bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including Bartonella: A Report of 3 Cases and a Literature Review
Authors: Horowitz Richard I. , Fallon John , Freeman Phyllis R.
Published: May 2024

Three patients with relapsing and remitting borreliosis, babesiosis, and bartonellosis, despite extended anti-infective therapy, were prescribed double-dose dapsone combination therapy (DDDCT) for 8 weeks, followed by one or several two-week courses of pulsed high-dose dapsone combination therapy (HDDCT). We discuss these patients’ cases to illustrate three important variables required for long-term remission. First, diagnosing and treating active co-infections, including Babesia and Bartonella were important. Babesia required rotations of multiple anti-malarial drug combinations and herbal therapies, and Bartonella required one or several 6-day HDDCT pulses to achieve clinical remission. Second, all prior oral, intramuscular (IM), and/or intravenous (IV) antibiotics used for chronic Lyme disease (CLD)/post-treatment Lyme disease syndrome (PTLDS), irrespective of the length of administration, were inferior in efficacy to short-term pulsed biofilm/persister drug combination therapy i.e., dapsone, rifampin, methylene blue, and pyrazinamide, which improved resistant fatigue, pain, headaches, insomnia, and neuropsychiatric symptoms. Lastly, addressing multiple factors on the 16-point multiple systemic infectious disease syndrome (MSIDS) model was important in achieving remission. In conclusion, DDDCT with one or several 6–7-day pulses of HDDCT, while addressing abnormalities on the 16-point MSIDS map, could represent a novel effective clinical and anti-infective strategy in CLD/PTLDS and associated co-infections including Bartonella.
Exploring Propolis as a Sustainable Bio-Preservative Agent to Control Foodborne Pathogens in Vacuum-Packed Cooked Ham
Authors: Rendueles Eugenia , Mauriz Elba , Sanz-Gómez Javier , González-Paramás Ana M. , Adanero-Jorge Félix , García-Fernández Camino
Published: May 2024

The search for natural food additives makes propolis an exciting alternative due to its known antimicrobial activity. This work aims to investigate propolis’ behavior as a nitrite substitute ingredient in cooked ham (a ready-to-eat product) when confronted with pathogenic microorganisms of food interest. The microbial evolution of Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, and Clostridium sporogenes inoculated at known doses was examined in different batches of cooked ham. The design of a challenge test according to their shelf life (45 days), pH values, and water activity allowed the determination of the mesophilic aerobic flora, psychotropic, and acid lactic bacteria viability. The test was completed with an organoleptic analysis of the samples, considering possible alterations in color and texture. The cooked ham formulation containing propolis instead of nitrites limited the potential growth (δ < 0.5 log10) of all the inoculated microorganisms until day 45, except for L. monocytogenes, which in turn exhibited a bacteriostatic effect between day 7 and 30 of the storage time. The sensory analysis revealed the consumer’s acceptance of cooked ham batches including propolis as a natural additive. These findings suggest the functionality of propolis as a promising alternative to artificial preservatives for ensuring food safety and reducing the proliferation risk of foodborne pathogens in ready-to-eat products.
Bacillus velezensis YXDHD1-7 Prevents Early Blight Disease by Promoting Growth and Enhancing Defense Enzyme Activities in Tomato Plants
Authors: Li Wangxi , Sun Lili , Wu Hangtao , Gu Wenjie , Lu Yusheng , Liu Chong , Zhang Jiexin , Li Wanling , Zhou Changmin , Geng Haoyang , Li Yaying , Peng Huanlong , Shi Chaohong , Wang Dan , Peng Guixiang
Published: May 2024

Bacillus velezensis is well known as a plant growth-promoting rhizobacteria (PGPR) and biocontrol agent. Nevertheless, there are very few reports on the study of B. velezensis on tomato early blight, especially the biocontrol effects among different inoculation concentrations. In this study, an IAA-producing strain, Bacillus velezensis YXDHD1-7 was isolated from the tomato rhizosphere soil, which had the strongest inhibitory effect against Alternaria solani. Inoculation with bacterial suspensions of this strain promoted the growth of tomato seedlings effectively. Furthermore, inoculations at 106, 107, and 108 cfu/mL resulted in control efficacies of 100%, 83.15%, and 69.90%, respectively. Genome sequencing showed that it possesses 22 gene clusters associated with the synthesis of antimicrobial metabolites and genes that are involved in the production of IAA. Furthermore, it may be able to produce spermidine and volatile compounds that also enhance plant growth and defense responses. Our results suggest that strain YXDHD1-7 prevents early blight disease by promoting growth and enhancing the defense enzyme activities in tomato plants. This strain is a promising candidate for an excellent microbial inoculant that can be used to enhance tomato production.
Management Strategies for Common Animal Bites in Pediatrics: A Narrative Review on the Latest Progress
Authors: Septelici Dragos , Carbone Giulia , Cipri Alessandro , Esposito Susanna
Published: May 2024

