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In this paper, the recently proposed structural optimization strategy, the Galilei-Optimization (GO), is adapted for improving the toughness response of a holed two-dimensional lattice system made of a network of micro-beams whose geometrical arrangement was prescribed. By taking advantage of the possibility of minimizing stress gradients and stress peaks around the hole via GO, we redesigned the cross sections of the lattice beam elements, equalizing the stresses over the entire domain. Consequently, the resulting optimized microstructure highlighted a significant enhancement of the overall toughness due to a drastic decrease of the stress concentration factor in the hole proximity, preserving the initial stiffness and lowering the total overall weight. To validate the robustness of the procedure and the numerical Finite Element outcomes, two non-optimized and optimized structures were actually built up through 3D printing and tested in the laboratory under the same boundary conditions used for the simulations. This evidence confirmed the effectiveness of the proposed method in obtaining optimized beam-like plates with high toughness, which could pave the way for designing new light materials with extreme mechanical performance well beyond the sole stiffness and strength.

Abstract The rechallenge strategy is based on the concept that a subset of patients with RAS wild‐type (WT) metastatic colorectal cancer (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti‐EGFR based‐therapy. We performed a pooled analysis of two‐phase II prospective trials to determine the role of rechallenge in third‐line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from CAVE and CRICKET trials that received as third‐line therapy cetuximab rechallenge were collected. Overall survival (OS), Progression‐free survival (PFS), Overall response rate (ORR), Stable disease (SD) >6 months were calculated. Adverse events were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95% Confidence Interval, CI 3.0–4.9) with median OS (mOS) of 16.9 months (95% CI 11.7–22.1). For CRICKET patients, mPFS was 3.9 months (95% CI 1.7–6.2); mOS was 13.1 months (95% CI 7.3–18.9) with OS rates at 12, 18, and 24 months of 62%, 23%, and 0%, respectively. For CAVE patients, mPFS was 4.1 months (95% CI 3.0–5.2); mOS was 18.6 months (95% CI 11.7–25.4) with OS rates at 12, 18, 24 months of 61%, 52%, 21%, respectively. Skin rash was more frequently reported in CAVE trial (87.9% vs. 30.8%; p = 0.001), whereas a increased incidence of hematological toxicities was observed in CRICKET trial (53.8%% vs. 12.1%; p = 0.003). Third‐line cetuximab rechallenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy.

ABSTRACTThis study presents an original mapping of hydrological karst features of the Matese massif (southern Italy), whose relevance is given by large basal springs supplying millions of people and the hydroelectric exploitation of the major endorheic areas. We mapped dolines and endorheic areas from 1- and 5-meter Digital Elevation Models (DEM) using Geographic Information System (GIS) tools and techniques. Instead, ponors, caves, and karst springs were mapped mainly based on cartographic and literature analyses. We identified 321 endorheic areas occupying 31% of the massif area and 489 dolines, distinguished in (i) solution (N = 433) and collapse dolines (N = 56), the latter located in the discharge zones of the massif and connected to ascendant flows of CO2- and H2S-rich groundwater. The map shows the hydrological features of a karst massif from a more detailed and new perspective, and it can be helpful in water management, groundwater resource protection, environmental safeguarding, and ecological development.

The LHC heavy-ion program with ^{208}Pb^{82+} beams will benefit from a significant increase of the beam intensity when entering its high-luminosity era in Run 3 (2023). The stored energy is expected to surpass 20 MJ per beam. The LHC is equipped with a betatron collimation system, which intercepts the transverse beam halo and protects sensitive equipment such as superconducting magnets against beam losses. However, nuclear fragmentation and electromagnetic dissociation of ^{208}Pb^{82+} ions in collimators generates a flux of secondary fragments, which are lost in downstream dispersion suppressor and arc cells. These secondary ions may pose a performance limitation in upcoming runs since they can induce magnet quenches. In order to mitigate this risk, an alternative collimation technique, relying on bent crystals as primary collimators, will be used in forthcoming heavy-ion runs. In this paper, we study the power deposition in superconducting magnets by means of tracking and fluka shower simulations, comparing the standard collimation system against the crystal-based one. In order to quantify the predictive ability of the simulation model, we present absolute benchmarks against beam loss monitor measurements from the 2018 ^{208}Pb^{82+} run at 6.37 ZTeV. The benchmarks cover several hundred meters of beamline, from the primary collimators to the first arc cells. Based on these studies, we provide a detailed analysis of ion fragmentation and leakage to the cold magnets and quantify the expected quench margin in future ^{208}Pb^{82+} runs.

The aim of the present study was to investigate the culturable microflora of pool frogs (Pelophylax lessonae) and their belonging aquatic environment. A total of 60 samples (56 frog cutaneous swabs, 4 water samples) were inoculated onto different selective and differential agar plates to isolate Gram-positive and Gram-negative bacteria or yeasts. Microbial investigation of the water hosting frogs was also performed. Isolates were identified by API system and their antibiotic resistance profiles were evaluated by disk diffusion method on Mueller Hinton agar plates. Aeromonas hydrophila and En-terococcus durans were detected in almost all collected samples. Many of the bacterial isolates showed multidrug-resistant profiles. Importantly, this study highlights that skin frog microbiota is correlated to the belonging environment, and, moreover, some isolated bacterial strains resulted to be of interest in animal and public health, since the park was frequented by visitors of all ages.

Reconstruction after excision of infiltrating basal cell carcinomas (BCCs) of the upper pole of the ear can be achieved with different techniques. The concept of spare-part surgery, which allows the surgeon to perform primary reconstruction of a defect without harvesting tissue from the adjacent areas, has been applied to the ear anatomy. We describe our experience with the use of a fillet flap from the residual external ear in two patients out of a series of six, undergoing reconstruction of ear defects after infiltrating BCC resection between January 2011 and December 2014. Reconstruction with the fillet of pinna flap was proven to be an easy surgical technique with good functional and cosmetic outcomes. Our technique, not previously reported, enhances the versatility of ear reconstruction.

Total Hip Arthroplasty has been one of the most successful surgical procedure in terms of patient outcomes and satisfaction. However, due to increase in life expectancy and the related incidence of age-dependent bone diseases, a growing number of cases of intra-operative fractures lead to revision surgery with high rates of morbidity and mortality. Surgeons choose the type of the implant, either cemented or cementless prosthesis, on the basis of the age, the quality of the bone and the general medical conditions of the patients. Generally, no quantitative measures are available to assess the intra-operative fracture risk. Consequently, the decision-making process is mainly based on surgical operators’ expertise and qualitative information obtained from imaging. Motivated by this scenario, we here propose a mechanical-supported strategy to assist surgeons in their decisions, by giving intelligible maps of the risk fracture which take into account the interplay between the actual mechanical strength distribution inside the bone tissue and its response to the forces exerted by the implant. In the presented study, we produce charts and patient-specific synthetic “traffic-light” indicators of fracture risk, by making use of ad hoc analytical solutions to predict the stress levels in the bone by means of Computed Tomography-based mechanical and geometrical parameters of the patient. We felt that if implemented in a friendly software or proposed as an app, the strategy could constitute a practical tool to help the medical decision-making process, in particular with respect to the choice of adopting cemented or cementless implant.

