period, V2), day 60 (intermediate evaluation, V3), and day 105 (V4) and the Constipaq questionnaire (the sum of Constipation Scoring System (CSS) and patient assessment constipation quality of life (PAC-QoL)) was administered. A group of healthy subjects was enrolled as controls (HC). At V1, the mean serum 5-HT level in the whole patient group was significantly higher (P=0.027) than in HC subjects, while serum BDNF did not. At the end of probiotic administration (V4), 5-HT and BDNF levels were significantly lower than the initial values (V1) (P=0.008 and P=0.015, respectively). 5-HT and BDNF serum concentration were significantly associated (r=0.355; P=0.007). Neither 5-HT nor BDNF serum levels correlated with the CSS item scores and with the PAC-QoL. Lastly, the regression analysis demonstrated that the presence of the S allele of the 5-HTTLPR accounted for the reduction in the 5-HT concentration at V4. In conclusion, the long-term administration of LR DSM 17938 demonstrated that such a probiotic strain could improve FC by affecting 5-HT and BDNF serum concentrations.

The influence of speed and size on avian terrestrial locomotor biomechanics: Predicting locomotion in extinct theropod dinosaurs.

How extinct, non-avian theropod dinosaurs moved is a subject of considerable interest and controversy. A better understanding of non-avian theropod locomotion can be achieved by better understanding terrestrial locomotor biomechanics in their modern descendants, birds. Despite much research on the subject, avian terrestrial locomotion remains little explored in regards to how kinematic and kinetic factors vary together with speed and body size. Here, terrestrial locomotion was investigated in twelve species of ground-dwelling bird, spanning a 1,780-fold range in body mass, across almost their entire speed range. Particular attention was devoted to the ground reaction force (GRF), the force that the feet exert upon the ground. Comparable data for the only other extant obligate, striding biped, humans, were also collected and studied. In birds, all kinematic and kinetic parameters examined changed continuously with increasing speed, while in humans all but one of those same parameters changed abruptly at the walk-run transition. This result supports previous studies that show birds to have a highly continuous locomotor repertoire compared to humans, where discrete 'walking' and 'running' gaits are not easily distinguished based on kinematic patterns alone. The influences of speed and body size on kinematic and kinetic factors in birds are developed into a set of predictive relationships that may be applied to extinct, non-avian theropods. The resulting predictive model is able to explain 79-93% of the observed variation in kinematics and 69-83% of the observed variation in GRFs, and also performs well in extrapolation tests. However, this study also found that the location of the whole-body centre of mass may exert an important influence on the nature of the GRF, and hence some caution is warranted, in lieu of further investigation.

New sepsis criteria: do they replace or complement what is known in the approach to the infectious patient?

There have recently been profound changes in both the definitions of sepsis and septic shock and the diagnostic criteria established for daily clinical practice. In addition, a new screening tool known as qSOFA has been introduced to identify patients at risk of a poor short-term outcome. This score has been accompanied by some controversy due to presenting a lower sensitivity than the systemic inflammatory response criteria previously used to identify such patients. In this article, we shall summarise and analyse the most important recently published studies in relation to these new criteria.

Using step width to compare locomotor biomechanics between extinct, non-avian theropod dinosaurs and modern obligate bipeds.

How extinct, non-avian theropod dinosaurs locomoted is a subject of considerable interest, as is the manner in which it evolved on the line leading to birds. Fossil footprints provide the most direct evidence for answering these questions. In this study, step width-the mediolateral (transverse) distance between successive footfalls-was investigated with respect to speed (stride length) in non-avian theropod trackways of Late Triassic age. Comparable kinematic data were also collected for humans and 11 species of ground-dwelling birds. Permutation tests of the slope on a plot of step width against stride length showed that step width decreased continuously with increasing speed in the extinct theropods (p < 0.001), as well as the five tallest bird species studied (p < 0.01). Humans, by contrast, showed an abrupt decrease in step width at the walk-run transition. In the modern bipeds, these patterns reflect the use of either a discontinuous locomotor repertoire, characterized by distinct gaits (humans), or a continuous locomotor repertoire, where walking smoothly transitions into running (birds). The non-avian theropods are consequently inferred to have had a continuous locomotor repertoire, possibly including grounded running. Thus, features that characterize avian terrestrial locomotion had begun to evolve early in theropod history.

Melanocytic nevi and non-neoplastic hyperpigmentations.