Animal bites are a common reason for children to visit primary care and emergency departments. Dog bites are the most prevalent, followed by cat bites at 20–30%. Other animals such as bats, monkeys, snakes, and rats collectively contribute less than 1% of cases. Hospitalization is necessary in only 4% of animal bite incidents. The main aim of this narrative review is to summarize the main protocols currently followed in pediatrics in cases involving the most common bites from different animal species. Analysis of the literature showed that the management of common animal bites in children presents a multifaceted challenge requiring a comprehensive understanding of the epidemiology, clinical presentation, and treatment modalities associated with each specific species. Effective wound management is paramount in reducing the risk of infection and promoting optimal healing outcomes. Additionally, tetanus vaccination status should be assessed and updated as necessary, and prophylactic antibiotics may be indicated in certain cases to prevent secondary infections. Furthermore, the role of rabies prophylaxis cannot be overstated, particularly in regions where rabies is endemic or following bites from high-risk animals. In addition to medical management, psychosocial support for both the child and their caregivers is integral to the overall care continuum. Future studies exploring the efficacy of novel treatment modalities, such as topical antimicrobial agents or advanced wound dressings, may offer new insights into optimizing wound healing and reducing the risk of complications.
Malian Children’s Core Gut Mycobiome
Authors: Abdillah Abdourahim , Kodio Aly , Ranque Stéphane
Published: May 2024

Because data on the fungal gut community structure of African children are scarce, we aimed to describe it by reanalysing rRNA ITS1 and ITS2 metabarcoding data from a study designed to assess the influence of microbiota in malaria susceptibility in Malian children from the Dogon country. More specifically, we aimed to establish the core gut mycobiome and compare the gut fungal community structure of breastfed children, aged 0–2 years, with other age groups. Briefly, DNA was extracted from 296 children’s stool samples. Both rRNA ITS1 and ITS2 genomic barcodes were amplified and subjected to Illumina MiSeq sequencing. The ITS2 barcode generated 1,975,320 reads and 532 operational taxonomic units (OTUs), while the ITS1 barcode generated 647,816 reads and 532 OTUs. The alpha diversity was significantly higher by using the ITS1 compared to the ITS2 barcode (p < 0.05); but, regardless of the ITS barcode, we found no significant difference between breastfed children, aged 0–2 years, compared to the other age groups. The core gut mycobiome of the Malian children included Saccharomyces cerevisiae, Candida albicans, Pichia kudriavzevii, Malassezia restricta, Candida tropicalis and Aspergillus section Aspergillus, which were present in at least 50% of the 296 children. Further studies in other African countries are warranted to reach a global view of African children’s core gut mycobiome.
A New Insight into the Genesis of Graphite Deposits in Madagascar Using U–Pb Zircon Dating and Electron Microprobe Analysis
Authors: Yang Ming-Jian , Di Yong-Jun , Zhang Da , Wu Da-Tian , Fang Ye , Zhang Xin-Ming
Published: May 2024

Madagascar is globally recognized as an important producer of high-quality flaky graphite. However, current research on graphite deposits in Madagascar remains insufficient. Previous studies have linked the genesis of Madagascan graphite deposits to the metamorphism of sedimentary organic matter. Here, we provide a case study of graphite deposits in Madagascar, combining new data from the Ambahita graphite deposit (AMG) in southern Madagascar with data from the Antanisoa graphite deposit (ANG) in central Madagascar and the Vohitasara graphite deposit (VOG) on the east coast of Madagascar. We note that the mineral assemblages of graphite-bearing rocks in the AMG, ANG, and VOG are not typical of metamorphic mineral assemblages but rather the results of filling and metasomatism by mantle-derived fluids that occurred after peak metamorphism. Electron microprobe analysis indicates that the graphite of the AMG, VOG, and ANG is usually associated with phlogopite or Mg-biotite; the phlogopite shares a common genesis with other widespread phlogopite deposits across Madagascar. We reveal that the distribution of graphite deposits in Madagascar is primarily controlled by ductile shear zones between blocks. Ductile shear zones that extend deep into the mantle can provide an ideal migration channel and architecture for the emplacement of mantle-derived fluids. The graphite mineralization formed no earlier than the peak metamorphism (490 Ma) and no later than the intrusion of pegmatite veins (389 ± 5 Ma). The distribution of graphite deposits, graphite orebody morphologies, mineral associations, and geochemical data suggest that the genesis of graphite deposits in Madagascar is linked to mantle-derived fluid filling rather than the metamorphism of sediments, as previously suggested. These findings have important implications for similar deposits in Madagascar and potentially globally.
Oxygen Defects Containing TiN Films for the Hydrogen Evolution Reaction: A Robust Thin-Film Electrocatalyst with Outstanding Performance
Authors: Laghrissi Ayoub , Es-Souni Mohammed
Published: May 2024

