bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential Antiviral Action of Alkaloids
Authors: Abookleesh Frage L. , Al-Anzi Bader S. , Ullah Aman
Published: January 2022

Viral infections and outbreaks have become a major concern and are one of the main causes of morbidity and mortality worldwide. The development of successful antiviral therapeutics and vaccines remains a daunting challenge. The discovery of novel antiviral agents is a public health emergency, and extraordinary efforts are underway globally to identify safe and effective treatments for different viral diseases. Alkaloids are natural phytochemicals known for their biological activities, many of which have been intensively studied for their broad-spectrum of antiviral activities against different DNA and RNA viruses. The purpose of this review was to summarize the evidence supporting the efficacy of the antiviral activity of plant alkaloids at half-maximum effective concentration (EC50) or half-maximum inhibitory concentration (IC50) below 10 μM and describe the molecular sites most often targeted by natural alkaloids acting against different virus families. This review highlights that considering the devastating effects of virus pandemics on humans, plants, and animals, the development of high efficiency and low-toxicity antiviral drugs targeting these viruses need to be developed. Furthermore, it summarizes the current research status of alkaloids as the source of antiviral drug development, their structural characteristics, and antiviral targets. Overall, the influence of alkaloids at the molecular level suggests a high degree of specificity which means they could serve as potent and safe antiviral agents waiting for evaluation and exploitation.
Physicochemical, Structural, Thermal and Rheological Properties of Flour and Starch Isolated from Avocado Seeds of Landrace and Hass Cultivars
Authors: De Dios-Avila Ndahita , Tirado-Gallegos Juan Manuel , Rios-Velasco Claudio , Luna-Esquivel Gregorio , Isiordia-Aquino Néstor , Zamudio-Flores Paul Baruk , Estrada-Virgen Mario Orlando , Cambero-Campos Octavio Jhonathan
Published: January 2022

The objective of this study was to obtain and characterize flours and starches from the avocado seeds of Hass and landrace cultivars. The morphological, physical-chemical, structural, thermal and rheological characteristics were evaluated. The flour yield of the Hass and landrace cultivars was 41.56 to 46.86% (w/w), while for starch, it was 35.47 to 39.57% (w/w) (cv. Hass and landrace, respectively). Scanning electron microscopy (SEM) revealed the presence of oval starch granules and other particles in flour, in contrast to flours, starches showed lower ash, proteins and lipids content. However, the amylose content was higher in starches (42.25–48.2%). Flours showed a higher gelatinization temperature (Tp = 73.17–73.62 °C), and their starches presented greater gelatinization enthalpy (∆Hgel = 11.82–13.43 J/g). All samples showed a B-type diffraction pattern, and the crystallinity was higher in the flours. The rheological analysis (flow curves and viscoelastic tests) evidenced a pseudoplastic (n = 0.28–0.36) behavior in all samples analyzed, but the consistency index (k) was higher in starches. In general, the flours and starches from avocado seeds presented interesting proximal, thermal and functional properties for possible application in food systems, and these findings could contribute to the revaluation of this by-product.
High Resolution Infrared Spectroscopy in Support of Ozone Atmospheric Monitoring and Validation of the Potential Energy Function
Authors: Barbe Alain , Mikhailenko Semen , Starikova Evgeniya , Tyuterev Vladimir
Published: January 2022

The first part of this review is a brief reminder of general information concerning atmospheric ozone, particularly related to its formation, destruction, observations of its decrease in the stratosphere, and its increase in the troposphere as a result of anthropogenic actions and solutions. A few words are said about the abandonment of the Airbus project Alliance, which was expected to be the substitute of the supersonic Concorde. This project is over due to the theoretical evaluation of the impact of a fleet in the stratosphere and has been replaced by the A380, which is now operating. The largest part is devoted to calculations and observations of the transitions in the infrared range and their applications for the atmosphere based both on effective models (Hamiltonian, symmetry rules, and dipole moments) and ab initio calculations. The complementarities of the two approaches are clearly demonstrated, particularly for the creation of an exhaustive line list consisting of more than 300,000 lines reaching experimental accuracies (from 0.00004 to 0.001 cm−1) for positions and a sub percent for the intensities in the 10 microns region. This contributes to definitively resolving the issue of the observed discrepancies between line intensity data in different spectral regions: between the infrared and ultraviolet ranges, on the one hand, and between 10 and 5 microns on the other hand. The following section is devoted to the application of recent work to improve the knowledge about the behavior of potential function at high energies. A controversial issue related to the shape of the potential function in the transition state range near the dissociation is discussed.
The Adsorption of Small Molecules on the Copper Paddle-Wheel: Influence of the Multi-Reference Ground State
Authors: Krstić Marjan , Fink Karin , Sharapa Dmitry I.
Published: January 2022

We report a theoretical study of the adsorption of a set of small molecules (C2H2, CO, CO2, O2, H2O, CH3OH, C2H5OH) on the metal centers of the “copper paddle-wheel”—a key structural motif of many MOFs. A systematic comparison between DFT of different rungs, single-reference post-HF methods (MP2, SOS–MP2, MP3, DLPNO–CCSD(T)), and multi-reference approaches (CASSCF, DCD–CAS(2), NEVPT2) is performed in order to find a methodology that correctly describes the complicated electronic structure of paddle-wheel structure together with a reasonable description of non-covalent interactions. Apart from comparison with literature data (experimental values wherever possible), benchmark calculations with DLPNO–MR–CCSD were also performed. Despite tested methods show qualitative agreement in the majority of cases, we showed and discussed reasons for quantitative differences as well as more fundamental problems of specific cases.
Phytochemical Profiling, In Vitro Biological Activities, and In Silico Molecular Docking Studies of Dracaena reflexa
Authors: Ghalloo Bilal Ahmad , Khan Kashif-ur-Rehman , Ahmad Saeed , Aati Hanan Y. , Al-Qahtani Jawaher H. , Ali Barkat , Mukhtar Imran , Hussain Musaddique , Shahzad Muhammad Nadeem , Ahmed Imtiaz
Published: January 2022

