Global sensitivity analysis in epidemiological modeling.

Operations researchers worldwide rely extensively on quantitative simulations to model alternative aspects of the COVID-19 pandemic. Proper uncertainty quantification and sensitivity analysis are fundamental to enrich the modeling process and communicate correctly informed insights to decision-makers. We develop a methodology to obtain insights on key uncertainty drivers, trend analysis and interaction quantification through an innovative combination of probabilistic sensitivity techniques and machine learning tools. We illustrate the approach by applying it to a representative of the family of susceptible-infectious-recovered (SIR) models recently used in the context of the COVID-19 pandemic. We focus on data of the early pandemic progression in Italy and the United States (the U.S.). We perform the analysis for both cases of correlated and uncorrelated inputs. Results show that quarantine rate and intervention time are the key uncertainty drivers, have opposite effects on the number of total infected individuals and are involved in the most relevant interactions.

Isolation, complete genome sequencing and in silico genome mining of Burkholderia for secondary metabolites.

Recent years, Burkholderia species have emerged as a new source of natural products (NPs) with increasing attractions. Genome mining suggests the Burkholderia genomes include many natural product biosynthetic gene clusters (BGCs) which are new targets for drug discovery. In order to collect more Burkholderia, here, a strain S-53 was isolated from the soil samples on a mountain area in Changde, P.R. China and verified by comparative genetic analysis to belong to Burkholderia. The complete genome of Burkholderia strain S-53 is 8.2 Mbps in size with an average G + C content of 66.35%. Its taxonomy was both characterized by 16S rRNA- and whole genome-based phylogenetic trees. Bioinformatic prediction in silico revealed it has a total of 15 NP BGCs, some of which may encode unknown products. It is expectable that availability of these BGCs will speed up the identification of new secondary metabolites from Burkholderia and help us understand how sophisticated BGC regulation works.

Giant Gold Nanowire Vesicle-Based Colorimetric and SERS Dual-Mode Immunosensor for Ultrasensitive Detection of Vibrio parahemolyticus.

Conventional methods for the detection of Vibrio parahemolyticus (VP) usually need tedious, labor-intensive processes, and have low sensitivity, which further limits their practical applications. Herein, we developed a simple and efficient colorimetry and surface-enhanced Raman scattering (SERS) dual-mode immunosensor for sensitive detection of VP, by employing giant Au vesicles with anchored tiny gold nanowires (AuNW) as a smart probe. Due to the larger specific surface and special hollow structure of giant Au vesicles, silver staining would easily lead to vivid color change for colorimetric analysis and further amplify SERS signals. The t-test was further used to determine if two sets of data from colorimetry and SERS were significantly different from each other. The result shows that there was no significant difference between data from the two methods. Two sets of data can mutually validate each other and avoid false positive and negative detection. The designed colorimetry-SERS dual-mode sensor would be very promising in various applications such as food safety inspection, personal healthcare, and on-site environmental monitoring.

pH and Temperature Dual-Responsive Plasmonic Switches of Gold Nanoparticle Monolayer Film for Multiple Anticounterfeiting.

Two-dimensional (2D) gold nanoparticle (Au NP) monolayer film possesses a lot of fascinating peculiarities, and has shown promising applications in photoelectrical devices, catalysis, spectroscopy, sensors, and anticounterfeiting. Because of the localized surface plasmon resonance (LSPR) property predetermined by the natural structure of metal nanoparticles, it is usually difficult to realize the reversible LSPR transition of 2D film. In this work, we report on the fabrication of a large-area free-standing Au NP monolayer film with dual-responsive switchable plasmonic property using a pH- or thermal-responsive dendronized copolymer as a stimuli-sensitive linker. In this system, an oligoethylene-glycol-based (OEG-based) dendronized copolymer (named PG1A) with pH or temperature sensitivity was first modified onto the surface of a Au NP. Then, polyethylene glycol dibenzyl aldehyde (PEG-DA) was introduced to interact with the amino moieties from PG1A before the process of oil-water interfacial self-assembly of NPs, resulting in an elastic, robust, pH- or temperature-sensitive interpenetrating network among Au NPs in monolayer films. In addition, the film could exhibit reversibly plasmonic shifts of about 77 nm and inherent color changes through varying temperature or pH. The obtained free-standing monolayer film also shows an excellent transferable property, which can be easily transferred onto substrates such as plastic molds, PDMS, copper grids, and silicon wafers. In virtue of these peculiarities of the free-standing property, special plasmonic signal, and homologous macroscopic color, the transferred film was primely applied to an anticounterfeiting security label with clear color change at the designed spots, providing a new avenue to plasmonic nanodevices with various applications.