Density functional theory (DFT) calculations of hydrogen adsorption on titanium nitride had previously shown that hydrogen may adsorb on both titanium and nitrogen sites with a moderate adsorption energy. Further, the diffusion barrier was also found to be low. These findings may qualify TiN, a versatile multifunctional material with electronic conductivity, as an electrode material for the hydrogen evolution reaction (HER). This was the main impetus of this study, which aims to experimentally and theoretically investigate the electrocatalytic properties of TiN layers that were processed on a Ti substrate using reactive ion sputtering. The properties are discussed, focusing on the role of oxygen defects introduced during the sputtering process on the HER. Based on DFT calculations, it is shown that these oxygen defects alter the electronic environment of the Ti atoms, which entails a low hydrogen adsorption energy in the range of −0.1 eV; this leads to HER performances that match those of Pt-NPs in acidic media. When a few nanometer-thick layers of Pd-NPs are sputtered on top of the TiN layer, the performance is drastically reduced. This is interpreted in terms of oxygen defects being scavenged by the Pd-NPs near the surface, which is thought to reduce the hydrogen adsorption sites.
The Time-Dependent Interfacial Adhesion between Artificial Rock and Fresh Mortar Modified by Nanoclay
Authors: Wang Xiaoyun , Van Tittelboom Kim , Zhang Jiaolong , Tao Yaxin , Rong Yao , Taerwe Luc , De Schutter Geert , Yuan Yong
Published: May 2024

The time-dependent interfacial adhesion between rock and fresh mortar is key for printing concrete linings in mountain tunnels. However, a scientific deficit exists in the time-dependent evolution of the interfacial adhesion, which can cause adhesion failure when printing tunnel lining. Nanoclay has the potential to increase the interfacial adhesion and eliminate the adhesion failure. Before the actual printing of tunnel linings, the time-dependent interfacial adhesion between artificial rock and fresh mortar modified by nanoclay should be understood. This paper studied the time-dependent interfacial adhesion based on fast tack tests, fast shear tests, and isothermal calorimetry tests. With the addition of nanoclay, the maximum tensile stress and the maximum shear stress increased. Compared with a reference series, the maximum interfacial tensile stress in a 0.3% nanoclay series increased by 106% (resting time 1 min) and increased by 209% (resting time 32 min). A two-stage evolution of the interfacial adhesion was found with the addition of nanoclay. In the first stage, the time-dependent interfacial adhesion increased rapidly. A 0.3% NC series showed an increase rate six times higher than that of the reference series. As the matrices aged, the increase rate slowed down and followed a linear pattern of increase, still higher than that of the reference series. The stiffening of fresh matrices resulted in the interface failure mode transition from a ductile failure to a brittle failure. The effect of nanoclay on flocculation and on accelerating the hydration contributed to the time-dependent interfacial adhesion between artificial rock and fresh mortar.
Optimizing Josephson Junction Reproducibility in 30 kV E-Beam Lithography: An Analysis of Backscattered Electron Distribution
Authors: Rebello Arthur M. , Ruela Lucas M. , Moreto Gustavo , Klein Naiara Y. , Martins Eldues , Oliveira Ivan S. , Sinnecker João P. , Rouxinol Francisco
Published: May 2024

This paper explores methods to enhance the reproducibility of Josephson junctions, which are crucial elements in superconducting quantum technologies, when employing the Dolan technique in 30 kV e-beam processes. The study explores the influence of dose distribution along the bridge area on reproducibility, addressing challenges related to fabrication sensitivity. Experimental methods include e-beam lithography, with electron trajectory simulations shedding light on the behavior of backscattered electrons. Wedescribe the fabrication of various Josephson junction geometries and analyze the correlation between the success rates of different lithography patterns and the simulated distribution of backscattered electrons. Our findings demonstrate a success rate of up to 96.3% for the double-resist 1-step low-energy e-beam lithography process. As a means of implementation strategy, we provide a geometric example that takes advantage of simulated stability regions to administer a controlled, uniform dose across the junction area, introducing novel features to overcome the difficulties associated with fabricating bridge-like structures.
Pyroclastic Dust from Arequipa-Peru Decorated with Iron Oxide Nanoparticles and Their Ecotoxicological Properties in Water Flea D. magna
Authors: Ramos-Guivar Juan A. , Alca-Ramos Yacu V. , Manrique-Castillo Erich V. , Mendoza-Villa F. , Checca-Huaman Noemi-Raquel , Rueda-Vellasmin Renzo , Passamani Edson C.
Published: May 2024

A novel magnetic composite made of Peruvian pyroclastic dust material decorated with maghemite nanoparticles was synthesized and characterized using a variety of analytic techniques. The 13 nm maghemite nanoparticles were grown on the pyroclastic dust using the conventional coprecipitation chemical route. A short-term acute assay was developed to study the ecotoxicological behavior of the water flea, Daphnia magna. A 24 h-lethal concentration (LC50) value equal to 123.6 mg L−1 was determined only for the magnetic composite. While the pyroclastic dust material did not exhibit a lethal concentration, it caused morphologically significant changes (p < 0.05) for heart and tail parameters at high concentrations. Morphologies exposed to the magnetic composite above the 24 h-LC50 revealed less tolerance and significant changes in the body, heart, antenna, and eye. Hence, it affects biomarker growth and swimming. The reproduction rate was not affected by the raw pyroclastic dust material. However, the number of individuals showed a decrease with increasing composite concentrations. The present study indicates the LC50 value, which can be used as a reference concentration for in-situ water cleaning with this material without damaging or changing the Daphnia magna ecosystem.
Adjoint Algorithm Design of Selective Mode Reflecting Metastructure for BAL Applications
Authors: Li Zean , Zhang Xunyu , Qiu Cheng , Xu Yingshuai , Zhou Zhipeng , Wei Ziyuan , Qiao Yiman , Chen Yongyi , Wang Yubing , Liang Lei , Lei Yuxin , Song Yue , Jia Peng , Zeng Yugang , Qin Li , Ning Yongqiang , Wang Lijun
Published: May 2024