Dracaena reflexa, a traditionally significant medicinal plant, has not been extensively explored before for its phytochemical and biological potential. The present study was conducted to evaluate the bioactive phytochemicals and in vitro biological activities of D. reflexa, and perform in silico molecular docking validation of D. reflexa. The bioactive phytochemicals were assessed by preliminary phytochemical testing, total bioactive contents, and GC-MS analysis. For biological evaluation, the antioxidant (DPPH, ABTS, CUPRAC, and ABTS), antibacterial, thrombolytic, and enzyme inhibition (tyrosinase and cholinesterase enzymes) potential were determined. The highest level of total phenolic contents (92.72 ± 0.79 mg GAE/g extract) was found in the n-butanol fraction while the maximum total flavonoid content (110 ± 0.83 mg QE/g extract) was observed in methanolic extract. The results showed that n-butanol fraction exhibited very significant tyrosinase inhibition activity (73.46 ± 0.80) and acetylcholinesterase inhibition activity (64.06 ± 2.65%) as compared to other fractions and comparable to the standard compounds (kojic acid and galantamine). The methanolic extract was considered to have moderate butyrylcholinesterase inhibition activity (50.97 ± 063) as compared to the standard compound galantamine (53.671 ± 0.97%). The GC-MS analysis of the n-hexane fraction resulted in the tentative identification of 120 bioactive phytochemicals. Furthermore, the major compounds as identified by GC-MS were analyzed using in silico molecular docking studies to determine the binding affinity between the ligands and the enzymes (tyrosinase, acetylcholinesterase, and butyrylcholinesterase enzymes). The results of this study suggest that Dracaena reflexa has unquestionable pharmaceutical importance and it should be further explored for the isolation of secondary metabolites that can be employed for the treatment of different diseases.
Healthy Properties of a New Formulation of Pomegranate-Peel Extract in Mice Suffering from Experimental Autoimmune Encephalomyelitis
Authors: Vallarino Giulia , Salis Annalisa , Lucarini Elena , Turrini Federica , Olivero Guendalina , Roggeri Alessandra , Damonte Gianluca , Boggia Raffaella , Di Cesare Mannelli Lorenzo , Ghelardini Carla , Pittaluga Anna
Published: January 2022

A new formulation of a pomegranate-peel extract (PEm) obtained by PUAE (Pulsed Ultrasound-Assisted Extraction) and titrated in both ellagic acid (EA) and punicalagin is proposed, characterized and then analyzed for potential health properties in mice suffering from the experimental autoimmune encephalomyelitis (EAE). PEm effects were compared to those elicited by a formulation containing EA (EAm). Control and EAE mice were chronically administered EAm and Pem dissolved in the drinking water, starting from the day 10 post-immunization (d.p.i.), with a “therapeutic” protocol to deliver daily 50 mg/kg of EA. Treated EAE mice did not limit their daily access to the beverage, nor did they show changes in body weight, but they displayed a significant amelioration of “in vivo” clinical symptoms. “Ex vivo” histochemical analysis showed that spinal-cord demyelination and inflammation in PEm and EAm-treated EAE mice at 23 ± 1 d.p.i. were comparable to those in the untreated EAE animals, while microglia activation (measured as Ionized Calcium Binding Adaptor 1, Iba1 staining) and astrocytosis (quantified as glial fibrillar acid protein, GFAP immunopositivity) significantly recovered, particularly in the gray matter. EAm and PEm displayed comparable efficiencies in controlling the spinal pathological cellular hallmarks in EAE mice, and this would support their delivery as dietary supplementation in patients suffering from multiple sclerosis (MS).
Copolymers Containing 1-Methyl-2-phenyl-imidazole Moieties as Permanent Dipole Generating Units: Synthesis, Spectroscopic, Electrochemical, and Photovoltaic Properties
Authors: Kulszewicz-Bajer Irena , Nowakowski Robert , Zagórska Małgorzata , Maranda-Niedbała Agnieszka , Mech Wojciech , Wróbel Zbigniew , Drapała Jakub , Wielgus Ireneusz , Korona Krzysztof P.
Published: January 2022