The data produced at the particle physics experiments at the Large Hadron Collider (LHC) contain not only the signals from the collisions, but also a background component from proton losses around the accelerator. Understanding, identifying and possibly mitigating this machine-induced background is essential for an efficient data taking, especially for some new physics searches. Among the sources of background are hadronic and electromagnetic showers from proton losses on nearby collimators due to beam-halo cleaning. In this article, the first dedicated LHC measurements of this type of background are presented. Controlled losses of a low-intensity beam on collimators were induced, while monitoring the backgrounds in the ATLAS detector. The results show a clear correlation between the experimental backgrounds and the setting of the tertiary collimators (TCTs). Furthermore, the results are used to show that during normal LHC physics operation the beam halo contributes to the total beam-induced background at the level of a percent or less. A second measurement, where the collimator positions are tightened during physics operation, confirms this finding by setting a limit of about 10% to the contribution from all losses on the TCTs, i.e. the sum of beam halo and elastic beam-gas scattering around the ring. Dedicated simulations of the halo-related background are presented and good agreement with data is demonstrated. These simulations provide information about features that are not experimentally accessible, like correlations between backgrounds and the distributions of proton impacts on the collimators. The results provide vital information about the dependence between background and collimator settings, which is of central importance when optimizing the LHC optics for maximum peak luminosity.

In vitro embryo production (IVEP) is largely applied world wide to animal breeding. One of the principal steps of the IVEP is represented by embryo culture (Khurana and Niemann., 2000). In the past, embryos were grown in co-culture systems with other cells such as oviductal epithelial cells, cumulus cells, Buffalo rat liver (BRL) and VERO cells (Duszewska et al., 2000). These cells are able to supply the nutrients for embryo development by their replication and metabolism. Nevertheless, the metabolic activity of these cells is also responsible of an early lowering of pH in the culture medium: that needs to be changed every two days. Furthermore, with this culture system it is impossible to standardize all the procedure: in fact the result is dependent from several variables, as the quality of the cells and their concentration in co-culture. The use of defined culture media is necessary to acquire a better comprehension of metabolism and biochemical requirements for IVEP........

Solid biomass is often mixed with coal for cofiring in power plants to reduce greenhouse gases emissions. The resulting powder mixtures can give rise to handling and feeding problems due to the occurrence of intermittent flow or blockage. In this paper the flow properties of mixtures of a coal-petcoke powder and two types of biomass materials, dried olive husk (OH) and grape seed meal (GSM), were studied. The most significant effects on the cohesive properties of some powder mixtures were found for low biomass content mixtures due to their higher fraction of fine particles.

Although diffusional flow creep is often considered out of practical engineering applications, the need for a model capable to account for the resulting action of both diffusional and dislocation type creep is justified by the increasing demands of reliable creep design for very long lives (exceeding lOO.OOOh), high stress-low temperatures and high temperature-low stress regimes. In this paper, a creep model formulation, in which the change of the creep mechanism has been accounted for through an explicit dependence of the creep exponent n on stress and temperature, has been proposed. An application example of the proposed approach to high purity aluminum is given.

BackgroundBiventricular failure is associated with high in‐hospital mortality. Limited data regarding the efficacy of biventricular Impella axial flow catheters (BiPella) support for biventricular failure exist. The aim of this study was to explore the clinical utility of percutaneously delivered BiPella as a novel acute mechanical support strategy for patients with cardiogenic shock complicated by biventricular failure. Methods and ResultsWe retrospectively analyzed data from 20 patients receiving BiPella for biventricular failure from 5 tertiary‐care hospitals in the United States. Left ventricular support was achieved with an Impella 5.0 (n=8), Impella CP (n=11), or Impella 2.5 (n=1). All patients received the Impella RP for right ventricular (RV) support. BiPella use was recorded in the setting of acute myocardial infarction (n=11), advanced heart failure (n=7), and myocarditis (n=2). Mean flows achieved were 3.4±1.2 and 3.5±0.5 for left ventricular and RV devices, respectively. Total in‐hospital mortality was 50%. No intraprocedural mortality was observed. Major complications included limb ischemia (n=1), hemolysis (n=6), and Thrombolysis in Myocardial Infarction major bleeding (n=7). Compared with nonsurvivors, survivors were younger, had a lower number of inotropes or vasopressors used before BiPella, and were more likely to have both devices implanted simultaneously during the same procedure. Compared with nonsurvivors, survivors had lower pulmonary artery pressures and RV stroke work index before BiPella. Indices of RV afterload were quantified for 14 subjects. Among these patients, nonsurvivors had higher pulmonary vascular resistance (6.8; 95% confidence interval [95% CI], 5.5–8.1 versus 1.9; 95% CI, 0.8–3.0; P

Cardiogenic shock (CS) remains a major cause of in-hospital mortality in the setting of acute myocardial infarction. CS begins as a hemodynamic problem with impaired cardiac output leading to reduced systemic perfusion, increased residual volume within the left and right ventricles, and increased cardiac filling pressures. A critical step towards the development of future algorithms is a clear understanding of the treatment objectives for CS. In this review, we introduce the “door to support” time as an emerging target of therapy to improve outcomes associated with CS, define four key treatment objectives in the management of CS, discuss the importance of early hemodynamic assessment and appropriate selection of acute mechanical circulatory support (AMCS) devices for CS, and introduce a classification scheme that identifies subtypes of CS based on cardiac filling pressures.

Unholy War:. Terror in the Name of Islam, by John L. Esposito. New York, London: Oxford University Press, 2002, 196 pp., $25. In the wake of the terrorist assaults on [...]