Broad-area lasers (BALs) have found applications in a variety of crucial fields on account of their high output power and high energy transfer efficiency. However, they suffer from poor spatial beam quality due to multi-mode behavior along the waveguide transverse direction. In this paper, we propose a novel metasurface waveguide structure acting as a transverse mode selective back-reflector for BALs. In order to effectively inverse design such a structure, a digital adjoint algorithm is introduced to adapt the considerably large design area and the high degree of freedom. As a proof of the concept, a device structure with a design area of 40 × 20 μm2 is investigated. The simulation results exhibit high fundamental mode reflection (above 90%), while higher-order transverse mode reflections are suppressed below 0.2%. This is, to our knowledge, the largest device structure designed based on the inverse method. We exploited such a device and the method and further investigated the device’s robustness and feasibility of the inverse method. The results are elaborately discussed.
Klein Tunneling in β12 Borophene
Authors: Lai Jinhao , Wang Lekang , Li Fu , Zhang Hongbin , Zhang Qingtian
Published: May 2024

Motivated by the recent observation of Klein tunneling in 8-Pmmn borophene, we delve into the phenomenon in β12 borophene by employing tight-binding approximation theory to establish a theoretical mode. The tight-binding model is a semi-empirical method for establishing the Hamiltonian based on atomic orbitals. A single cell of β12 borophene contains five atoms and multiple central bonds, so it creates the complexity of the tight-binding model Hamiltonian of β12 borophene. We investigate transmission across one potential barrier and two potential barriers by changing the width and height of barriers and the distance between two potential barriers. Regardless of the change in the barrier heights and widths, we find the interface to be perfectly transparent for normal incidence. For other angles of incidence, perfect transmission at certain angles can also be observed. Furthermore, perfect and all-angle transmission across a potential barrier takes place when the incident energy approaches the Dirac point. This is analogous to the “super”, all-angle transmission reported for the dice lattice for Klein tunneling across a potential barrier. These findings highlight the significance of our theoretical model in understanding the complex dynamics of Klein tunneling in borophene structures.
UV/Ozone-Treated and Sol–Gel-Processed Y2O3 Insulators Prepared Using Gelation-Delaying Precursors
Authors: Lee Sangwoo , Cho Yoonjin , Heo Seongwon , Bae Jin-Hyuk , Kang In-Man , Kim Kwangeun , Lee Won-Yong , Jang Jaewon
Published: May 2024

In this study, a Y2O3 insulator was fabricated via the sol–gel process and the effect of precursors and annealing processes on its electrical performance was studied. Yttrium(III) acetate hydrate, yttrium(III) nitrate tetrahydrate, yttrium isopropoxide oxide, and yttrium(III) tris (isopropoxide) were used as precursors, and UV/ozone treatment and high-temperature annealing were performed to obtain Y2O3 films from the precursors. The structure and surface morphologies of the films were characterized via grazing-incidence X-ray diffraction and scanning probe microscopy. Chemical component analysis was performed via X-ray spectroscopy. Electrical insulator characteristics were analyzed based on current density versus electrical field data and frequency-dependent dielectric constants. The Y2O3 films fabricated using the acetate precursor and subjected to the UV/ozone treatment showed a uniform and flat surface morphology with the lowest number of oxygen vacancy defects and unwanted byproducts. The corresponding fabricated capacitors showed the lowest current density (Jg) value of 10−8 A/cm2 at 1 MV/cm and a stable dielectric constant in a frequency range of 20 Hz–100 KHz. At 20 Hz, the dielectric constant was 12.28, which decreased to 10.5 at 105 Hz. The results indicate that high-quality, high-k insulators can be fabricated for flexible electronics using suitable precursors and the suggested low-temperature fabrication methods.
Heat-Annealed Zinc Oxide on Flexible Carbon Nanotube Paper and Exposed to Gradient Light to Enhance Its Photoelectric Response
Authors: Liu Jih-Hsin , Shen Pi-Yu
Published: May 2024

Buckypaper (BP), a flexible and porous material, exhibits photovoltaic properties when exposed to light. In this study, we employed radio frequency (RF) sputtering of zinc oxide (ZnO) followed by rapid thermal annealing to enhance the photovoltaic response of BP. We investigated the impact of various sputtering parameters, such as the gas flow ratio of argon to oxygen and deposition time, on the morphology, composition, resistivity, and photovoltaic characteristics of ZnO-modified BP. Additionally, the photovoltaic performance of the samples under different illumination modes and wavelengths was compared. It was found that optimal sputtering conditions—argon to oxygen flow ratio of 1:2, deposition time of 20 min, and power of 100 watts—resulted in a ZnO film thickness of approximately 45 nanometers. After annealing at 400 °C for 10 min, the ZnO-modified BP demonstrated a significant increase in photocurrent and photovoltage, along with a reduction in resistivity, compared to unmodified BP. Moreover, under gradient illumination, the ZnO-modified BP exhibited a photovoltage enhancement of 14.70-fold and a photocurrent increase of 13.86-fold, compared to uniform illumination. Under blue light, it showed a higher photovoltaic response than under other colors. The enhancement in photovoltaic response is attributed to the formation of a Schottky junction between ZnO and BP, an increased carrier concentration gradient, and an expanded light absorption spectrum. Our results validate that ZnO sputtering followed by annealing is an effective method for modifying BP for photovoltaic applications such as solar cells and photodetectors.
Pain Catastrophizing: How Far Have We Come
Authors: Simic Katarina , Savic Boris , Knezevic Nebojsa Nick
Published: May 2024