New donor–acceptor conjugated alternating or random copolymers containing 1-methyl-2-phenylbenzimidazole and benzothiadiazole (P1), diketopyrrolopyrrole (P4), or both acceptors (P2) are reported. The specific feature of these copolymers is the presence of a permanent dipole-bearing moiety (1-methyl-2-phenyl imidazole (MPI)) fused with the 1,4-phenylene ring of the polymer main chain. For comparative reasons, polymers of the same main chain but deprived of the MPI group were prepared, namely, P5 with diketopyrrolopyrrole and P3 with both acceptors. The presence of the permanent dipole results in an increase of the optical band gap from 1.51 eV in P3 to 1.57 eV in P2 and from 1.49 eV in P5 to 1.55 eV in P4. It also has a measurable effect on the ionization potential (IP) and electrochemical band gap (EgCV), leading to their decrease from 5.00 and 1.83 eV in P3 to 4.92 and 1.79 eV in P2 as well as from 5.09 and 1.87 eV in P5 to 4.94 and 1.81 eV in P4. Moreover, the presence of permanent dipole lowers the exciton binding energy (Eb) from 0.32 eV in P3 to 0.22 eV in P2 and from 0.38 eV in P5 to 0.26 eV in P4. These dipole-induced changes in the polymer properties should be beneficial for photovoltaic applications. Bulk heterojunction solar cells fabricated from these polymers (with PC71BM acceptor) show low series resistance (rs), indicating good electrical transport properties. The measured power conversion efficiency (PCE) of 0.54% is limited by the unfavorable morphology of the active layer.
Alkaloids and Colon Cancer: Molecular Mechanisms and Therapeutic Implications for Cell Cycle Arrest
Authors: Khan Haroon , Alam Waqas , Alsharif Khalaf F. , Aschner Michael , Pervez Samreen , Saso Luciano
Published: January 2022

Cancer is the second most fatal disease worldwide, with colon cancer being the third most prevalent and fatal form of cancer in several Western countries. The risk of acquisition of resistance to chemotherapy remains a significant hurdle in the management of various types of cancer, especially colon cancer. Therefore, it is essential to develop alternative treatment modalities. Naturally occurring alkaloids have been shown to regulate various mechanistic pathways linked to cell proliferation, cell cycle, and metastasis. This review aims to shed light on the potential of alkaloids as anti-colon-cancer chemotherapy agents that can modulate or arrest the cell cycle. Preclinical investigated alkaloids have shown anti-colon cancer activities and inhibition of cancer cell proliferation via cell cycle arrest at different stages, suggesting that alkaloids may have the potential to act as anticancer molecules.
Unplugged Activities in Cross-Curricular Teaching: Effect on Sixth Graders’ Computational Thinking and Learning Outcomes
Authors: Merino-Armero José Miguel , González-Calero José Antonio , Cózar-Gutiérrez Ramón , del Olmo-Muñoz Javier
Published: January 2022

There is a debate about the way to introduce computational thinking (CT) in schools. Different proposals are on the table; these include the creation of new computational areas for developing CT, the introduction of CT in STEM areas, and the cross-curricular integration of CT in schools. There is also concern that no student should be left behind, independently of their economic situation. To this effect, an unplugged approach is the most cost-effective solution. In addition, this topic is interesting in the context of a pandemic situation that has prevented the sharing of materials between students. This study analyzes an unplugged cross-curricular introduction of CT in the Social Sciences area among sixth grade students. A group of 14 students was selected to carry out an unplugged intervention design—where they were required to program an imaginary robot on paper—in the Social Sciences area. Their CT development and academic results were compared to those of 31 students from the control group who continued attending regular classes. Results showed that an unplugged teaching style of CT in Social Sciences lessons significantly increased CT (p < 0.001) and with a large effect size (d = 1.305) without differences in students’ academic achievement. The findings show that children can potentially develop their CT in non-STEM lessons, learning the same curricular contents, and maintaining their academic results.
Valorizing the Unexplored Filtration Waste of Brewing Industry for Green Silver Nanocomposite Synthesis
Authors: Rangam Neha , Sudagar Alcina , Ruszczak Artur , Borowicz Paweł , Tóth József , Kövér László , Michałowska Dorota , Roszko Marek , Noworyta Krzysztof , Lesiak Beata
Published: January 2022

The brewing industry generates a substantial amount of by-products rich in polyphenols, carbohydrates, sugars, sulfates, nitrogen compounds, organic carbon, and several elements, including chlorine, magnesium, and phosphorus. Although limited quantities of these by-products are used in fertilizers and composts, a large amount is discarded as waste. Therefore, it is crucial to identify different ways of valorizing the by-products. Research regarding the valorization of the brewery by-products is still in its nascent stage; therefore, it still has high potential. Herein, we report the valorization of the brewery by-product from the filtration stage of the brewing process (BW9) to synthesize silver nanocomposites as this waste has remained largely unexplored. The BW9 nanocomposites have been compared to those obtained from the brewery product B. The chemical composition analysis of BW9 and B revealed several organic moieties capable of reducing metal salts and capping the formed nanoparticles. Therefore, the brewery waste from stage 9 was valorized as a precursor and added to silver-based precursor at various temperatures (25, 50, and 80 °C) and for various time periods (10, 30, and 120 min) to synthesize silver nanocomposites. The nanocomposites obtained using BW9 were compared to those obtained using the main product of the brewing industry, beer (B). Synthesized nanocomposites composed of AgCl as a major phase and silver metal (Agmet) was incorporated in minor quantities. In addition, Ag3PO4 was also found in B nanocomposites in minor quantities (up to 34 wt.%). The surface morphology depicted globular nanoparticles with layered structures. Small ball-like aggregates on the layer representative of Ag3PO4 were observed in B nanocomposites. The surface of nanocomposites was capped with organic content and functional groups present in the brewery products. The nanocomposites demonstrated high antibacterial activity against Escherichia coli (E. coli), with BW9 nanocomposites exhibiting a higher activity than B nanocomposites.
Stochastic Microsensors Based on Carbon Nanotubes for Molecular Recognition of the Isocitrate Dehydrogenases 1 and 2
Authors: Stefan-van Staden Raluca-Ioana , Cioates Negut Catalina , Gheorghe Sorin Sebastian , Sfirloaga Paula
Published: January 2022