AbstractBackground: Several reports indicate a decreased cortisol response to adrenocorticotropic hormone in preterm infants developing chronic lung disease and in preterm infants with refractory hypotension. Low-dose hydrocortisone (HC) may allow for beneficial effects. Objective: Our aim was to assess whether HC is able to increase survival without chronic lung disease. Methods: We performed a double-blind, randomized, placebo-controlled trial. Fifty mechanically ventilated infants (birth weight: 500–1,249 g) were randomized to receive treatment (HC 0.5 mg/kg/12 h for 9 days, then HC 0.5 mg/kg/24 h for 3 days) or placebo. Major outcome was survival without oxygen dependence at 36 weeks of postconceptional age (O2-free survival). Results: The basic characteristics were similar between the two groups. O2-free survival was higher in the HC group (64 vs. 32%). The advantage was particularly evident among infants without antenatal steroids. The mortality rate was 16% in the HC group versus 40% in the control group (difference not significant). Hypotension after recruitment was reduced by HC (0 vs. 30%). The incidence of gastrointestinal perforation and other adverse effects was similar between the two groups. Conclusions: HC prophylaxis improved O2-free survival and early cardiocirculatory function in our population, without important short-term effects. The neurodevelopmental outcome will be assessed at 2 years.Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The identification of new effective therapeutic options for non-small-cell lung cancer (NSCLC) represents a crucial challenge in oncology. Recent studies indicate that cancer-associated fibroblasts (CAFs) participate in tumor progression by establishing a favorable microenvironment that promotes cancer progression. Therefore, the development of strategies inhibiting the interplay between CAFs and cancer cells is considered a winning approach for the development of effective anti-cancer drugs. Among other factors, the signal transducer and activator of transcription-3 (STAT3) has been reported as a key mediator of CAF oncogenic actions, representing a promising therapeutic target. Here, we applied an aptamer-based conjugate (named Gint4.T-STAT3), containing a STAT3 siRNA linked to an aptamer binding and inhibiting the platelet-derived growth factor receptor (PDGFR)β, to obtain STAT3-specific silencing and interfere with CAF pro-tumorigenic functions. We demonstrated that this molecule effectively delivers the STAT3 siRNA in NSCLC cells, and blocks CAF-induced cancer cell growth and migration and reduced spheroid dimension. In addition, we found that Gint4.T-STAT3 alters CAF phenotype, thus functioning as a double-acting molecule able to inhibit the entire tumor bulk. Our data provide a proof of principle for the targeting of CAF pro-tumor functions through an aptamer-based drug, and can open innovative horizons in NSCLC therapy.

We present the growth of self-assisted GaAs nanowires (NWs) with selectable number density on bare Si(1 1 1), not covered by the silicon oxide. We determine the number density of the NWs by initially self-assembling GaAs islands on whose top a single NW is nucleated. The number density of the initial GaAs base islands can be tuned by droplet epitaxy and the same degree of control is then transferred to the NWs. This procedure is completely performed during a single growth in an ultra-high vacuum environment and requires neither an oxide layer covering the substrate, nor any pre-patterning technique. [ABSTRACT FROM AUTHOR]

Here the authors generate an RNA-based platform to neutralize the major epigenetic player DNMT1. Using this targeted approach, aberrant DNA methylation in cancer can be corrected.

The transmembrane glycoprotein cluster of differentiation 19 (CD19) is a B cell–specific surface marker, expressed on the majority of neoplastic B cells, and has recently emerged as a very attractive biomarker and therapeutic target for B-cell malignancies. The development of safe and effective ligands for CD19 has become an important need for the development of targeted conventional and immunotherapies. In this regard, aptamers represent a very interesting class of molecules. Additionally referred to as ‘chemical antibodies’, they show many advantages as therapeutics, including low toxicity and immunogenicity. Here, we isolated a nuclease-resistant RNA aptamer binding to the human CD19 glycoprotein. In order to develop an aptamer also useful as a carrier for secondary reagents, we adopted a cell-based SELEX (Systematic Evolution of Ligands by EXponential Enrichment) protocol adapted to isolate aptamers able to internalise upon binding to their cell surface target. We describe a 2′-fluoro pyrimidine modified aptamer, named B85.T2, which specifically binds to CD19 and shows an exquisite stability in human serum. The aptamer showed an estimated dissociation constant (KD) of 49.9 ± 13 nM on purified human recombinant CD19 (rhCD19) glycoprotein, a good binding activity on human B-cell chronic lymphocytic leukaemia cells expressing CD19, and also an effective and rapid cell internalisation, thus representing a promising molecule for CD19 targeting, as well as for the development of new B-cell malignancy-targeted therapies.

1,3:2,4-Dibenzylidene-D-sorbitol (DBS) and 12-hydroxystearic acid (12-HSA) are well-known as low-molecular-weight organogelators (LMOGs) capable of gelling an organic liquid phase. Considering their unique chemical and physical properties, we assessed their potential effects in new lipstick formulations by discrimination testing; in vitro measurements of the sun protection factor (SPF); and thermal, mechanical and texture analyzes. DBS and 12-HSA were used to formulate four types of lipsticks: L1 (1% DBS), L2 (10% 12-HSA), L3 (1.5% DBS) and L4 (control, no LMOGs). The lipsticks were tested for sensory perception with an untrained panel of 16 consumers. LMOG formulations exhibited higher UVA protection factor (UVA-PF) and in vitro SPF, particularly in the 12-HSA-based lipstick. Regarding thermal properties, the 12-HSA-based lipstick and those without LMOGs were more heat-amenable compared to thermoresistant DBS-based lipsticks. The results also showed the viscoelastic and thermally reversible properties of LMOGs and their effect of increasing pay-off values. In general, the texture analysis indicated that 12-HSA-based lipstick was significantly harder to bend compared to control, while the other formulations became softer and easier to bend throughout the stability study. This work suggests the potential use of LMOGs as a structuring agent for lipsticks, paving the way towards more photoprotective and sustainable alternatives.

Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer worldwide, with the highest incidence in developed countries. NSCLC patients often face resistance to currently available therapies, accounting for frequent relapses and poor prognosis. Indeed, despite great recent advancements in the field of NSCLC diagnosis and multimodal therapy, most patients are diagnosed at advanced metastatic stage, with a very low overall survival. Thus, the identification of new effective diagnostic and therapeutic options for NSCLC patients is a crucial challenge in oncology. A promising class of targeting molecules is represented by nucleic-acid aptamers, short single-stranded oligonucleotides that upon folding in particular three dimensional (3D) structures, serve as high affinity ligands towards disease-associated proteins. They are produced in vitro by SELEX (systematic evolution of ligands by exponential enrichment), a combinatorial chemistry procedure, representing an important tool for novel targetable biomarker discovery of both diagnostic and therapeutic interest. Aptamer-based approaches are promising options for NSCLC early diagnosis and targeted therapy and may overcome the key obstacles of currently used therapeutic modalities, such as the high toxicity and patients’ resistance. In this review, we highlight the most important applications of SELEX technology and aptamers for NSCLC handling.

Tumor mass consists of a complex ensemble of malignant cancer cells and a wide variety of resident and infiltrating cells, secreted factors, and extracellular matrix proteins that are referred as tumor microenvironment (TME). Cancer associated fibroblasts (CAFs) are key TME components that support tumor growth, generating a physical barrier against drugs and immune infiltration, and contributing to regulate malignant progression. Thus, it is largely accepted that therapeutic approaches aimed at hampering the interactions between tumor cells and CAFs can enhance the effectiveness of anti-cancer treatments. In this view, nucleic acid therapeutics have emerged as promising molecules. Here, we summarize recent knowledge about their role in the regulation of CAF transformation and tumor-promoting functions, highlighting their therapeutic utility and challenges.

The global threat of Al Qaeda post 9/11 and ISIL, increased Sunni-Shia conflicts, and violence in the Middle East and Pakistan dominate headlines and challenge governments in the region and globally. Both Muslim extremists and some Western experts and observers speak of a clash of civilizations or a culture war in Muslim-West relations. Both the discourse and violence yet again raise questions about the relationship of Islam to violence and terrorism: is Islam a particularly violent religion? Critics cite Quranic passages, doctrines like jihad and events in Muslim history as strong indicators and proof that Islam is the primary driver of Muslim extremism and terrorism. What do the Quran and Islamic law have to say about violence, jihad and warfare? What are the primary drivers of terrorism in the name of Islam today? This article will address these questions in the context of development of global jihadist movements, in particular Al Qaeda and ISIL, their roots, causes, ideology and agenda.