Humidity-Responsive Gold Aerogel for Real-Time Monitoring of Human Breath.

Humidity sensors have received considerable attention in recent years because of their significance and wide applications in agriculture, industries, goods stores, and medical fields. However, the conventional humidity sensors usually possessed a complex sensing mechanism and low sensitivity and required a time-consuming, labor-intensive process. The exploration for an ideal sensing material to amplify the sensitivity of humidity sensors is still a big challenge. Herein, we developed a simple, low-cost, and scalable fabrication strategy to construct a highly sensitive humidity sensor based on polymer/gold nanoparticle (AuNP) hybrid materials. The hybrid polymer/AuNP aerogel was prepared by a simple freeze-drying method. By taking advantage of the conductivity of AuNPs and high surface area of the highly porous structure, the hybrid poly- N-isopropylacrylamide (PNIPAm)/AuNP aerogel showed high sensitivity to water molecules. Interestingly, the hybrid PNIPAm/AuNP aerogel-based humidity sensor can be used to detect human breath in different states, such as normal breath, fast breath, and deep breath, or in different individuals such as persons with illness, persons who are smoking, and persons who are normal, which is promising in practical flexible wearable devices for human health monitoring. In addition, the humidity sensor can be used in whistle tune recognition.

Nanozyme-based lateral flow assay for the sensitive detection of Escherichia coli O157:H7 in milk.

Lateral flow assay (LFA) has been applied in many fields due to its relative ease of use and cost-effectiveness. However, it has low sensitivity and its applications are limited. Probe materials play a significant role in improving the detection efficiency and sensitivity of LFA. In this study, by using concave palladium-platinum (Pd-Pt) nanoparticles as a nanozyme probe, we developed a sensitive LFA based on the sandwich format for qualitative and quantitative detection of Escherichia coli O157:H7. The sensitivity of the LFA was improved by applying the 3,3',5,5'-tetramethylbenzidine (TMB) substrate onto the test line where the nanozyme was accumulated in the presence of analytes. The nanozyme showed high catalytic performance toward TMB and greatly enhanced the signal intensity of the test line. The sensitivity of the nanozyme-based LFA was 9.0 × 102 cfu/mL in milk, which was 111-fold higher than that of traditional colloidal gold-based LFA. The proposed method has remarkable potential in the detection of various pathogens in real samples.

Bimetallic Au/Ag Core-Shell Superstructures with Tunable Surface Plasmon Resonance in the Near-Infrared Region and High Performance Surface-Enhanced Raman Scattering.

Due to the larger surface area and the synergistic effects between two noble metals, the bimetallic superstructures exhibit enhanced distinctive optical, catalytic, and photothermal performances and surface-enhanced Raman scattering (SERS) "hot-spot" effect, and thus have attracted great interest in various applications. Compared with the common Pd, Pt hierarchical structures coated onto Au nanoparticles (NPs), easily synthesized via fast autocatalytic surface growth arising from intrinsic properties of Pd and Pt metals, precisely controlling the hierarchical Ag growth onto Au NPs is rarely reported. In our present study, the reducing agent dopamine dithiocarbamate (DDTC) was covalently capped onto the first metal core (Au) to delicately control the growth model of the second metal (Ag). This results in heterogeneous nucleation and growth of Ag precursor on the surface of Au nanorods (NRs), and further formation of cornlike bimetallic Au/Ag core-shell superstructures, which usually cannot be achieved from traditional epitaxial growth. The thickness of the hierarchical Ag shell was finely tuned in a size range from 8 to 22 nm by simply varying the amount of the ratio between Ag ions and DDTC capped on Au NR core. The tunable Ag shell leads to anisotropic bimetallic Au/Ag core-shell superstructures, displaying two distinctive plasmonic resonances in the near-infrared region (NIR). In particular, the longitudinal surface plasmon resonance exhibits a broadly tunable range from 840 to 1277 nm. Additionally, the rich hot spots from obtained Au/Ag superstructures significantly enhance the SERS performance.