The perception of pain is strongly influenced by various social, emotional, and cognitive factors. A psychological variable which has consistently been shown to exert its influence on pain is a cognitive process referred to as pain catastrophizing. Numerous studies have found it to be a strong predictor of pain intensity and disability across different clinical populations. It signifies a maladaptive response to pain marked by an exaggerated negative assessment, magnification of symptoms related to pain, and, in general, a tendency to experience marked pain-related worry, as well as experiencing feelings of helplessness when it comes to dealing with pain. Pain catastrophizing has been correlated to many adverse pain-related outcomes, including poor treatment response, unsatisfactory quality of life, and high disability related to both acute and chronic pain. Furthermore, there has been consistent evidence in support of a correlation between pain catastrophizing and mental health disorders, such as anxiety and depression. In this review, we aim to provide a comprehensive overview of the current state of knowledge regarding pain catastrophizing, with special emphasis on its clinical significance, and emerging treatment modalities which target it.
Evaluation of the Effect of Parenting Style and Parental Mealtime Actions on the Eating Behavior of Children with Epilepsy
Authors: Balcı Tutku , Çakır Biçer Nihan , Gazeteci Tekin Hande , Edem Pınar
Published: May 2024

Background: Research on the interaction of parenting style, parents’ mealtime behaviors, and children’s eating behavior in the presence of chronic disease is limited. This study aimed to investigate the impact of parenting style and parental mealtime actions on the eating behavior of children with epilepsy. Methods: Thirty-one children with epilepsy, thirty-one healthy children (aged 4–9 years), and their parents were included. The Multidimensional Assessment of Parenting Scale (MAPS), Parent Mealtime Action Scale, Children’s Eating Behavior Questionnaire, and Healthy Eating Index (HEI)-2015 were applied. The MAPS, HEI-2015 scores, and body mass index for age Z scores were similar in both groups (p > 0.05). In the epilepsy group, the food approach behavior score was higher, and positive correlations were noted between broadband negative parenting and food approach behavior, and the HEI-2015 score and broadband positive parenting (p < 0.05). Regression analysis showed that broadband negative parenting and snack modeling increased the food approach behavior in the epilepsy group. Owing to the chronic disease, the effects of parent–child interaction on the child’s eating behavior in the epilepsy group differed from those of healthy children reported in the literature.
Data on Demodex Ectoparasite Infestation in Patients Attending an Outpatient Clinic in Greece
Authors: Kargadouri Anastasia , Beleri Stavroula , Patsoula Eleni
Published: May 2024

Demodex mites are acari, common ectoparasites of humans and other mammalian pilosebaceous units. Demodicosis occurs when mites overpopulate the skin, causing several skin disorders. Our aim was to investigate the prevalence of demodicosis in patients with suspicious clinical features, such as cheek redness, itching, and skin sensitivity, who presented at the outpatient clinic of the Andreas Syggros Dermatology Hospital in Greece. We studied 184 individuals aged between 18 and 97 years and analyzed the content of pilosebaceous units by microscopy to determine the density of Demodex mites. Samples were evaluated as positive when Demodex spp. densities equaled or exceeded 5 mites per square cm. Sixty-six percent of the examined subjects were positive for demodicosis. The age distribution was statistically normal (p = 0.2), and the median age was 51.29 years. Seventy percent of the patients were females, and 30% were males, while 64.46% of the demodicosis-positive individuals were females, and 35.54% were males. We observed a rise in the percentage of males as the age of the patients increased. Demodicosis can be a challenging disease because it presents apart from the typical symptoms, with a variety of nonspecific symptoms mimicking other dermatological skin conditions. Therefore, it is important to investigate Demodex spp. in patients who present with common facial dermatological diseases to improve treatment results. Further studies could contribute to a better understanding of the pathogenic role of Demodex mites and how this role is affected by mite density, host sex and age.
Mass Production of Rg1-Loaded Small Extracellular Vesicles Using a 3D Bioreactor System for Enhanced Cardioprotective Efficacy of Doxorubicin-Induced Cardiotoxicity
Authors: Di Yunfeng , Zhao Shuang , Fan Huilan , Li Wei , Jiang Guangjian , Wang Yong , Li Chun , Wang Wei , Wang Jingyu
Published: May 2024