MicroRNAs (miRNAs) are short non-protein-coding RNA molecules that regulate the expression of a wide variety of genes. They act by sequence-specific base pairing in the 3’ untranslated region (3’UTR) of the target mRNA leading to mRNA degradation or translation inhibition. Recent studies have implicated miRNAs in a wide range of biological processes and diseases including development, metabolism and cancer, and revealed that expression levels of individual miRNAs may serve as reliable molecular biomarkers for cancer diagnosis and prognosis. Therefore, a major challenge is to develop innovative tools able to couple high sensitivity and specificity for rapid detection of miRNAs in a given cell or tissue. In this review, we focus on the latest innovative approaches proposed for miRNA profiling in cancer and discuss their advantages and disadvantages.

The selective delivery of drugs in a cell- or tissue-specific manner represents the main challenge for medical research; in order to reduce the occurrence of unwanted off-target effects. In this regard, nucleic acid aptamers have emerged as an attractive class of carrier molecules due to their ability to bind with high affinity to specific ligands; their high chemical flexibility; as well as tissue penetration capability. To date, different aptamer-drug systems and aptamer–nanoparticles systems, in which nanoparticles function together with aptamers for the targeted delivery, have been successfully developed for a wide range of therapeutics, including toxins; peptides; chemotherapeutics and oligonucleotides. Therefore, aptamer-mediated drug delivery represents a powerful tool for the safe and effective treatment of different human pathologies, including cancer; neurological diseases; immunological diseases and so on. In this review, we will summarize recent progress in the field of aptamer-mediated drug delivery and we will discuss the advantages, the achieved objectives and the challenges to be still addressed in the near future, in order to improve the effectiveness of therapies.

Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R. Analysis of IRS1 immunostaining in 24 cases of primary CRC with paired colonic epithelium and hepatic metastasis showed that staining intensity was significantly higher in metastases relative to both primary CRC (P

Human studies of therapeutic angiogenesis, stem-cell, and progenitor-cell therapy have failed to demonstrate consistent clinical benefit. Recent studies have shown that heparin increases circulating levels of anti-angiogenic peptides. Given the widely prevalent use of heparin in percutaneous and surgical procedures including those performed as part of studies examining the benefit of therapeutic angiogenesis and cell-based therapy, we compared the effects of unfractionated heparin (UFH) on angiogenic peptides with those of bivalirudin, a relatively newer anticoagulant whose effects on angiogenic peptides have not been studied.We measured soluble fms-like tyrosine kinase-1 (sFLT1), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble Endoglin (sEng) serum levels by enzyme linked immunosorbent assays (ELISA) in 16 patients undergoing elective percutaneous coronary intervention. Compared to baseline values, sFLT1 and PlGF levels increased by 2629±313% and 253±54%, respectively, within 30 minutes of UFH therapy (p500% (p

This special issue of the American Journal of Islamic Social Sciences on Ismail al Faruqi is prepared to honor the memory and contribution of Professor Ismail al Faruqi to the academia, the history of Islamic thought, and the development of the Muslim community (Ummah). Providing a perspective twenty-five years after Professor al Faruqi’s death, it provides thought-provoking papers relating of the person, mission, and intellectual jihad initiated by Professor al Faruqi. Ismail Raji al Faruqi (1921–1986) was a great scholar of Islam in modern times. His scholarship covered a broad spectrum of Islamic studies: the study of religion, Islamic thought, approaches to knowledge, history, culture, education, interfaith dialogue, aesthetics, ethics, politics, economics, science, and gender issues. He had indeed an encyclopedic knowledge, a rare person among contemporary Muslim scholars. Ismail al-Faruqi laid the foundation for a new interpretation and analysis of the quintessence of tawhid and its relevance in various dimensions of human life and thought. He also made unique contributions to the study of Islam and its relevance to the contemporary age. In fact, many of his unique contributions to Islamic scholarship remain especially relevant today and have been carried on and extended by many of his former. Professor al Faruqi was a founder of “the school of Islamization of knowledge,” which has been incorporated at several international Islamic universities. His school of thought, academic approach, and practice is also being applied by hundreds of his students who are teaching and doing research at different universities in all continents. This special issue of the American Journal of Islamic Social Sciences, revisits the intellectual legacy and continuing influence of Professor Ismail al Faruqi since his death ...

The responses of my colleagues provide a good representation of the extraordinarily diverse views of Islam, Muslims, and Muslim politics that exist today. Like it or not, we are stuck with the phrase moderate Muslim. Yet, as I read our comments, I keep thinking that for too many, non-Muslims and Muslims alike, moderate means someone “like us.” Thus, moderate is equated with progressive or liberal Muslims but excludes conservatives or traditionalists. Ariel Cohen, in his identification of several moderate Muslims, mentions Amina Wadud’s leading of a mixed-gender Friday prayer. This underscores the problem with moderate, especially when the concept is juxtaposed with extremist. If a woman leading an official prayer service were a criterion for moderate, then many Christian and Jewish groups, denominations, and their leaders (e.g., the recently deceased Pope John Paul II) would fail the test and not be moderates. But they certainly would not be extremists either. Should we, then, add such other litmus tests as position on birth control, abortion, and gay rights? If we go down this road, I wonder how Jews and Christians would react to Muslim countries or Muslim experts and political commentators who attempted to set the definition of a moderate Jew or a moderate Catholic, with the implication that all others were extremists. If, as some non- Muslims have done with regard to Islam, Muslims established institutes and think tanks to define, monitor, or implement their notions of moderate Jew or moderate Christian, how long would it be before they would be accused of being anti-Semitic or anti-Catholic? Would we define a moderate Jew vs. an extremist Jew as one who rejects scriptural justification for claims to Israel, rejects the logic and creation of settlements by religiously motivated Jews, possesses an enlightened understanding of the origins of Judaism and of the Hebrew scriptures; rejects all those biblical passages in which God commands acts of violence and warfare; and eschews any mixing of their faith with politics in Israel, with the support of fundamentalist or religious nationalist groups, schools, or settlements?