This is the first of three chapters that will be progressively published on Pathologica as updating activity of the Italian Study Group of Dermatopathology (GISD), Italian Society of Pathology and Cytology (SIAPeC IAP). The first chapter concerns non-neoplastic hyperpigmented skin lesions and nevi, the second will address the topics of dysplastic nevus, borderline and low malignant potential melanocytic proliferations and the third melanoma in its variants and differential diagnoses with a supplement on the immunohistochemistry and molecular support to diagnostic and prognostic definition of nevi and melanomas. Although we believe that great advances were made in the application of ancillary genetic, immunohistochemical and molecular techniques, for the diagnosis and biological characterization of melanocytic tumors the morphology still remains the gold standard. These chapters are not intended as substitutes or even claim to be compared to the numerous and valuable texts that are also recently published, but they want to present, concisely and quickly available, all of those traits that we believe essential to the histopathological evaluation of a melanocytic lesion. No morphological parameter is exclusive and individually sufficient to make the correct diagnosis of nevus or melanoma but to reach a final conclusive and appropriate interpretation a set of morphological characters must be evaluated and compared. I was lucky enough to be able to examine several thousand cases and to draw lessons from each of these increasing my diagnostic experience. I had a great lesson by my teacher and good friend Prof. Martin C. Mihm Jr of Boston, dermato-pathologist with undisputed international reputation, who, with great passion, patience and friendship, transferred me much of his experience and knowledge and for which I always thank him. Special thanks I would like to address Dr. Agostino Crupi, dermatologist, skin-oncologist and brilliant dermatoscopist who taught me how the diagnosis of melanocytic lesions starts from the clinic examination and the mutual comparison between dermatologist and pathologist is a great richness of knowledge for both. Finally thank to my collaborators Barbara Rubino, Barbara Bruni and Antonella Festa for the large number of material collected in these years at the Pathology Service of the IRCCS Policlinico San Donato and a particular thank to Marco Turina who collaborated in the drafting of this text.

[International adoption of children from Ethiopia and language: a pilot study]. / Adopcion internacional de niños de Etiopia y lenguaje: un estudio piloto.

INTRODUCTION: Children who have gone through international adoption offer a great and unique learning opportunity around language development. Time elapsed since the first international adoptions took place in Spain has given a unique opportunity to research and conclude whether learning the second language follows the same developmental patterns and outcomes as compared to acquiring tongue language. AIM: To verify whether the evaluated subjects have reached the expected use and language proficiency for their chronological age. SUBJECTS AND METHODS: This pilot study focuses on the evaluation of language acquired in the first years of adolescence of 7 Ethiopian children who have lived over 8 years in Spain. CELF-4 test and the verbal tests of the WISC-IV have been administered. Scores have been analyzed and compared to the control group (same age group). In order to generate qualitative information about parents' concerns an on-line questionnaire has been administered in a form of a semi-structured interview. RESULTS: Both the CELF-4 test and the WISC-IV verbal tests reflect average or low average results in language abilities. Qualitative interviews reflect deep concern about academic outcome. CONCLUSIONS: Subjects in this study are showing an average to low average proficiency in the Spanish language. The results, nevertheless, do not explain the academic difficulties shown.

TITLE: Adopcion internacional de niños de Etiopia y lenguaje: un estudio piloto.Introduccion. Los niños que han vivido una adopcion internacional ofrecen una oportunidad unica de conocer como ocurre el desarrollo del lenguaje. El tiempo que ha transcurrido desde que en nuestro pais se iniciaran las primeras adopciones internacionales esta permitiendo investigar si el desarrollo inicial del lenguaje culmina en una equiparacion real. Objetivo. Comprobar si se ha producido en los sujetos evaluados una equiparacion real en el lenguaje de acuerdo con lo esperado con su edad cronologica. Sujetos y metodos. En este estudio piloto se realiza una valoracion del lenguaje adquirido en los primeros años de la adolescencia de siete niños etiopes que han vivido ya mas de ocho años en España. Para ello se analizan las puntuaciones obtenidas por los siete sujetos en la prueba CELF-4 y en las puntuaciones de las pruebas verbales del WISC-IV, teniendo como referencia a su grupo normativo de edad (grupo control). Para obtener informacion cualitativa sobre las preocupaciones de los padres se ha administrado un cuestionario online a traves de una entrevista semiestructurada. Resultados. Tanto el CELF-4 como las pruebas verbales del WISC-IV estan reflejando un funcionamiento promedio o promedio-bajo en las competencias verbales analizadas. Las entrevistas cualitativas reflejan elevados niveles de preocupacion acerca del rendimiento academico. Conclusiones. Los sujetos del estudio parecen mostrar un funcionamiento promedio o promedio bajo en el uso del castellano. Las puntuaciones obtenidas, sin embargo, no parecen poder explicar las dificultades que estan manifestando en el ambito escolar.