Background: Small extracellular vesicles (sEVs) obtained from human umbilical cord mesenchymal stromal cells (MSCs) have shown cardioprotective efficacy in doxorubicin-induced cardiotoxicity (DIC). However, their clinical application is limited due to the low yield and high consumption. This study aims to achieve large-scale production of sEVs using a three-dimensional (3D) bioreactor system. In addition, sEVs were developed to deliver Ginsenoside Rg1 (Rg1), a compound derived from traditional Chinese medicine, Ginseng, that has cardioprotective properties but limited bioavailability, to enhance the treatment of DIC. Methods: The 3D bioreactor system with spinner flasks was used to expand human umbilical cord MSCs and collect MSC-conditioned medium. Subsequently, sEVs were isolated from the conditioned medium using differential ultra-centrifugation (dUC). The sEVs were loaded with Ginsenoside Rg1 by electroporation and evaluated for cardioprotective efficacy using Cell Counting Kit-8 (CCK-8) analysis, Annexin V/PI staining and live cell count of H9c2 cells under DIC. Results: Using the 3D bioreactor system with spinner flasks, the expansion of MSCs reached ~600 million, and the production of sEVs was up to 2.2 × 1012 particles in five days with significantly reduced bench work compared to traditional 2D flasks. With the optimized protocol, the Ginsenoside Rg1 loading efficiency of sEVs by electroporation was ~21%, higher than sonication or co-incubation. Moreover, Rg1-loaded sEVs had attenuated DOX-induced cardiotoxicity with reduced apoptosis compared to free Ginsenoside Rg1 or sEVs. Conclusions: The 3D culture system scaled up the production of sEVs, which facilitated the Rg1 delivery and attenuated cardiomyocyte apoptosis, suggesting a potential treatment of DOX-induced cardiotoxicity.
Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV
Authors: Mayer Bryan T. , Zhang Lily , deCamp Allan C. , Yu Chenchen , Sato Alicia , Angier Heather , Seaton Kelly E. , Yates Nicole , Ledgerwood Julie E. , Mayer Kenneth , Caskey Marina , Nussenzweig Michel , Stephenson Kathryn , Julg Boris , Barouch Dan H. , Sobieszczyk Magdalena E. , Edupuganti Srilatha , Kelley Colleen F. , McElrath M. Juliana , Gelderblom Huub C. , Pensiero Michael , McDermott Adrian , Gama Lucio , Koup Richard A. , Gilbert Peter B. , Cohen Myron S. , Corey Lawrence , Hyrien Ollivier , Tomaras Georgia D. , Huang Yunda
Published: May 2024

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.
Development and Efficacy Evaluation of Innovative Cosmetic Formulations with Caryocar brasiliense Fruit Pulp Oil Encapsulated in Freeze-Dried Liposomes
Authors: Kakuda Letícia , Maia Campos Patrícia M. B. G. , Oliveira Wanderley P.
Published: May 2024

Encapsulation and drying technologies allow the engineering of innovative raw materials from plant biodiversity, with potential applications in pharmaceutical and cosmetic fields. Lipid-based nanoencapsulation stands out for its efficiency, ease of production, and versatility in encapsulating substances, whether hydrophilic or lipophilic. This work aimed at encapsulating pequi oil in liposomes and freeze-dried liposomes to enhance its stability and functional benefits, such as skin hydration and anti-aging effects, for use in innovative cosmetic formulations. Pequi oil—extracted from the Caryocar brasiliense fruit pulp, a plant species from Brazilian plant biodiversity—is rich in secondary metabolites and fatty acids. Liposomes and dried liposomes offer controlled production processes and seamless integration into cosmetic formulations. The physicochemical analysis of the developed liposomes confirmed that the formulations are homogeneous and electrokinetically stable, as evidenced by consistent particle size distribution and zeta potential values, respectively. The gel-type formulations loaded with the dried liposomes exhibit enhanced skin hydration, improved barrier function, and refined microrelief, indicating improvements in skin conditions. These results highlight the potential of dried liposomes containing pequi oil for the development of innovative cosmeceutical products. This research contributes to the valorization of Brazilian biodiversity by presenting an innovative approach to leveraging the dermatological benefits of pequi oil in cosmetic applications.
Development of 5-Fluorouracil/pH-Responsive Adjuvant-Embedded Extracellular Vesicles for Targeting αvβ3 Integrin Receptors in Tumors
Authors: Kim Jiseung , Lee Eunsol , Lee Eun Seong
Published: May 2024

To selectively target and treat murine melanoma B16BL6 tumors expressing αvβ3 integrin receptors, we engineered tumor-specific functional extracellular vesicles (EVs) tailored for the targeted delivery of antitumor drugs. This objective was achieved through the incorporation of a pH-responsive adjuvant, cyclic arginine-glycine-aspartic acid peptide (cRGD, serving as a tumor-targeting ligand), and 5-fluorouracil (5-FU, employed as a model antitumor drug). The pH-responsive adjuvant, essential for modulating drug release, was synthesized by chemically conjugating 3-(diethylamino)propylamine (DEAP) to deoxycholic acid (DOCA, a lipophilic substance capable of integrating into EVs’ membranes), denoted as DEAP-DOCA. The DOCA, preactivated using N-(2-aminoethyl)maleimide (AEM), was chemically coupled with the thiol group of the cRGD-DOCA through the thiol–maleimide click reaction, resulting in the formation of cRGD-DOCA. Subsequently, DEAP-DOCA, cRGD-DOCA, and 5-FU were efficiently incorporated into EVs using a sonication method. The resulting tumor-targeting EVs, expressing cRGD ligands, demonstrated enhanced in vitro/in vivo cellular uptake specifically for B16BL6 tumors expressing αvβ3 integrin receptors. The ionization characteristics of the DEAP in DEAP-DOCA induced destabilization of the EVs membrane at pH 6.5 through protonation of the DEAP substance, thereby expediting 5-FU release. Consequently, an improvement in the in vivo antitumor efficacy was observed for B16BL6 tumors. Based on these comprehensive in vitro/in vivo findings, we anticipate that this EV system holds substantial promise as an exceptionally effective platform for antitumor therapeutic delivery.
Characterization of Surfactant Spheroidal Micelle Structure for Pharmaceutical Applications: A Novel Analytical Framework
Authors: De Caro Liberato , Stoll Thibaud , Grandeury Arnaud , Gozzo Fabia , Giannini Cinzia
Published: May 2024