The Debate Question 1: Various commentators have frequently invoked the importance of moderate Muslims and the role that they can play in fighting extremism in the Muslim world. But it is not clear who is a moderate Muslim. The recent cancellation of Tariq Ramadan’s visa to the United States, the raids on several American Muslim organizations, and the near marginalization of mainstream American Muslims in North America pose the following question: If moderate Muslims are critical to an American victory in the war on terror, then why does the American government frequently take steps that undermine moderate Muslims? Perhaps there is a lack of clarity about who the moderate Muslims are. In your view, who are these moderate Muslims and what are their beliefs and politics? JLE: Our human tendency is to define what is normal or moderate in terms of someone just like “us.” The American government, as well as many western and Muslim governments and experts, define moderate by searching for reflections of themselves. Thus, Irshad Manji or “secular” Muslims are singled out as self-critical moderate Muslims by such diverse commentators as Thomas Friedman or Daniel Pipes. In an America that is politicized by the “right,” the Republican and religious right, and post-9/11 by the threat of global terrorism and the association of Islam with global terrorism, defining a moderate Muslim becomes even more problematic. Look at the situations not only in this country but also in Europe, especially France. Is a moderate Muslim one who accepts integration, or must it be assimilation? Is a moderate Muslim secular, as in laic (which is really anti-religious)? Is a moderate Muslim one who accepts secularism, as in the separation of church and state, so that no religion is privileged and the rights of all (believer and nonbeliever) are protected? Is a moderate Muslim one who accepts a particular notion of gender relations, not simply the equality of women and men but a position against wearing hijab? (Of course let’s not forget that we have an analogous problem with many Muslims whose definition of being a Muslim, or of being a “good” Muslim woman, is as narrowly defined.) In today’s climate, defining who is a moderate Muslim depends on the politics or religious positions of the individuals making the judgment: Bernard Lewis, Daniel Pipes, Gilles Kepel, Stephen Schwartz, Pat Robertson, and Tom DeLay. The extent to which things have gotten out of hand is seen in attempts to define moderate Islam or what it means to be a good European or American Muslim. France has defined the relationship of Islam to being French, sought to influence mosques, and legislated against wearing hijab in schools. In the United States, non-Muslim individuals and organizations, as well as the government, establish or fund organizations that define or promote “moderate Islam,” Islamic pluralism, and so on, as well as monitor mainstream mosques and organizations. The influence of foreign policy plays a critical role. For some, if not many, the litmus test for a moderate Muslim is tied to foreign policy issues, for example, how critical one is of American or French policy or one’s position in regard to Palestine/Israel, Algeria, Kashmir, and Iraq. Like many Muslim regimes, many experts and ideologues, as well as publications like The Weekly Standard, National Review, The Atlantic, The New York Sun and media like Fox Television, portray all Islamists as being the same. Mainstream and extremist (they deny any distinction between the two) and indeed all Muslims who do not completely accept their notion of secularism, the absolute separation of religion and the state, are regarded as a threat. Mainstream Islamists or other Islamically oriented voices are dismissed as “wolves in sheep’s clothing.” What is important here is to emphasize that it is not simply that these individuals, as individual personalities, have influence and an impact, but that their ideas have taken on a life of their own and become part of popular culture. In a post-9/11 climate, they reinforce the worst fears of the uninformed in our populace. The term moderate is in many ways deceptive. It can be used in juxtaposition to extremist and can imply that you have to be a liberal reformer or a progressive in order to pass the moderate test, thus excluding more conservative or traditionalist positions. Moderates in Islam, as in all faiths, are the majority or mainstream in Islam. We assume this in regard to such other faiths as Judaism and Christianity. The Muslim mainstream itself represents a multitude of religious and socioeconomic positions. Minimally, moderate Muslims are those who live and work “within” societies, seek change from below, reject religious extremism, and consider violence and terrorism to be illegitimate. Often, in differing ways, they interpret and reinterpret Islam to respond more effectively to the religious, social, and political realities of their societies and to international affairs. Some seek to Islamize their societies but eschew political Islam; others do not. Politically, moderate Muslims constitute a broad spectrum that includes individuals ranging from those who wish to see more Islamically oriented states to “Muslim Democrats,” comparable to Europe’s Christian Democrats. The point here is, as in other faiths, the moderate mainstream is a very diverse and disparate group of people who can, in religious and political terms, span the spectrum from conservatives to liberal reformers. They may disagree or agree on many matters. Moderate Jews and Christians can hold positions ranging from reform to ultraorthodox and fundamentalist and, at times, can bitterly disagree on theological and social policies (e.g., gay rights, abortion, the ordination of women, American foreign and domestic policies). So can moderate Muslims.

Carob pulp flour has antidiabetic and antioxidant activities, is naturally sweet, and is rich in fibers. It is obtained from carob pod pulp from the evergreen tree Ceratonia siliqua L., which is grown in Mediterranean areas and is known for locust bean gum production. Despite its valuable effects on health, such as the modulation of the glycemic index, this ingredient has a tremendous impact on technological and hedonic features, mainly on color, flavor, and texture. In this paper, the qualitative features and consumers' acceptance of a carob-based gluten-free bakery product where rice flour was substituted at 40% with carob pulp flour were studied. A panel group of experts described the bread as dark, quite dense, sweet, aromatic, and with a limited bubble dispersion. On the other hand, the sensory assessment and the willingness to pay of consumers were assessed in two groups (a fully informed one about heathy attributes of the food and a blind one). The results indicated a moderate appreciation of the overall quality of the product (average score between 4 and 5 points on a 9-point Likert scale). The information about the food's healthy properties and the ability to maintain a low glycemic index did not enhance the consumers' perception of the product, while previous knowledge and involvement in the product consumption were perceived to have primary importance regarding the final consumers' choice. Finally, an accelerated shelf-life test was run on the packaged snack to evaluate the general quality and stability. The protective packaging helped in limiting bread decay and maintaining the textural characteristics.