Giant Vesicles with Anchored Tiny Gold Nanowires: Fabrication and Surface-Enhanced Raman Scattering.

Sensitivity and reproducibility are two major concerns to improve the performance and extend the range of practical applications of surface-enhanced Raman scattering (SERS). A theoretical report reveals that hot spots formed by gold nanoparticles with a tip-to-tip configuration would generate the maximum electric field enhancement because of the lightning rod effect. In our present study, we constructed a giant vesicle consisting of anchored tiny gold nanowires to provide a high density of sharp tip-to-tip nanogaps for SERS application. The tiny gold nanowires were directly grown and anchored onto the surfaces of polystyrene (PS) microspheres by a seed-mediated method. Then, the removal of PS microspheres by tetrahydrofuran led to the formation of the giant gold vesicles with hierarchical cage structures, providing the sharp tips and high density of hot spots for improving SERS performance. Compared with the nonwire structure (island and inhibited nanoparticle), giant gold vesicles with tiny wires showed a higher SERS enhancement factor (9.90 × 107) and quantitative SERS analysis in the range of 10-4 to 10-7 M. In addition, the large-scale giant gold vesicle array on the silica substrate resulted in a high reproducibility of SERS signals with the variation of intensities less than 7.6%.

Macroscopic Assembly of Gold Nanorods into Superstructures with Controllable Orientations by Anisotropic Affinity Interaction.

Two-dimensional or three-dimensional highly ordered arrays of anisotropic nanoparticles provide attracting properties that are highly desired by the industry. Traditional assembly methods such as evaporation usually produces the nanostructure arrays only up to the millimeter scale with poor control of nanoparticle orientation, making them hardly applicable for industrial needs. Here, we report a facile method to assemble centimeter-scale gold nanorod (Au NR) arrays with highly controlled nanoparticle orientation and high reproducibility. We selectively functionalized the transverse or longitudinal facets of Au NRs with polyethylene glycol (PEG) molecules and utilized the interfacial polymeric affinity between the PEG domains on Au NRs and the PEGylated substrate to achieve the anisotropic self-assembly. The side-PEGylated Au NRs formed closely packed horizontal arrays, whereas the end-PEGylated Au NRs formed vertically standing arrays on the substrate, respectively. The obtained Au NR arrays with different orientations showed anisotropic surface-enhanced Raman scattering (SERS) performance. We showed that the vertically ordered Au NR arrays exhibited 3 times higher SERS signals than the horizontally ordered arrays.

Novel carboxymethyl chitosan-graphene oxide hybrid particles for drug delivery.

We describe an electrostatic droplet generation method to prepare a novel carboxymethyl chitosan-graphene oxide hybrid particles for delivery purpose. Under an adjustable electrostatic field, graphene oxide and carboxymethyl chitosan mixed solution was sprayed as uniform micro-droplets, which were solidified as particles in CaCl2 solution. Such hybrid particles are wished to have excellent stability in saline solution, and better delivery properties than pristine carboxymethyl chitosan particles. The effects of micro-droplets generation conditions on particles formation were systematically investigated. At conditions of 40 mg/ml of carboxymethyl chitosan, 2 mg/ml of graphene oxide, 3 ml/h of feed speed, electrostatic field parameters was 9 kV and 20 cm, uniformly sized carboxymethyl chitosan-graphene oxide particles in the diameter range of 250-300 µm was successfully prepared. In NaCl saline, these particles could maintain stable for at least a week, while pristine carboxymethyl chitosan particles quickly collapsed within an hour. The results of loading experiments showed that carboxymethyl chitosan-graphene oxide particles could effectively adsorb gatifloxacin, ofloxacin, bovine serum albumin, lysozyme, doxorubicin hydrochloride. And gatifloxacin was chosen as a model drug to study the exact effect of graphene oxide content on the loading and release properties. In 40:2 group, the highest loading capacity of 0.45 ± 0.19 mg/mg was achieved, and also a good sustained release was available. Above all, we believed that carboxymethyl chitosan-graphene oxide particles as a versatile carrier, has great potential in Medicine and Pharmacy.