Balancing Biomechanical Constraints: Optimal Escape Speeds When There Is a Trade-off between Speed and Maneuverability.

The ability for prey to escape a pursuing predator is dependent both on the prey's speed away from the threat and on their ability to rapidly change directions, or maneuverability. Given that the biomechanical trade-off between speed and maneuverability limits the simultaneous maximization of both performance traits, animals should not select their fastest possible speeds when running away from a pursuing predator but rather a speed that maximizes the probability of successful escape. We explored how variation in the relationship between speed and maneuverability-or the shape of the trade-off-affects the optimal choice of speed for escaping predators. We used tablet-based games that simulated interactions between predators and prey (human subjects acting as predators attempting to capture "prey" moving across a screen). By defining a specific relationship between speed and maneuverability, we could test the survival of each of the possible behavioral choices available to this phenotype, i.e., the best combination of speed and maneuverability for prey fitness, based on their ability to escape. We found that the shape of the trade-off function affected the prey's optimal speed for success in escaping, the prey's maximum performance in escaping, and the breadth of speeds over which the prey's performance was high. The optimal speed for escape varied only when the trade-off between speed and maneuverability was non-linear. Phenotypes possessing trade-off functions for which maneuverability was only compromised at high speeds exhibited lower optimal speeds. Phenotypes that exhibited greater increases in maneuverability for any decrease in speed were more likely to have broader ranges of performance, meaning that individuals could attain their maximum performance across a broader range of speeds. We also found that there was a differential response of the subject's learning to these different components of locomotion. With increased experience through repeated trials, subjects were able to successfully catch faster and faster dots. However, no improvement was observed in the subject's ability to capture more maneuverable prey. Our work highlights the costs of high-speed movement on other traits, including maneuverability, which make the use of an animal's fastest speeds unlikely, even when attempting to escape predators. By investigating the shape of the trade-off functions between speed and maneuverability and the way the environment and morphology mediates this trade-off, we can begin to understand why animals choose to move at the speeds they do when they are running away from predators or attempting to capture prey.

Analysis of metallic traces from the biodegradation of endomedullary AZ31 alloy temporary implants in rat organs after long implantation times.

AZ31 alloy has been tested as a biodegradable material in the form of endomedullary implants in female Wistar rat femurs. In order to evaluate the accumulation of potentially toxic elements from the biodegradation of the implant, magnesium (Mg), aluminium (Al), zinc (Zn), manganese (Mn) and fluorine (F) levels have been measured in different organs such as kidneys, liver, lungs, spleen and brain. Several factors that may influence accumulation have been taken into account: how long the implant has been in place, whether or not the bone is fractured, and the presence of an MgF2 protective coating on the implant. The main conclusions and the clinical relevance of the study have been that AZ31 endomedullary implants have a degradation rate of about 60% after 13 months, which is fully compatible with fracture consolidation. Neither bone fracture nor an MgF2 coating seems to influence the accumulation of trace elements in the studied organs. Aluminium is the only alloying element in this study that requires special attention. The increase in Al recovered from the sampled organs represents 3.95% of the amount contained in the AZ31 implant. Al accumulates in a statistically significant way in all the organs except the brain. All of this suggests that in long-term tests AZ31 may be a suitable material for osteosynthesis.

Fracture bone healing and biodegradation of AZ31 implant in rats.

The ideal temporary implant should offer enough mechanical support to allow healing of the fracture and then biodegrade and be resorbed by metabolic mechanisms without causing any toxic effect. The aim of this research has been to simultaneously study in situ bone healing and the biodegradation of AZ31 Mg alloy as an osteosynthesis material. The in vivo study was carried out in AZ31 implants with and without Mg-fluoride coating inserted in un-fractured and fractured femurs of Wistar rats for long experimentation time, from 1 to 13 months, by means of computed tomography, histological and histomorphometric analysis. Tomography analysis showed the bone healing and biodegradation of AZ31 implants. The fracture is healed in 100% of the animals, and AZ31 maintains its mechanical integrity throughout the healing process. Biodegradation was monitored, quantifying the evolution of gas over time by 3D composition of tomography images. In all the studied groups, gas pockets disappear with time as a result of the diffusion process through soft tissues. Histomorphometric studies reveal that after 13 months the 46.32% of AZ31 alloy has been resorbed. The resorption of the coated and uncoated AZ31 implants inserted in fractured femurs after 1, 9 and 13 months does not have statistically significant differences. There is a balance between the biodegradation of AZ31 and bone healing which allows the use of AZ31 to be proposed as an osteosynthesis material.

Standardization and quality control of surgical treatment of cutaneous melanoma: looking for consensus of the Italian melanoma intergroup.