Two three-dimensional (3D) stochastic microsensors based on immobilization of protoporphyrin IX (PIX) in single-walled carbon nanotubes (SWCNT) and multi-walled carbon nanotubes (MWCNT) decorated with copper (Cu) and gold (Au) nanoparticles were designed and used for the molecular recognition of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) in biological samples (brain tumor tissues, whole blood). The linear concentration ranges obtained for the molecular recognition and quantification of IDH1 and IDH2 were: IDH1 (1 × 10−5–1 × 102 ng mL−1) and IDH2 (5 × 10−8 − 5 × 102 ng mL−1). The limits of quantification obtained using the proposed microsensors were: 10 fg mL–1 for IDH1 and 5 × 10−3 fg mL−1 for IDH2. The highest sensitivities were obtained for the microsensor based on MWCNT. High recoveries versus enzyme-linked immunosorbent assay (ELISA) standard method were recorded for the assays of IDH1 and IDH2, all values being higher than 99.00%, with relative standard deviations (RSD) lower than 0.10%.
Synergy of Electrostatic and Chemical Doping to Improve the Performance of Junctionless Carbon Nanotube Tunneling Field-Effect Transistors: Ultrascaling, Energy-Efficiency, and High Switching Performance
Authors: Tamersit Khalil , Kouzou Abdellah , Bourouba Hocine , Kennel Ralph , Abdelrahem Mohamed
Published: January 2022

The low on-current and direct source-to-drain tunneling (DSDT) issues are the main drawbacks in the ultrascaled tunneling field-effect transistors based on carbon nanotube and ribbons. In this article, the performance of nanoscale junctionless carbon nanotube tunneling field-effect transistors (JL CNTTFETs) is greatly improved by using the synergy of electrostatic and chemical doping engineering. The computational investigation is conducted via a quantum simulation approach, which solves self-consistently the Poisson equation and the non-equilibrium Green’s function (NEGF) formalism in the ballistic limit. The proposed high-performance JL CNTTFET is endowed with a particular doping approach in the aim of shrinking the band-to-band tunneling (BTBT) window and dilating the direct source-to-drain tunneling window, while keeping the junctionless paradigm. The obtained improvements include the on-current, off-current, ambipolar behavior, leakage current, I60 metric, subthreshold swing, current ratio, intrinsic delay, and power-delay product. The scaling capability of the proposed design was also assessed, where greatly improved switching performance and sub-thermionic subthreshold swing were recorded by using JL CNTTFET with 5 nm gate length. Moreover, a ferroelectric-based gating approach was employed for more enhancements, where further improvements in terms of switching performance were recorded. The obtained results and the conducted quantum transport analyses indicate that the proposed improvement approach can be followed to improve similar cutting-edge ultrascaled junctionless tunnel field-effect transistors based on emerging atomically thin nanomaterials.
Fabrication of Self-Assembling Carbon Nanotube Forest Fishnet Metamaterials
Authors: Pander Adam , Onishi Takatsugu , Hatta Akimitsu , Furuta Hiroshi
Published: January 2022

The investigation of the preparation of polystyrene (PS) nanosphere monolayers for the fabrication of carbon nanotube (CNT) forest fishnet metamaterial structures is studied in this paper, as a cheap alternative for top-down patterning methods. The precise control of dry etching conditions resulted in a highly controlled diameter of PS nanobeads, which were then used as a shadow mask for CNT fishnet preparation. The change of the size of the holes from 370 nm to 665 nm resulted in a gradual change of the CNT morphology from multi-walled to single-walled CNTs. The ultraviolet-visible (UV-Vis) reflectance spectra showed that the variation of the hole diameter resulted in the nonlinear light absorption in CNT fishnets that caused the change of the resonance frequency. The change of the fishnet wire width (inductance) and the hole size (capacitance) resulted in the blueshift of the broadband resonance frequency peak. The presented work has a significant potential to allow for the large-scale fabrication of CNT-based fishnet metamaterial structures for applications in energy harvesting, energy storage, solar cells, or optoelectronic devices, such as neuromorphic networks.
Advances in Celiac Disease and Gluten-Free Diet
Authors: Comino Isabel , Sousa Carolina
Published: January 2022

Celiac disease (CD) is a systemic disease that causes chronic enteropathy of the small intestine and develops through an inadequate immune response to gluten in genetically predisposed individuals [...]
Identification of Inhibitory Activities of Dietary Flavonoids against URAT1, a Renal Urate Re-Absorber: In Vitro Screening and Fractional Approach Focused on Rooibos Leaves
Authors: Toyoda Yu , Takada Tappei , Saito Hiroki , Hirata Hiroshi , Ota-Kontani Ami , Tsuchiya Youichi , Suzuki Hiroshi
Published: January 2022