We introduce an innovative theoretical framework tailored for the analysis of Pair Distribution Function (PDF) data derived from Small-Angle X-ray Scattering (SAXS) measurements of core-shell micelles. The new approach involves the exploitation of the first derivative of the PDF and the derivation of analytical equations to solve the core-shell micelle structure under the hypothesis of a spheroidal shape. These analytical equations enable us to determine the micelle’s aggregation number, degree of ellipticity, and contrast in electron density between the core-shell and shell-buffer regions after having determined the whole micelle size and its shell size from the analysis of the first derivative of the PDF. We have formulated an overdetermined system of analytical equations based on the unknowns that characterize the micelle structure. This allows us to establish a Figure of Merit, which is utilized to identify the most reliable solution within the system of equations.
Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics
Authors: Abioye Amos , Akintade Damilare , Mitchell James , Olorode Simisade , Adejare Adeboye
Published: May 2024

Despite the extensive research successes and continuous developments in modern medicine in terms of diagnosis, prevention, and treatment, the lack of clinically useful disease-modifying drugs or immunotherapeutic agents that can successfully treat or prevent neurodegenerative diseases is an ongoing challenge. To date, only one of the 244 drugs in clinical trials for the treatment of neurodegenerative diseases has been approved in the past decade, indicating a failure rate of 99.6%. In corollary, the approved monoclonal antibody did not demonstrate significant cognitive benefits. Thus, the prevalence of neurodegenerative diseases is increasing rapidly. Therefore, there is an urgent need for creative approaches to identifying and testing biomarkers for better diagnosis, prevention, and disease-modifying strategies for the treatment of neurodegenerative diseases. Overexpression of the endogenous α-synuclein has been identified as the driving force for the formation of the pathogenic α-synuclein (α-Syn) conformers, resulting in neuroinflammation, hypersensitivity, endogenous homeostatic responses, oxidative dysfunction, and degeneration of dopaminergic neurons in Parkinson’s disease (PD). However, the conformational plasticity of α-Syn proffers that a certain level of α-Syn is essential for the survival of neurons. Thus, it exerts both neuroprotective and neurotoxic (regulatory) functions on neighboring neuronal cells. Furthermore, the aberrant metastable α-Syn conformers may be subtle and difficult to detect but may trigger cellular and molecular events including immune responses. It is well documented in literature that the misfolded α-Syn and its conformers that are released into the extracellular space from damaged or dead neurons trigger the innate and adaptive immune responses in PD. Thus, in this review, we discuss the nonintuitive plasticity and immunogenicity of the α-Syn conformers in the brain immune cells and their physiological and pathological consequences on the neuroimmune responses including neuroinflammation, homeostatic remodeling, and cell-specific interactions that promote neuroprotection in PD. We also critically reviewed the novel strategies for immunotherapeutic delivery interventions in PD pathogenesis including immunotherapeutic targets and potential nanoparticle-based smart drug delivery systems. It is envisioned that a greater understanding of the nonintuitive immunogenicity of aberrant α-Syn conformers in the brain’s microenvironment would provide a platform for identifying valid therapeutic targets and developing smart brain delivery systems for clinically effective disease-modifying immunotherapeutics that can aid in the prevention and treatment of PD in the future.
The Role of a Cholecystokinin Receptor Antagonist in the Management of Chronic Pancreatitis: A Phase 1 Trial
Authors: Ciofoaia Victor , Chen Wenqiang , Tarek Bakain W. , Gay Martha , Shivapurkar Narayan , Smith Jill P.
Published: May 2024

Chronic pancreatitis (CP) is a rare but debilitating condition with an 8-fold increased risk of developing pancreatic cancer. In addition to the symptoms that come from the loss of endocrine and exocrine function in CP, the management of chronic pain is problematic. We previously showed that the CCK-receptor antagonist called proglumide could decrease inflammation, acinar-ductal metaplasia, and fibrosis in murine models of CP. We hypothesized that proglumide would be safe and diminish pain caused by CP. A Phase 1 open-labeled safety study was performed in subjects with clinical and radiographic evidence of CP with moderate to severe pain. After a 4-week observation period, the subjects were treated with proglumide in 400 mg capsules three times daily (1200 mg per day) by mouth for 12 weeks, and then subjects returned for a safety visit 4 weeks after the discontinuation of the study medication. The results of three pain surveys (Numeric Rating Scale, COMPAT-SF, and NIH PROMIS) showed that the patients had significantly less pain after 12 weeks of proglumide compared to the pre-treatment observation phase. Of the eight subjects in this study, two experienced nausea and diarrhea with proglumide. These side effects resolved in one subject with doses reduced to 800 mg per day. No abnormalities were noted in the blood chemistries. A blood microRNA blood biomarker panel that corresponded to pancreatic inflammation and fibrosis showed significant improvement. We conclude that proglumide is safe and well tolerated in most subjects with CP at a dose of 1200 mg per day. Furthermore, proglumide therapy may have a beneficial effect by decreasing pain associated with CP.
Natural Phytochemical and Visible Light at Different Wavelengths Show Synergistic Antibacterial Activity against Staphylococcus aureus
Authors: Jeong Jae-Young , Hwang You-Jin
Published: May 2024