Background: Islet transplantation has been associated with better metabolic control and quality of life than insulin treatment alone, but direct evidence of its effect on hard clinical endpoints is scarce. We aimed to assess the effect of islet transplantation on patient-graft survival in kidney transplant recipients with type 1 diabetes., Methods: In this retrospective cohort study, we enrolled all patients with type 1 diabetes who received a kidney graft in France during the study period, identified from the CRISTAL nationwide registry. Non-inclusion criteria included recipients from transplant centres that never proposed islet transplantation during the study period, recipients with a functional pancreas throughout the follow-up duration, recipients with more than two kidney transplants, HLA-sensitised recipients, recipients with less than 1 year of follow-up after kidney transplantation, misclassified recipients with type 2 diabetes, recipients aged over 65 years, recipients of kidney grafts from Donation after Circulatory Death donors, recipient with HIV or hepatitis, recipients with cancer, and recipients of combined liver-kidney transplants. Patients who also received islet-after-kidney (IAK) transplantation were compared with controls who received kidney transplantation alone according to a 1:2 matching method based on time-dependent propensity scores, ensuring patients comparability at the time of islet transplantation. The primary outcome was patient-graft survival, a composite outcome defined by death, re-transplantation, or return to dialysis., Findings: Between Jan 1, 2000, and Dec 31, 2017, 2391 patients with type 1 diabetes were identified as having received a kidney transplant, 47 patients of whom also received an islet transplantation. 2002 patients were not eligible for islet transplantation and 62 were excluded due to missing data. 327 eligible recipients from 15 centres were included in the study dataset for the target trial emulation. 40 patients who received IAK transplantation were successfully matched to 80 patients who received kidney transplantation alone. 13 (33%) of 40 patients in the IAK transplantation group returned to dialysis or died, compared with 36 (45%) of 80 patients in the kidney transplantation alone group. We found a significant benefit of islet transplantation compared with kidney transplantation alone on patient-graft survival, with a hazard ratio (HR) of 0·44 (95% CI 0·23-0·88; p=0·022), mainly explained by a protective effect on the risk of death (HR 0·41, 0·13-0·91; p=0·042). There was no meaningful association between IAK and death-censored graft survival (0·73, 0·30-1·89; p=0·36)., Interpretation: In kidney transplant recipients with type 1 diabetes, IAK transplantation was associated with a significantly better patient-graft survival compared with kidney transplantation alone, mainly due to a protective effect on the risk of death. These results potentially serve as compelling grounds for advocating wider access to islet transplantation in patients with type 1 diabetes undergoing kidney transplant, as reimbursement of islet transplantation is provided in few countries worldwide., Funding: Programme Hospitalier de la Recherche Clinique, Fondation pour la Recherche Medicale, and Fonds de Dotation Line Renaud-Loulou Gasté., Competing Interests: Declaration of interests MM, RL, YF, FB, GB, CA, LK, MLQ, DA, MB, AB-S, LF, PM, SL, LB, LE, MC, AH, JK-C, TB, M-CV, MH, and FP declare no competing interests. SC declares support for attending meetings or travel from Astra Zeneca, Alexion, Sanofi, and Pierre Fabre and participation on a data safety monitoring board or advisory board from Astra Zeneca, Alexion, Chiesi, Pierre Fabre, Pfizer, and Samsung Bioepis. OV declares payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Sanofi-Aventis, Eli-Lilly, and Novo-Nordisk and support for attending meetings or travel from Sanofi-Aventis., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Eosinophilic Esophagitis (EoE) is a chronic inflammatory condition of the esophagus triggered by food and aeroallergens. There is a need for noninvasive biomarkers that reliably detect EoE in patients with cardinal symptoms and predict treatment response to reduce endoscopic evaluations., Study: Nonasthmatic patients 18 years or above with suspected or diagnosed EoE, gastroesophageal reflux disease (GERD), and control individuals with indication for endoscopy were enrolled prospectively between November 2020 and May 2022. Participants underwent body plethysmography with fractionated exhaled nitric oxide (FeNO) level measurement. Besides, serum and fecal biomarkers were measured by ELISA. A follow-up examination was scheduled after treatment initiation in patients with active EoE., Results: The median FeNO level in active EoE (20 ppb) was higher compared with GERD (15 ppb, P=0.038) and control individuals (14 ppb, P=0.046). Median FeNO did not significantly differ in EoE patients who underwent follow-up assessment after treatment response (20 ppb vs. 18 ppb, P=0.771). Serum EDN, ECP, and the absolute eosinophil blood count (AEC) were elevated in active EoE compared with control individuals but not compared with GERD except for AEC. Serum EDN, ECP and AEC decreased in EoE in remission at follow-up assessment. None of the fecal biomarkers was elevated in active EoE or during treatment., Conclusions: Assessment of FeNO may have diagnostic value in differentiating patients with active EoE from non-EoE patients but is not a suitable marker for monitoring disease activity. Serum EDN, ECP, TARC, and AEC levels are emerging as potential candidates for monitoring disease activity in EoE., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Although minimally invasive distal pancreatectomy (MIDP) is considered a standard approach it still presents a non-negligible rate of conversion to open that is mainly related to some difficulty factors, as obesity. The aim of this study is to analyze the preoperative factors associated with conversion in obese patients with MIDP., Methods: In this multicenter study, all obese patients who underwent MIDP at 18 international expert centers were included. The preoperative factors associated with conversion to open surgery were analyzed., Results: Out of 436 patients, 91 (20.9%) underwent conversion to open, presenting higher blood loss, longer operative time and similar rate of major complications. Twenty (22%) patients received emergent conversion. At univariate analysis, the type of approach, radiological invasion of adjacent organs, preoperative enlarged lymphnodes and ASA ≥ III were significantly associated with conversion to open. At multivariate analysis, robotic approach showed a significantly lower conversion rate (14.6 % vs 27.3%, OR = 2.380, p = 0.001). ASA ≥ III (OR = 2.391, p = 0.002) and preoperative enlarged lymphnodes (OR = 3.836, p = 0.003) were also independently associated with conversion., Conclusion: Conversion rate is significantly lower in patients undergoing robotic approach. Radiological enlarged lymphnodes and ASA ≥ III are also associated with conversion to open. Conversion is associated with poorer perioperative outcomes, especially in case of intraoperative hemorrhage., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes., Methods: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS)., Results: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine., Conclusion: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC., Competing Interests: Declaration of Competing Interest LR reports consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Zymeworks. ACG reports consulting fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, IQVIA, MSD, Roche, Servier; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from AstraZeneca, Eisai. SLC serves an advisory member for AstraZeneca, MSD, Eisai, BMS, Ipsen, and Hengrui, received research funds from MSD, Eisai, Ipsen, SIRTEX, and Zailab, and honoraria from AstraZeneca, Eisai, Roche, Ipsen, and MSD. TP received consulting fees from Bayer, Ipsen, and AstraZeneca; institutional research funding from Roche, Bayer, and AstraZeneca; travel expenses from Roche. CB received honoraria as speaker (Astrazeneca, Incyte, Servier) and consultant (Incyte, Servier, Boehringer Ingelheim, Astrazeneca), received research funds (Avacta, Medannex, Servier) and her spouse is an employee of Astrazeneca. M. Ikeda reports honoraria from AstraZeneca, Chugai Pharma, Eisai, Incyte, Lilly Japan, MSD, Novartis, Ono Pharmaceutical, Takeda, Teijin Pharma, Nihon Servier, Taiho and research funding from AstraZeneca, Bayer, Bristol-Myers Squibb, Chiome Bioscience, Chugai, Eisai, Eli Lilly Japan, Delta-Fly Pharma, Invitae, J-Pharma, Merck biopharma, Merus N.V., MSD, Novartis, Nihon Servier, Ono, Syneos Health, and Rakuten Medical. GWP: Advisories and/or Speaker fees: Servier, Bayer, Roche Amgen, Merck, MSD, BMS, Sanofi, Lilly, Astra Zeneca, Astellas, Pierre-Fabre, Incyte, Arcus, CECOG. F. F. has received travel support from Ipsen, Abbvie, Astrazeneca and speaker’s fees from AbbVie, MSD, Ipsen, Astrazeneca. LP: Advisory role: AstraZeneca, Servier, Travel expenses: AstraZeneca, Ipsen. GG: Consulting Fees: Astra Zeneca, MSD, Servier, Seagen, Bayer, Amgen, Novartis, Ipsen, BMS. Travel Expenses: Astra Zeneca, Servier, Bayer, Novartis. S.L. reports research funding (to Institution) from Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, Servier; personal honoraria as invited speaker from Amgen, Astra Zeneca, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, Servier; participation in advisory board for Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda, Rottapharm. JD received consulting fees and/or speaker honoraria from Amgen, AstraZeneca, Bayer, BMS, Eisai, Need Inc., Ipsen, Lilly, MediMix, Merck, MSD, Novartis, Roche and Servier. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Improved expertise and technological advancements have enabled the safe and effective performance of complex and high-risk-indicated percutaneous coronary intervention (CHIP) in patients previously considered inoperable or high-risk. Mechanical circulatory support (MCS) devices play a crucial role in stabilizing hemodynamics during percutaneous coronary intervention (PCI) -related ischemia, thereby reducing the risk of major adverse events and achieving a more complete revascularization. However, the use of MCS devices in protected PCI is not without risks, including peri-procedural myocardial infarction (MI), bleeding, and access-related complications. Despite numerous observational studies, there is a significant lack of randomized clinical trials comparing different MCS devices in various CHIP scenarios and evaluating their long-term safety and efficacy profiles. This review aims to summarize the current evidence regarding the benefits of MCS devices during CHIPs, offer a practical guide for selecting appropriate devices based on clinical scenarios, and highlight the unanswered questions that future trials need to address.