Hyperuricemia, a lifestyle-related disease characterized by elevated serum urate levels, is the main risk factor for gout; therefore, the serum urate-lowering effects of human diets or dietary ingredients have attracted widespread interest. As Urate transporter 1 (URAT1) governs most urate reabsorption from primary urine into blood, URAT1 inhibition helps decrease serum urate levels by increasing the net renal urate excretion. In this study, we used a cell-based urate transport assay to investigate the URAT1-inhibitory effects of 162 extracts of plant materials consumed by humans. Among these, we focused on Aspalathus linearis, the source of rooibos tea, to explore its active ingredients. Using liquid–liquid extraction with subsequent column chromatography, as well as spectrometric analyses for chemical characterization, we identified quercetin as a URAT1 inhibitor. We also investigated the URAT1-inhibitory activities of 23 dietary ingredients including nine flavanols, two flavanonols, two flavones, two isoflavonoids, eight chalcones, and a coumarin. Among the tested authentic chemicals, fisetin and quercetin showed the strongest and second-strongest URAT1-inhibitory activities, with IC50 values of 7.5 and 12.6 μM, respectively. Although these effects of phytochemicals should be investigated further in human studies, our findings may provide new clues for using nutraceuticals to promote health.
Dietetic Management of Adults with Phenylketonuria (PKU) in the UK: A Care Consensus Document
Authors: Robertson Louise , Adam Sarah , Ellerton Charlotte , Ford Suzanne , Hill Melanie , Randles Gemma , Woodall Alison , Young Carla , MacDonald Anita
Published: January 2022

There is an increasing number of adults and elderly patients with phenylketonuria (PKU) who are either early, late treated, or untreated. The principal treatment is a phenylalanine-restricted diet. There is no established UK training for dietitians who work with adults within the specialty of Inherited Metabolic Disorders (IMDs), including PKU. To address this, a group of experienced dietitians specializing in IMDs created a standard operating procedure (SOP) on the dietetic management of adults with PKU to promote equity of care in IMD dietetic services and to support service provision across the UK. The group met virtually over a period of 12 months until they reached 100% consensus on the SOP content. Areas of limited evidence included optimal blood phenylalanine reporting times to patients, protein requirements in older adults, management of weight and obesity, and management of disordered eating and eating disorders. The SOP does not include guidance on maternal PKU management. The SOP can be used as a tool for training dietitians new to the specialty and to raise the standard of education and care for patients with PKU in the UK.
The Mediation Role of the Risk of Non-Alcoholic Fatty Liver Disease in Relationship between Lutein and Zeaxanthin and Cognitive Functions among Older Adults in the United States
Authors: Chen Chen , Lu Zhonghai , Zhang Dongfeng , Li Suyun
Published: January 2022

Background: Previous studies showed lutein and zeaxanthin (L and Z) may influence cognitive function by different mechanisms. Our study aimed to be the first to examine whether the risk of non-alcoholic fatty liver disease (NAFLD) mediated the possible association between the dietary intake of L and Z and cognitive function. Methods: We conducted a cross-sectional analysis of participants aged 60 years or over in the National Health and Nutrition Examination Survey (NHANES) 2011–2014. Multivariable linear regression was used to investigate the association between the dietary intake of L and Z and cognitive function, and structural equation modeling tested the mediation effect. Results: The fatty liver index for the United States population (US FLI) acted as a mediator in the association between the higher intake of L and Z and the Animal Fluency Test, the Digit Symbol Substitution Test (DSST), and composite score and mediated 13.89%, 17.87%, and 13.79% of the total association in dietary L and Z intake (14.29%, 13.68%, and 10.34% of the total association in total L and Z intake), respectively. Conclusion: Our study indicated the potential role of the risk of NAFLD as a mediator of associations between the dietary intake of L and Z and cognitive function in the geriatric American population.
Beneficial Effects of Antioxidants in Male Infertility Management: A Narrative Review
Authors: Cilio Simone , Rienzo Monica , Villano Gianluca , Mirto Benito Fabio , Giampaglia Gaetano , Capone Federico , Ferretti Gianpiero , Di Zazzo Erika , Crocetto Felice
Published: January 2022

Background: Infertility, defined as the failure to conceive after one year of regular, unprotected intercourse, affects 50–80 million people worldwide. A male factor is involved in approximately 20–30% of cases. In the etiology of male infertility, the association between poor semen quality and oxidative stress (OS) is well known. High levels of reactive oxygen species (ROS) allow the oxidation of DNA, proteins, and lipids of sperm cells, modifying their vitality, motility, and morphology. Methods: To evaluate the effects of antioxidants on sperm in infertile men, we queried the MEDLINE database (via the PubMed interface) for published studies in the last 10 years (2011–2021). The following keywords were used: “infertility” and -“inositol”, -“alpha-lipoic acid”, -“zinc”, -“folate”, -“coenzyme Q10”, -“selenium”, and -“vitamin”. Results: Inositol regulates OS levels in sperm cells thanks to its role in mitochondrial reactions and is involved in several processes favoring sperm–oocyte interactions. Alpha-lipoic acid (ALA) reduces ROS damage and improves semen parameters in terms of spermatozoa’s motility, morphology, and count. Poor zinc nutrition may be related to low quality of sperm. Supplementation of folate plus zinc has a positive effect on the sperm concentration and morphology. Supplementation with CoQ10 increases sperm concentration, total and progressive motility. Selenium (Se) supplementation improves the overall semen quality and is related to a higher ejaculated volume. Among vitamins, only vitamin B12 shows a positive effect on semen quality; it increases sperm count and motility and reduces sperm DNA damage. Conclusions: In men showing low-quality semen, diet supplementation with antioxidants may improve the sperm quality by alleviating OS-induced sperm damage and enhancing hormone synthesis and spermatozoa concentration, motility, and morphology. Future clinical trials should be focused on the possible association of several antioxidants to take advantage of combined mechanisms of action.
Recent Advances in the Rheumatic Fever and Rheumatic Heart Disease Continuum
Authors: Rwebembera Joselyn , Nascimento Bruno Ramos , Minja Neema W. , de Loizaga Sarah , Aliku Twalib , dos Santos Luiza Pereira Afonso , Galdino Bruno Fernandes , Corte Luiza Silame , Silva Vicente Rezende , Chang Andrew Young , Dutra Walderez Ornelas , Nunes Maria Carmo Pereira , Beaton Andrea Zawacki
Published: January 2022