Preparation and characterization of molecularly imprinted poly(hydroxyethyl methacrylate) microspheres for sustained release of gatifloxacin.

Molecularly imprinted poly(hydroxyethyl methacrylate) microspheres (PHEMA MIPMs) were prepared via precipitation polymerization in this article, using gatifloxacin (GFLX), hydroxyethyl methacrylate (HEMA), and ethylene glycol dimethacrylate (EGDMA) as template molecule, functional monomer and cross-linker, respectively. The effects of reaction medium, initial total monomers, cross-linker and molecular imprinting on the polymerization were investigated systematically. The interaction between GFLX and HEMA in pre-solution was studied by UV-Visible spectrophotometer, both size and morphology of products were characterized by a scanning electron microscope. When the total initial monomer concentration was 1 vol%, EGDMA content was 70 mol%, a group of uniform PHEMA MIPMs were prepared at different GFLX/MAA molar ratios, with diameter range from 2.06 ± 0.07 to 2.82 ± 0.20 µm. The results of drug loading and in vitro release experiments demonstrated that PHEMA MIPMs could achieve a higher GFLX loading content and a more acceptable sustained release than non-imprinted ones.

Right or left: the role of nanoparticles in pulmonary diseases.

Due to the rapid development of the nanotechnology industry in the last decade, nanoparticles (NPs) are omnipresent in our everyday life today. Many nanomaterials have been engineered for medical purposes. These purposes include therapy for pulmonary diseases. On other hand, people are endeavoring to develop nanomaterials for improvement or replacement of traditional therapies. On the other hand, nanoparticles, as foreign material in human bodies, are reported to have potential adverse effects on the lung, including oxidase stress, inflammation, fibrosis and genotoxicity. Further, these damages could induce pulmonary diseases and even injuries in other tissues. It seems that nanoparticles may exert two-sided effects. Toxic effects of nanomaterials should be considered when their use is developed for therapies. Hence this review will attempt to summarize the two-side roles of nanoparticles in both therapies for pulmonary diseases and initiation of lung diseases and even secondary diseases caused by lung injuries. Determinants of these effects such as physicochemical properties of nanoparticles will also be discussed.

Dispersion Relations for Active Undulators in Overdamped Environments.

Organisms that locomote by propagating waves of body bending can maintain performance across heterogeneous environments by modifying their gait frequency $\omega$ or wavenumber $k$. We identify a unifying relationship between these parameters for overdamped undulatory swimmers (including nematodes, spermatozoa, and mm-scale fish) moving in diverse environmental rheologies, in the form of an active `dispersion relation' $\omega\propto k^{\pm2}$. A model treating the organisms as actively driven viscoelastic beams reproduces the experimentally observed scaling. The relative strength of rate-dependent dissipation in the body and the environment determines whether $k^2$ or $k^{-2}$ scaling is observed. The existence of these scaling regimes reflects the $k$ and $\omega$ dependence of the various underlying force terms and how their relative importance changes with the external environment and the neuronally commanded gait.

Nanotoxicity: a growing need for study in the endocrine system.