As the risk of antibiotic-resistant bacteria increases, interest in non-antibiotic treatment is also increasing. Among the methods used in non-antibiotic therapy, natural antibiotics such as essential oils have disadvantages such as low efficiency. In the case of phototherapy, the light used for antibacterial activities has low penetration into the human body because of its short wavelength, making it of low medical utility. To solve this problem, this study aimed to determine conditions for enhancing the antibacterial activity of natural phytochemicals and visible light. Four natural phytochemical extracts that showed high antibacterial properties in previous studies were analyzed. Synergistic effects on antibacterial activity and cytotoxicity were determined when natural phytochemical extracts and visible light were simultaneously used. As a result, it was confirmed that the antibacterial activity increased by four times when Sanguisorba officinalis L. was irradiated with 465 nm for 10 min and 520 nm for 40 min, and Uncaria gambir Roxb. was irradiated with 465 nm for 10 min and 520 nm for 60 min compared to when Sanguisorba officinalis L. and Uncaria gambir Roxb. were used alone. The synergistic effect on antibacterial activity was independent of the absorption peak of the natural phytochemical extracts. In addition, in the case of natural phytochemical extracts with improved antibacterial activity, it was confirmed that the improvement of antibacterial activity was increased in inverse proportion to the light irradiation wavelength and in proportion to the light irradiation time. The antibacterial activity was enhanced regardless of antibiotic resistance. In the case of cytotoxicity, it was confirmed that there was no toxicity to A549 cells when treated with 465 nm, the shortest wavelength among the natural phytochemical extracts. These results show how to replace blue light, which has been underutilized due to its low transmittance and cytotoxicity. They also demonstrate the high medical potential of using natural phytochemical and visible light as a combination therapy.
Intermodal Fiber Interferometer with Spectral Interrogation and Fourier Analysis of Output Signals for Sensor Application
Authors: Petrov Aleksandr , Golovchenko Andrey , Bisyarin Mikhail , Ushakov Nikolai , Kotov Oleg
Published: May 2024

Interferometric fiber-optic sensors provide very high measurement accuracy and come with many other benefits. As such, the study of signal processing techniques for fiber-optic interferometers in order to extract information about external perturbation is an important area of research. In this work, the method of Fourier analysis was applied to extract information from the output signals of an intermodal fiber interferometer with spectral interrogation. It is shown that the external perturbation can be measured by obtaining the phase spectrum of the spectral transfer function of an intermodal fiber interferometer and determining the phase difference of a certain pair of mode groups. A mathematical model of this approach was developed, taking into account the parameters of the laser and the optical fiber, the number of excited mode groups, and the parameters of external perturbation. The theoretically considered method of Fourier analysis was experimentally verified, and it was proved to provide a linear response to external perturbation in a wide dynamic range.
Evaluating Propagation Techniques for Cannabis sativa L. Cultivation: A Comparative Analysis of Soilless Methods and Aeroponic Parameters
Authors: Weingarten Matthew , Mattson Neil , Grab Heather
Published: May 2024

Given the rapid growth of the Cannabis industry, developing practices for producing young plants with limited genetic variation and efficient growth is crucial to achieving reliable and successful cultivation results. This study presents a multi-faceted experiment series analyzing propagation techniques for evaluating proficiency in the growth and development of Cannabis vegetative cuttings. This research encompasses various (1) soilless propagation methods including aeroponics, horticultural (phenolic) foam, and rockwool; (2) transplant timings; (3) aeroponic spray intervals; and (4) aeroponic reservoir nutrient concentrations, to elucidate their impact on rooting and growth parameters amongst two Cannabis cultivars. Aeroponics was as effective as, and in some cases more effective than, soilless propagation media for root development and plant growth. In aeroponic systems, continuous spray intervals, compared to intermittent, result in a better promotion of root initiation and plant growth. Moreover, raised nutrient concentrations in aeroponic propagation demonstrated greater rooting and growth. The effects of experimental treatment were dependent on the cultivar and sampling day. These findings offer valuable insights into how various propagation techniques and growth parameters can be tailored to enhance the production of vegetative cuttings. These results hold critical implications for cultivators intending to achieve premium harvests through efficient propagule methods and optimization strategies in the competitive Cannabis industry. Ultimately, our findings suggest that aeroponic propagation, compared to alternative soilless methods, is a rapid and efficient process for cultivating vegetative cuttings of Cannabis and offers sustainable advantages in resource conservation and preservation.