Nearly a century after rheumatic fever (RF) and rheumatic heart disease (RHD) was eradicated from the developed world, the disease remains endemic in many low- and middle-income countries (LMICs), with grim health and socioeconomic impacts. The neglect of RHD which persisted for a semi-centennial was further driven by competing infectious diseases, particularly the human immunodeficiency virus (HIV) pandemic. However, over the last two-decades, slowly at first but with building momentum, there has been a resurgence of interest in RF/RHD. In this narrative review, we present the advances that have been made in the RF/RHD continuum over the past two decades since the re-awakening of interest, with a more concise focus on the last decade’s achievements. Such primary advances include understanding the genetic predisposition to RHD, group A Streptococcus (GAS) vaccine development, and improved diagnostic strategies for GAS pharyngitis. Echocardiographic screening for RHD has been a major advance which has unearthed the prevailing high burden of RHD and the recent demonstration of benefit of secondary antibiotic prophylaxis on halting progression of latent RHD is a major step forward. Multiple befitting advances in tertiary management of RHD have also been realized. Finally, we summarize the research gaps and provide illumination on profitable future directions towards global eradication of RHD.
Achromobacter spp. in a Cohort of Non-Selected Pre- and Post-Lung Transplant Recipients
Authors: Crone Cornelia Geisler , Rezahosseini Omid , Schultz Hans Henrik Lawaetz , Qvist Tavs , Johansen Helle Krogh , Nielsen Susanne Dam , Perch Michael
Published: January 2022

Achromobacter is an opportunistic pathogen that mainly causes chronic lung infections in cystic fibrosis (CF) patients and is associated with increased mortality. Little is known about Achromobacter spp. in the lung transplant recipient (LTXr) population. We aimed at describing rates of Achromobacter spp. infection in LTXr prior to, in relation to, and after transplantation, as well as all-cause mortality proportion in infected and uninfected LTXr. We included 288 adult LTXr who underwent lung transplantation (LTX) between 1 January 2010 and 31 December 2019 in Denmark. Bronchoalveolar lavage was performed at regular intervals starting two weeks after transplantation. Positive cultures of Achromobacter spp. were identified in nationwide microbiology registries, and infections were categorized as persistent or transient, according to the proportion of positive cultures. A total of 11 of the 288 LTXr had transient (n = 7) or persistent (n = 4) Achromobacter spp. infection after LTX; CF was the underlying disease in 9 out of 11 LTXr. Three out of the four patients, with persistent infection after LTX, also had persistent infection before LTX. The cumulative incidence of the first episode of infection one year after LTX was 3.8% (95% CI: 1.6–6.0). The incidence rates of transient and persistent infection in the first year after LTX were 27 (12–53) and 15 (5–37) per 1000 person-years of follow-up, respectively. The all-cause mortality proportion one year after LTX was 27% in the Achromobacter spp. infected patients and 12% in the uninfected patients (p = 0.114). Achromobacter spp. mainly affected LTXr with CF as the underlying disease and was rare in non-CF LTXr. Larger studies are needed to assess long-term outcomes of Achromobacter spp. in LTXr.
Acknowledgment to Reviewers of Pathophysiology in 2021
Authors:   Pathophysiology Editorial Office
Published: January 2022

Rigorous peer-reviews are the basis of high-quality academic publishing [...]
Impact of Linker Modification and PEGylation of Vancomycin Conjugates on Structure-Activity Relationships and Pharmacokinetics
Authors: Umstätter Florian , Werner Julia , Zerlin Leah , Mühlberg Eric , Kleist Christian , Klika Karel D. , Hertlein Tobias , Beijer Barbro , Domhan Cornelius , Zimmermann Stefan , Ohlsen Knut , Haberkorn Uwe , Mier Walter , Uhl Philipp
Published: January 2022

As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics. The glycopeptide vancomycin is considered an antibiotic of last resort. Its use is challenged by bacterial strains exhibiting various types of resistance. Therefore, in this study, highly active polycationic peptide-vancomycin conjugates with varying linker characteristics or the addition of PEG moieties were synthesized to optimize pharmacokinetics while retaining or even increasing antimicrobial activity in comparison to vancomycin. The antimicrobial activity of the novel conjugates was determined by microdilution assays on susceptible and vancomycin-resistant bacterial strains. VAN1 and VAN2, the most promising linker-modified derivatives, were further characterized in vivo with molecular imaging and biodistribution studies in rodents, showing that the linker moiety influences both antimicrobial activity and pharmacokinetics. Encouragingly, VAN2 was able to undercut the resistance breakpoint in microdilution assays on vanB and vanC vancomycin-resistant enterococci. Out of all PEGylated derivatives, VAN:PEG1 and VAN:PEG3 were able to overcome vanC resistance. Biodistribution studies of the novel derivatives revealed significant changes in pharmacokinetics when compared with vancomycin. In conclusion, linker modification of vancomycin-polycationic peptide conjugates represents a promising strategy for the modulation of pharmacokinetic behavior while providing potent antimicrobial activity.
JAK2 in Myeloproliferative Neoplasms: Still a Protagonist
Authors: Bader Michael Stephan , Meyer Sara Christina
Published: January 2022