Nanomaterials (NMs) are engineered for commercial purposes such as semiconductors, building materials, cosmetics, and drug carriers, while natural nanoparticles (NPs) already exist in the environment. Due to their unique physicochemical properties, they may interact actively with biological systems. Some of these interactions might be detrimental to human health, and therefore studies on the potential 'nanotoxicity' of these materials in different organ systems are warranted. The purpose of developing the concept of nanotoxicity is to recognize and evaluate the hazards and risks of NMs and evaluate safety. This review will summarize and discuss recent reports derived from cell lines or animal models concerning the effects of NMs on, and their application in, the endocrine system of mammalian and other species. It will present an update on current studies of the effects of some typical NMs-such as metal-based NMs, carbon-based NMs, and dendrimers-on endocrine functions, in which some effects are adverse or unwanted and others are favorable or intended. Disruption of endocrine function is associated with adverse health outcomes including reproductive failure, metabolic syndrome, and some types of cancer. Further investigations are therefore required to obtain a thorough understanding of any potential risk of pathological endocrine disruption from products containing NMs. This review aims to provide impetus for further studies on the interactions of NMs with endocrine functions.

AAV-mediated gene augmentation therapy of CRB1 patient-derived retinal organoids restores the histological and transcriptional retinal phenotype.

Retinitis pigmentosa and Leber congenital amaurosis are inherited retinal dystrophies that can be caused by mutations in the Crumbs homolog 1 (CRB1) gene. CRB1 is required for organizing apical-basal polarity and adhesion between photoreceptors and Müller glial cells. CRB1 patient-derived induced pluripotent stem cells were differentiated into CRB1 retinal organoids that showed diminished expression of variant CRB1 protein observed by immunohistochemical analysis. Single-cell RNA sequencing revealed impact on, among others, the endosomal pathway and cell adhesion and migration in CRB1 patient-derived retinal organoids compared with isogenic controls. Adeno-associated viral (AAV) vector-mediated hCRB2 or hCRB1 gene augmentation in Müller glial and photoreceptor cells partially restored the histological phenotype and transcriptomic profile of CRB1 patient-derived retinal organoids. Altogether, we show proof-of-concept that AAV.hCRB1 or AAV.hCRB2 treatment improved the phenotype of CRB1 patient-derived retinal organoids, providing essential information for future gene therapy approaches for patients with mutations in the CRB1 gene.

Characterization and AAV-mediated CRB gene augmentation in human-derived CRB1KO and CRB1KOCRB2+/- retinal organoids.

The majority of patients with mutations in CRB1 develop either early-onset retinitis pigmentosa as young children or Leber congenital amaurosis as newborns. The cause for the phenotypic variability in CRB1-associated retinopathies is unknown, but might be linked to differences in CRB1 and CRB2 protein levels in Müller glial cells and photoreceptor cells. Here, CRB1KO and CRB1KOCRB2+/- differentiation day 210 retinal organoids showed a significant decrease in the number of photoreceptor nuclei in a row and a significant increase in the number of photoreceptor cell nuclei above the outer limiting membrane. This phenotype with outer retinal abnormalities is similar to CRB1 patient-derived retinal organoids and Crb1 or Crb2 mutant mouse retinal disease models. The CRB1KO and CRB1KOCRB2+/- retinal organoids develop an additional inner retinal phenotype due to the complete loss of CRB1 from Müller glial cells, suggesting an essential role for CRB1 in proper localization of neuronal cell types. Adeno-associated viral (AAV) transduction was explored at early and late stages of organoid development. Moreover, AAV-mediated gene augmentation therapy with AAV.hCRB2 improved the outer retinal phenotype in CRB1KO retinal organoids. Altogether, these data provide essential information for future gene therapy approaches for patients with CRB1-associated retinal dystrophies.

CRB1 is required for recycling by RAB11A+ vesicles in human retinal organoids.

CRB1 gene mutations can cause early- or late-onset retinitis pigmentosa, Leber congenital amaurosis, or maculopathy. Recapitulating human CRB1 phenotypes in animal models has proven challenging, necessitating the development of alternatives. We generated human induced pluripotent stem cell (iPSC)-derived retinal organoids of patients with retinitis pigmentosa caused by biallelic CRB1 mutations and evaluated them against autologous gene-corrected hiPSCs and hiPSCs from healthy individuals. Patient organoids show decreased levels of CRB1 and NOTCH1 expression at the retinal outer limiting membrane. Proximity ligation assays show that human CRB1 and NOTCH1 can interact via their extracellular domains. CRB1 patient organoids feature increased levels of WDFY1+ vesicles, fewer RAB11A+ recycling endosomes, decreased VPS35 retromer complex components, and more degradative endolysosomal compartments relative to isogenic control organoids. Taken together, our data demonstrate that patient-derived retinal organoids enable modeling of retinal degeneration and highlight the importance of CRB1 in early endosome maturation receptor recycling in the retina.