Cocoa ( Theobroma cacao , L.) represents an important market that gained relevance and became an esteemed commodity thanks to cocoa powder, chocolate, and other related products. This work analyzed 59 cocoa powder samples from the European market. Three distinct subgroups were identified: organic or conventional, alkalized or not alkalized, and raw or roasted processing. The impact of the technological process on their pH, color, and compositional traits, as well as their content of biogenic amines and salsolinol, was evaluated. The phenolic fraction was also investigated through both common and emerging methods. The results depict that the influence of the agronomical practices (organic/conventional) did not significantly ( p < 0.05) affect the composition of the cocoa powders; similarly, the roasting process was not a determinant of the compounds traced. On the other hand, the alkalinization process greatly impacted color and pH, no matter the cocoa's provenience or obtention or other processes, also resulting in reducing the phenolic fraction of the treated samples. Principal component analysis confirmed that the alkali process acts on pH, color, and phenolic composition but not on the content of other bioactive molecules (biogenic amines and salsolinol). All the samples were safe, while the alkalized powders saw a great reduction in beneficial biocompounds. A novel strategy could be to emphasize on the label whether cocoa powder is non-alkalized to meet the demand for more beneficial products.

Background: In kidney transplant recipients with positive serology (R+) for the cytomegalovirus (CMV), 2 strategies are used to prevent infection, whose respective advantages over the other are still debated. This study aimed to evaluate the cost-effectiveness and cost utility of antiviral prophylaxis against CMV versus preemptive therapy, considering CMV infection-free survival over the first year posttransplantation as the main clinical outcome., Methods: Clinical, laboratory, and economic data were collected from 186 kidney transplant patients CMV (R+) included in the cohort study (85 patients who benefited from CMV prophylaxis and 101 from preemptive therapy). Costs were calculated from the hospital perspective and quality-adjusted life years (QALYs) using the EQ5D form. Using nonparametric bootstrapping, the incremental cost-effectiveness ratio (ICER) and cost utility were estimated (euros) for each case of infection avoided and each QALY gained for 1 y, respectively., Results: Prophylaxis significantly decreased the risk of CMV infection over the first year posttransplantation (hazard ratio 0.22, 95% confidence interval = 0.12-0.37, P  < 0.01). Compared with preemptive therapy, prophylaxis saved financial resources (€1155 per patient) and was more effective (0.42 infection avoided per patient), resulting in an ICER = €2769 per infection avoided. Prophylaxis resulted in a net gain of 0.046 in QALYs per patient and dominated over preemptive therapy with €1422 cost-saving for 1 QALY gained., Conclusions: This study shows that CMV prophylaxis, although considered as a more expensive strategy, is more cost-effective than preemptive therapy for the prevention of CMV infections in renal transplant patients. Prophylaxis had a positive effect on quality of life at reasonable costs and resulted in net savings for the hospital., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Members of the KCTD protein family play key roles in fundamental physio-pathological processes including cancer, neurodevelopmental/neuropsychiatric, and genetic diseases. Here, we report the crystal structure of the KCTD1 P20S mutant, which causes the scalp-ear-nipple syndrome, and molecular dynamics (MD) data on the wild-type protein. Surprisingly, the structure unravels that the N-terminal region, which precedes the BTB domain (preBTB) and bears the disease-associated mutation, adopts a folded polyproline II (PPII) state. The KCTD1 pentamer is characterized by an intricate architecture in which the different subunits mutually exchange domains to generate a closed domain swapping motif. Indeed, the BTB of each chain makes peculiar contacts with the preBTB and the C-terminal domain (CTD) of an adjacent chain. The BTB-preBTB interaction consists of a PPII-PPII recognition motif whereas the BTB-CTD contacts are mediated by an unusual (+/-) helix discontinuous association. The inspection of the protein structure, along with the data emerged from the MD simulations, provides an explanation of the pathogenicity of the P20S mutation and unravels the role of the BTB-preBTB interaction in the insurgence of the disease. Finally, the presence of potassium bound to the central cavity of the CTD pentameric assembly provides insights into the role of KCTD1 in metal homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Alpha-synuclein, encoded by the SNCA gene, is a pivotal protein implicated in the pathogenesis of synucleinopathies, including Parkinson's disease. Current approaches for modulating alpha-synuclein levels involve antisense nucleotides, siRNAs, and small molecules targeting SNCA's 5'-UTR mRNA. Here, we propose a groundbreaking strategy targeting G-quadruplex structures to effectively modulate SNCA gene expression and lowering alpha-synuclein amount. Novel G-quadruplex sequences, identified on the SNCA gene's transcription starting site and 5'-UTR of SNCA mRNAs, were experimentally confirmed for their stability through biophysical assays and in vitro experiments on human genomic DNA. Biological validation in differentiated SH-SY5Y cells revealed that well-known G-quadruplex ligands remarkably stabilized these structures, inducing the modulation of SNCA mRNAs expression, and the effective decrease in alpha-synuclein amount. Besides, a novel peptide nucleic acid conjugate, designed to selectively disrupt of G-quadruplex within the SNCA gene promoter, caused a promising lowering of both SNCA mRNA and alpha-synuclein protein. Altogether our findings highlight G-quadruplexes' key role as intriguing biological targets in achieving a notable and successful reduction in alpha-synuclein expression, pointing to a novel approach against synucleinopathies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.

The mammalian cortex is comprised of cells with different morphological, physiological, and molecular properties that can be classified according to shared properties into cell types. Defining the contribution of each cell type to the computational and cognitive processes that are guided by the cortex is essential for understanding its function in health and disease. We use transcriptomic and epigenomic cortical cell type taxonomies from mice and humans to define marker genes and enhancers, and to build genetic tools for cortical cell types. Here, we present a large toolkit for selective targeting of cortical populations, including mouse transgenic lines and recombinant adeno-associated virus (AAV) vectors containing genomic enhancers. We report evaluation of fifteen new transgenic driver lines and over 680 different enhancer AAVs covering all major subclasses of cortical cells, with many achieving a high degree of specificity, comparable with existing transgenic lines. We find that the transgenic lines based on marker genes can provide exceptional specificity and completeness of cell type labeling, but frequently require generation of a triple-transgenic cross for best usability/specificity. On the other hand, enhancer AAVs are easy to screen and use, and can be easily modified to express diverse cargo, such as recombinases. However, their use depends on many factors, such as viral titer and route of administration. The tools reported here as well as the scaled process of tool creation provide an unprecedented resource that should enable diverse experimental strategies towards understanding mammalian cortex and brain function., Competing Interests: Declaration of Interests H.Z. is on the scientific advisory board of MapLight Therapeutics, Inc. The other authors declare no competing interests.