The discovery of the activating V617F mutation in Janus kinase 2 (JAK2) has been decisive for the understanding of myeloproliferative neoplasms (MPN). Activated JAK2 signaling by JAK2, CALR, and MPL mutations has become a focus for the development of targeted therapies for patients with MPN. JAK2 inhibitors now represent a standard of clinical care for certain forms of MPN and offer important benefits for MPN patients. However, several key aspects remain unsolved regarding the targeted therapy of MPN with JAK2 inhibitors, such as reducing the MPN clone and how to avoid or overcome a loss of response. Here, we summarize the current knowledge on the structure and signaling of JAK2 as central elements of MPN pathogenesis and feature benefits and limitations of therapeutic JAK2 targeting in MPN.
A3 Adenosine Receptor Antagonists with Nucleoside Structures and Their Anticancer Activity
Authors: Spinaci Andrea , Buccioni Michela , Dal Ben Diego , Maggi Federica , Marucci Gabriella , Francucci Beatrice , Santoni Giorgio , Lambertucci Catia , Volpini Rosaria
Published: January 2022

The overexpression of the A3 adenosine receptor (AR) in a number of cancer cell types makes it an attractive target for tumor diagnosis and therapy. Hence, in the search for new A3AR ligands, a series of novel 2,N6-disubstituted adenosines (Ados) was synthesized and tested in radioligand binding and functional assays at ARs. Derivatives bearing a 2-phenethylamino group in the N6-position were found to exert higher A3AR affinity and selectivity than the corresponding N6-(2,2-diphenylethyl) analogues. 2-Chloro-N6-phenylethylAdo (15) was found to be a potent full A3AR agonist with a Ki of 0.024 nM and an EC50 of 14 nM, in a cAMP accumulation assay. Unlike 15, the other ligands behaved as A3AR antagonists, which concentration-dependently reduced cell growth and exerted cytostatic activity on the prostate cancer cell line PC3, showing comparable and even more pronounced effects with respect to the ones elicited by the reference full agonist Cl-IB-MECA. In particular, the N6-(2,2-diphenylethyl)-2-phenylethynylAdo (12: GI50 = 14 µM, TGI = 29 µM, and LC50 = 59 µM) showed the highest activity proving to be a potential antitumor agent. The cytostatic effect of both A3AR agonist (Cl-IB-MECA) and antagonists (12 and other newly synthesized compounds) confirm previous observations according to which, in addition to the involvement of A3ARs, other cellular mechanisms are responsible for the anticancer effects of these ligands.
Hydrogels and Cubic Liquid Crystals for Non-Invasive Sampling of Low-Molecular-Weight Biomarkers—An Explorative In Vivo Study
Authors: Morin Maxim , Jankovskaja Skaidre , Ruzgas Tautgirdas , Henricson Joakim , Anderson Chris D. , Brinte Anders , Engblom Johan , Björklund Sebastian
Published: January 2022

The molecular composition of human skin is altered due to diseases, which can be utilized for non-invasive sampling of biomarkers and disease diagnostics. For this to succeed, it is crucial to identify a sampling formulation with high extraction efficiency and reproducibility. Highly hydrated skin is expected to be optimal for increased diffusion of low-molecular-weight biomarkers, enabling efficient extraction as well as enhanced reproducibility as full hydration represents a well-defined endpoint. Here, the aim was to explore water-based formulations with high water activities, ensuring satisfactory skin hydration, for non-invasive sampling of four analytes that may serve as potential biomarkers, namely tryptophan, tyrosine, phenylalanine, and kynurenine. The included formulations consisted of two hydrogels (chitosan and agarose) and two different liquid crystalline cubic phases based on the polar lipid glycerol monooleate, which were all topically applied for 2 h on 35 healthy subjects in vivo. The skin status of all sampling sites was assessed by electrical impedance spectroscopy and transepidermal water loss, enabling explorative correlations between biophysical properties and analyte abundancies. Taken together, all formulations resulted in the successful and reproducible collection of the investigated biomarkers. Still, the cubic phases had an extraction capacity that was approximately two times higher compared to the hydrogels.
Acknowledgment to Reviewers of Pharmaceutics in 2021
Authors:   Pharmaceutics Editorial Office
Published: January 2022

Rigorous peer-reviews are the basis of high-quality academic publishing [...]
Microfluidic Synthesis and Purification of Magnetoliposomes for Potential Applications in the Gastrointestinal Delivery of Difficult-to-Transport Drugs
Authors: Torres Carlos E. , Cifuentes Javier , Gómez Saúl C. , Quezada Valentina , Giraldo Kevin A. , Puentes Paola Ruiz , Rueda-Gensini Laura , Serna Julian A. , Muñoz-Camargo Carolina , Reyes Luis H. , Osma Johann F. , Cruz Juan C.
Published: January 2022