Right hepatic artery thrombosis in an essential polycythemia vera patient following pancreato-biliary surgery for severe pancreatitis.

Hepatic artery thrombosis (HAT) remains one of the major causes of graft failure and mortality in liver transplant recipients. But it is a very rare in non-transplantation patient with the complication of HAT. We reported herein a case of successful urokinase intra-arterial thrombolytic treatment for HAT in an essential polycythemia vera patient following pancreato-biliary surgery. This patient underwent debridement and T-tube drainage in common bile duct for severe pancreatitis and acute suppurative obstructive cholangitis. Significant elevation of liver transaminases and white blood cell counts was noted 30 days after operation and HAT was confirmed by CT-angiography and digital subtracted angiography. Apart from malena and malaise, this patient had scarcity of evident symptoms. The only obvious risk factor relating to HAT is thrombocytosis. This patient was continuously characterized by an excess of platelets from its admission to the onset of HAT. This patient was treated successfully with continuous transcatheter arterial thrombolysis using urokinase. The symptom including malena and malaise disappeared 3 days after thrombolysis. And the patient was treated with hydroxyurea for polycythemia vera thereafter. In conclusion, physicians should be alerted that HAT can be happened in non-transplantation patients especially in those of having hypercoagulability.

Correlation between Lpa, APO-A, APO-B, and Stenosis of Middle Cerebral Artery in Patients with Cerebral Ischemic Stroke.

Ischemic stroke (CIS) is characterized by a high incidence, disability, and mortality. Numerous studies have demonstrated that intracranial arterial stenosis is an important pathological basis of CIS, and its main cause is atherosclerosis. Dyslipidemia is an important risk factor for atherosclerosis. Lysophosphatidic acid (Lpa), apolipoprotein -A(APO-A), and apolipoprotein -B(APO-B) proved to be significantly correlated with the severity of coronary artery disease. This study retrospectively collected the case data of 186 patients with CIS treated from May 2020 to May 2022 and explored the correlation between Lpa, APO-A, APO-B, and middle cerebral artery (MCA) stenosis in CIS patients.

The efficacy and safety of adding bevacizumab in neoadjuvant therapy for locally advanced rectal cancer patients: A systematic review and meta-analysis.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) are more likely to suffer local recurrence and distant metastases, contributing to worse prognoses. Considering the provided dramatic reduction of local recurrences, neoadjuvant CRT (nCRT) followed by curative resection with total mesorectal excision (TME) and adjuvant chemotherapy has been established as standard therapy for LARC patients. However, the efficacy of adding bevacizumab in neoadjuvant therapy, especially in induction therapy-containing nCRT for LARC patients remains uncertain. MATERIALS: PubMed, Embase, and Web of Science were searched to retrieve records on the application of bevacizumab in a neoadjuvant setting for LARC patients. The endpoints of interest were pCR and the rates of patients suffering Grade 3/4 bevacizumab-specific adverse events, namely bleeding, wound healing complications, and gastrointestinal perforation. RESULTS: 29 cohorts covering 1134 subjects were included in this systematic review. The pooled pCR rate for bevacizumab-relevant cohorts was 21% (95% confidence interval (95% CI), 17-25%; I2 = 61.8%), the pooled estimates of Grade 3/4 bleeding, Grade 3/4 wound healing complication, Grade 3/4 gastrointestinal perforation were 1% (95% CI, 0-3%; I2 = 0%), 2% (95% CI, 1-5%; I2 = 4.7%), and 2% (95% CI, 0-5%; I2 = 0%), respectively. CONCLUSION: The addition of bevacizumab in the nCRT, especially in the TNT, for LARC patients provides promising efficacy and acceptable safety. However, the results should be interpreted cautiously due to the small amount of relevant data and need further confirmation by future studies.