The use of intravenous antiplatelet therapy during primary percutaneous coronary intervention (PPCI) is not fully standardized. The aim is to evaluate the effectiveness and safety of periprocedural intravenous administration of cangrelor or tirofiban in a contemporary ST-segment elevation myocardial infarction (STEMI) population undergoing PPCI. This was a multicenter prospective cohort study including consecutive STEMI patients who received cangrelor or tirofiban during PPCI at seven Italian centers. The primary effectiveness measure was the angiographic evidence of thrombolysis in myocardial infarction (TIMI) flow < 3 after PPCI. The primary safety outcome was the in-hospital occurrence of BARC (Bleeding Academic Research Consortium) 2-5 bleedings. The study included 627 patients (median age 63 years, 79% males): 312 received cangrelor, 315 tirofiban. The percentage of history of bleeding, pulmonary edema and cardiogenic shock at admission was comparable between groups. Patients receiving cangrelor had lower ischemia time compared to tirofiban. TIMI flow before PPCI and TIMI thrombus grade were comparable between groups. At propensity score-weighted regression analysis, the risk of TIMI flow < 3 was significantly lower in patients treated with cangrelor compared to tirofiban (adjusted OR: 0.40; 95% CI: 0.30-0.53). The risk of BARC 2-5 bleeding was comparable between groups (adjusted OR:1.35; 95% CI: 0.92-1.98). These results were consistent across multiple prespecified subgroups, including subjects stratified for different total ischemia time, with no statistical interaction. In this real-world multicenter STEMI population, the use of cangrelor was associated with improved myocardial perfusion assessed by coronary angiography after PPCI without increasing clinically-relevant bleedings compared to tirofiban., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the swiftly evolving business landscape, digital transformation (DT) has emerged as a crucial strategy for firms to gain a competitive edge. Despite the abundance of literature on DT in firms, there remains a dearth of empirical research that defines and analyzes crucial antecedents of small and medium-sized enterprises' (SMEs) DT from an internal perspective. To fill this research gap, this study examines the correlation between organizational agility and digital capability in cultivating SMEs' DT while also evaluating top management support as a moderating variable through the lens of internal factors of SMEs. The results indicate that both organizational agility and digital capability have a positive impact on SMEs' DT, with organizational agility significantly influencing digital capability. Furthermore, the findings highlight that digital capability serves as a mediator between organizational agility and SMEs' DT. In addition, top management support plays a moderating role in these relationships to a certain extent. Additionally, we explicate the concept of digital capabilities from the perspective of dynamic capability. Our study contributes to an enhanced understanding of the effect of organizational agility and digital capability on SMEs' DT, as well as the role of top management support. We provide recommendations for managers to enhance organizational agility and suggest that SMEs should improve their digital thinking to better perceive digital technology changes, enhance digital operation capabilities, and better integrate digital resources., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Study of alternating DNA GC sequences by different time-resolved spectroscopies has provided fundamental information on the interaction between UV light and DNA, a process of great biological importance. Multiple decay paths have been identified, but their interplay is still poorly understood. Here, we characterize the photophysics of GC-DNA by integrating different computational approaches, to study molecular models including up to 6 bases described at a full quantum mechanical level. Quantum dynamical simulations, exploiting a nonadiabatic linear vibronic coupling (LVC) model, coupled with molecular dynamics sampling of the initial structures of a (GC) 5 DNA duplex, provide new insights into the photophysics in the sub-picosecond time-regime. They indicate a substantial population transfer, within 50 fs, from the spectroscopic states towards G → C charge transfer states involving two stacked bases (CT intra ), thus explaining the ultrafast disappearance of fluorescence. This picture is consistent with that provided by quantum mechanical geometry optimizations, using time dependent-density functional theory and a polarizable continuum model, which we use to parametrize the LVC model and to map the main excited state deactivation pathways. For the first time, the infrared and excited state absorption signatures of the various states along these pathways are comprehensively mapped. The computational models suggest that the main deactivation pathways, which, according to experiment, lead to ground state recovery on the 10-50 ps time scale, involve CT intra followed by interstrand proton transfer from the neutral G to C - . Our calculations indicate that CT intra is populated to a larger extent and more rapidly in GC than in CG steps and suggest the likely involvement of monomer-like and interstrand charge transfer decay routes for isolated and less stacked CG steps. These findings underscore the importance of the DNA sequence and thermal fluctuations for the dynamics. They will also aid the interpretation of experimental results on other sequences., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Research has shown that differences between males and females are not in general intelligence, but only in some specific factors and tasks. We used the Italian standardization of the Leiter-3, which is a completely nonverbal cognitive battery, to investigate the nature of sex/gender (we used sex/gender to reflect the awareness that the effects of biological 'sex' and socially constructed 'gender' cannot be easily separated and that most individuals' identities are informed by both sex and gender) differences. In doing so we used a multigroup confirmatory factor analysis approach. Results confirmed that males and females perform similarly in general intelligence, but present with some specificities. Males perform better on some, but not all, tasks requiring the spatial manipulation of the stimuli, but females consistently outperform males in tasks such as the nonverbal Stroop, requiring inhibition and attention control to a larger extent. The clinical and practical implications of our findings are considerable. The identification of specific cognitive strengths and weaknesses in males and females underscores the importance of tailored approaches in clinical assessments and interventions., (© 2024. The Author(s).)

Leukodystrophies are a class of rare heterogeneous disorders which affect the white matter of the brain, ultimately leading to a disruption in brain development and a damaging effect on cognitive, motor and social-communicative development. These disorders present a great clinical heterogeneity, along with a phenotypic overlap and this could be partially due to contributions from environmental stimuli. It is in this context that there is a great need to investigate what other factors may contribute to both disease insurgence and phenotypical heterogeneity, and novel evidence are raising the attention toward the study of epigenetics and transcription mechanisms that can influence the disease phenotype beyond genetics. Modulation in the epigenetics machinery including histone modifications, DNA methylation and non-coding RNAs dysregulation, could be crucial players in the development of these disorders, and moreover an aberrant RNA maturation process has been linked to leukodystrophies. Here, we provide an overview of these mechanisms hoping to supply a closer step toward the analysis of leukodystrophies not only as genetically determined but also with an added level of complexity where epigenetic dysregulation is of key relevance. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNA RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development., (© 2024 The Author(s). WIREs RNA published by Wiley Periodicals LLC.)