Magnetite nanoparticles (MNPs) have gained significant attention in several applications for drug delivery. However, there are some issues related to cell penetration, especially in the transport of cargoes that show limited membrane passing. A widely studied strategy to overcome this problem is the encapsulation of the MNPs into liposomes to form magnetoliposomes (MLPs), which are capable of fusing with membranes to achieve high delivery rates. This study presents a low-cost microfluidic approach for the synthesis and purification of MLPs and their biocompatibility and functional testing via hemolysis, platelet aggregation, cytocompatibility, internalization, and endosomal escape assays to determine their potential application in gastrointestinal delivery. The results show MLPs with average hydrodynamic diameters ranging from 137 ± 17 nm to 787 ± 45 nm with acceptable polydispersity index (PDI) values (below 0.5). In addition, we achieved encapsulation efficiencies between 20% and 90% by varying the total flow rates (TFRs), flow rate ratios (FRRs), and MNPs concentration. Moreover, remarkable biocompatibility was attained with the obtained MLPs in terms of hemocompatibility (hemolysis below 1%), platelet aggregation (less than 10% with respect to PBS 1×), and cytocompatibility (cell viability higher than 80% in AGS and Vero cells at concentrations below 0.1 mg/mL). Additionally, promising delivery results were obtained, as evidenced by high internalization, low endosomal entrapment (AGS cells: PCC of 0.28 and covered area of 60% at 0.5 h and PCC of 0.34 and covered area of 99% at 4 h), and negligible nuclear damage and DNA condensation. These results confirm that the developed microfluidic devices allow high-throughput production of MLPs for potential encapsulation and efficient delivery of nanostructured cell-penetrating agents. Nevertheless, further in vitro analysis must be carried out to evaluate the prevalent intracellular trafficking routes as well as to gain a detailed understanding of the existing interactions between nanovehicles and cells.
RNA-Based Strategies for Cell Reprogramming toward Pluripotency
Authors: Bailly Anaëlle , Milhavet Ollivier , Lemaitre Jean-Marc
Published: January 2022

Cell therapy approaches to treat a wide range of pathologies have greatly benefited from cell reprogramming techniques that allow the conversion of a somatic cell into a pluripotent cell. Many technological developments have been made since the initial major discovery of this biological process. Recently reprogramming methods based on the use of RNA have emerged and seem very promising. Thus, in this review we will focus on presenting the interest of such methods for cell reprogramming but also how these RNA-based strategies can be extended to eventually lead to medical applications to improve healthspan and longevity.
Bioengineered Efficacy Models of Skin Disease: Advances in the Last 10 Years
Authors: Stanton Diana Nicole , Ganguli-Indra Gitali , Indra Arup Kumar , Karande Pankaj
Published: January 2022

Models of skin diseases, such as psoriasis and scleroderma, must accurately recapitulate the complex microenvironment of human skin to provide an efficacious platform for investigation of skin diseases. Skin disease research has been shifting from less complex and less relevant 2D (two-dimensional) models to significantly more relevant 3D (three-dimensional) models. Three-dimensional modeling systems are better able to recapitulate the complex cell–cell and cell–matrix interactions that occur in vivo within skin. Three-dimensional human skin equivalents (HSEs) have emerged as an advantageous tool for the study of skin disease in vitro. These 3D HSEs can be highly complex, containing both epidermal and dermal compartments with integrated adnexal structures. The addition of adnexal structures to 3D HSEs has allowed researchers to gain more insight into the complex pathology of various hereditary and acquired skin diseases. One method of constructing 3D HSEs, 3D bioprinting, has emerged as a versatile and useful tool for generating highly complex HSEs. The development of commercially available 3D bioprinters has allowed researchers to create highly reproducible 3D HSEs with precise integration of multiple adnexal structures. While the field of bioengineered models for study of skin disease has made tremendous progress in the last decade, there are still significant efforts necessary to create truly biomimetic skin disease models. In future studies utilizing 3D HSEs, emphasis must be placed on integrating all adnexal structures relevant to the skin disease under investigation. Thorough investigation of the intricate pathology of skin diseases and the development of effective treatments requires use of highly efficacious models of skin diseases.
Human Abductive Cognition Vindicated: Computational Locked Strategies, Dissipative Brains, and Eco-Cognitive Openness
Authors: Magnani Lorenzo
Published: January 2022

Locked and unlocked strategies are illustrated in this article as concepts that deal with important cognitive aspects of deep learning systems. They indicate different inference routines that refer to poor (locked) to rich (unlocked) cases of creative production of creative cognition. I maintain that these differences lead to important consequences when we analyze computational deep learning programs, such as AlphaGo/AlphaZero, which are able to realize various types of abductive hypothetical reasoning. These programs embed what I call locked abductive strategies, so, even if they present spectacular performances for example in games, they are characterized by poor types of hypothetical creative cognition insofar as they are constrained in what I call eco-cognitive openness. This openness instead characterizes unlocked human cognition that pertains to higher kinds of abductive reasoning, in both the creative and diagnostic cases, in which cognitive strategies are instead unlocked. This special kind of “openness” is physically rooted in the fundamental character of the human brain as an open system constantly coupled with the environment (that is, an “open” or “dissipative” system): its activity is the uninterrupted attempt to achieve the equilibrium with the environment in which it is embedded, and this interplay can never be switched off without producing severe damage to the brain. The brain cannot be conceived as deprived of its physical quintessence that is its openness. In the brain, contrary to the computational case, ordering is not derived from the outside thanks to what I have called in a recent book “computational domestication of ignorant entities”, but it is the direct product of an “internal” open dynamical process of the system.
Acknowledgment to Reviewers of Photonics in 2021
Authors:   Photonics Editorial Office
Published: January 2022

Rigorous peer-reviews are the basis of high-quality academic publishing [...]