BACKGROUND: Quality of surgical care can be an important contributor to differences in survival among patients, and this suggests considerable potential for quality improvement in surgery of melanoma. Although clinical practice guidelines (CPG) for melanoma have been produced by various organizations, none address in detail some aspects of care related to surgery, and this brings about a quite heterogeneous surgical approach. Thus, Quality Assurance (QA) programs in melanoma surgery are essential. METHODS: Using the RAND/UCLA Appropriateness Method, an Italian panel of expert surgeons and pathologists belonging to the Italian Melanoma Intergroup (IMI) were invited to vote on statements regarding surgical treatment of melanoma and potential quality indicators for QA. All statements/indicators were scored for appropriateness and judged as valid in cases of 90% agreement. RESULTS: Consensus was obtained on 15 statements regarding indications for and extent of surgery (wide excision, sentinel node biopsy and lymphadenectomy) and on 7 QA indicators suitable to measure surgical performance for internal audit. CONCLUSIONS: The obtained consensus represents the basis to start a standardized QA program in Italy. The benchmark values of each indicator will be completed and updated according to the forthcoming results of the Clinical National Melanoma Registry (CNMR). Promoting a QA program at each IMI institution should increase the standard of care for melanoma patients in Italy.

Modelling human eye under blast loading.

Primary blast injury (PBI) is the general term that refers to injuries resulting from the mere interaction of a blast wave with the body. Although few instances of primary ocular blast injury, without a concomitant secondary blast injury from debris, are documented, some experimental studies demonstrate its occurrence. In order to investigate PBI to the eye, a finite element model of the human eye using simple constitutive models was developed. The material parameters were calibrated by a multi-objective optimisation performed on available eye impact test data. The behaviour of the human eye and the dynamics of mechanisms occurring under PBI loading conditions were modelled. For the generation of the blast waves, different combinations of explosive (trinitrotoluene) mass charge and distance from the eye were analysed. An interpretation of the resulting pressure, based on the propagation and reflection of the waves inside the eye bulb and orbit, is proposed. The peculiar geometry of the bony orbit (similar to a frustum cone) can induce a resonance cavity effect and generate a pressure standing wave potentially hurtful for eye tissues.

Form follows function: morphological diversification and alternative trapping strategies in carnivorous Nepenthes pitcher plants.

Carnivorous plants of the genus Nepenthes have evolved a striking diversity of pitcher traps that rely on specialized slippery surfaces for prey capture. With a comparative study of trap morphology, we show that Nepenthes pitcher plants have evolved specific adaptations for the use of either one of two distinct trapping mechanisms: slippery wax crystals on the inner pitcher wall and 'insect aquaplaning' on the wet upper rim (peristome). Species without wax crystals had wider peristomes with a longer inward slope. Ancestral state reconstructions identified wax crystal layers and narrow, symmetrical peristomes as ancestral, indicating that wax crystals have been reduced or lost multiple times independently. Our results complement recent reports of nutrient source specializations in Nepenthes and suggest that these specializations may have driven speciation and rapid diversification in this genus.

Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways.

The heart responds to sustained overload by hypertrophic growth in which the myocytes distinctly thicken or elongate on increases in systolic or diastolic stress. Though potentially adaptive, hypertrophy itself may predispose to cardiac dysfunction in pathological settings. The mechanisms underlying the diverse morphology and outcomes of hypertrophy are uncertain. Here we used a focal adhesion kinase (FAK) cardiac-specific transgenic mice model (FAK-Tg) to explore the function of this non-receptor tyrosine kinase on the regulation of myocyte growth. FAK-Tg mice displayed a phenocopy of concentric cardiac hypertrophy, reflecting the relative thickening of the individual myocytes. Moreover, FAK-Tg mice showed structural, functional and molecular features of a compensated hypertrophic growth, and preserved responses to chronic pressure overload. Mechanistically, FAK overexpression resulted in enhanced myocardial FAK activity, which was proven by treatment with a selective FAK inhibitor to be required for the cardiac hypertrophy in this model. Our results indicate that upregulation of FAK does not affect the activity of Src/ERK1/2 pathway, but stimulated signaling by a cascade that encompasses PI3K, AKT, mTOR, S6K and rpS6. Moreover, inhibition of the mTOR complex by rapamycin extinguished the cardiac hypertrophy of the transgenic FAK mice. These findings uncover a unique role for FAK in regulating the signaling mechanisms that governs the selective myocyte growth in width, likely controlling the activity of PI3K/AKT/mTOR pathway, and suggest that FAK activation could be important for the adaptive response to increases in cardiac afterload. This article is part of a Special Issue entitled "Local Signaling in Myocytes".