Smart hydrogels that are responsive to various external (
electrical and/or thermal) stimulation have become increasingly popular in recent years for simple, rapid, and precise drug delivery that can ...be controlled and turned on or off with external stimuli. For such a switchable drug delivery material, highly homogeneous dispersion and distribution of the hydrophobic, electrically conductive nanomaterials throughout a hydrophilic three-dimensional (3D) hydrogel network remains a challenge and is essential for achieving well-connected electrical and thermal conducting paths. Herein we developed electrical and thermal stimulus-responsive 3D hydrogels based on (i) carbon nanotubes (CNTs) as the core unit and an electrical/thermal conductor, (ii) chitosan (Chit) as the shell unit and a hydrophilic dispersant, and (iii) poly(NIPAAm-
-BBVIm) (pNIBBIm) as the drug carrier and a temperature-responsive copolymer. By formulating the CNT-core and Chit-shell units and constructing a CNT sponge framework, uniform distribution and 3D connectivity of the CNTs were improved. The 3D hydrogel based on the CNT sponge, namely the 3D frame CNT-Chit/pNIBBIm hydrogel, delivered approximately 37% of a drug, ketoprofen used for the treatment of musculoskeletal pain, during about 30% shrinkage after electrical and thermal switches on/off and exhibited the best potential for future use in a smart transdermal drug delivery system. The physicochemical, mechanical, electrical, thermal, and biocompatible characteristics of this nanocarbon-based 3D frame hydrogel led to remarkable electrical and thermal stimulus-responsive properties capable of developing an excellent controllable and switchable drug delivery platform for biomedical engineering and medicine applications.
Solitary fibrous tumors (SFTs) are
NAB2
-
STAT6
fusion-associated neoplasms. There are several subtypes of
NAB2-STAT6
fusions, but their clinical significances are still unclear. Moreover, the ...mechanisms of malignant progression are also poorly understood. In this study, using 91 SFT cases, we examined whether fusion variants are associated with clinicopathological parameters and also investigated the molecular mechanism of malignant transformation using whole-exome sequencing. We detected variant 1b (
NAB2
ex4-
STAT6
ex2) in 51/91 (56%) cases and variants 2a/2b (
NAB2
ex6-
STAT6
ex16/17) in 17/91 (19%) cases. The
NAB2-STAT6
fusion variant types were significantly associated with their primary site (
P
< 0.001). In addition, a
TERT
promoter mutation was detected in 7/73 (10%) cases, and it showed a significant association with malignant SFTs (
P
= 0.003). To identify molecular changes during malignant progression, we selected an index patient to obtain parallel tissue samples from the primary and metastatic tumors. In the metastatic tissue, 10 unique molecular alterations, including those in
TP53
and
APAF1
, were detected. In vitro functional experiments showed that
APAF1
depletion increased the tumor potency of cells expressing NAB2-STAT6 fusion protein under treatment with staurosporine. We found that TP53 immunopositivity (
P
= 0.006) and loss of APAF1 immunoreactivity (
P
< 0.001) were significantly associated with malignant SFTs. Our study suggests that dysfunction of
TP53
and
APAF1
leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation.
Key messages
We firstly found that the
TERT
promoter mutation was strongly associated with malignant SFTs (
P
= 0.003) and the representative 1b (
NAB2
ex4-
STAT6
ex2) or 2a (
NAB2
ex6-
STAT6
ex16) fusion variants similarly contribute to tumorigenicity.
We also found that TP53 immunopositivity (
P
= 0.006) and loss of APAF1 immunoreactivity (
P
< 0.001) were significantly associated with malignant SFTs.
Our study suggests that dysfunction of
TP53
and
APAF1
leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation.
Lipocalin‐2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD ...using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post‐tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2‐deficient mice, compared with wild‐type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood–brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1‐neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF‐1α–LCN2–VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.
Main Points
Astrocyte‐derived LCN2 mediates hippocampal damage in rodent models of vascular dementia, with higher plasma levels of LCN2 protein in patients with vascular dementia, suggesting the possibility of effective glia‐based treatment for vascular dementia.
Here, the sodium storage mechanism in commercial grade hard carbon with a low surface area is comprehensively investigated using electrochemical impedance spectroscopy (EIS), the galvanostatic ...intermittent titration technique, and in situ Raman spectroscopy for fresh and cycled electrodes. The reversible shift of the carbon G‐band peak on Raman spectra and substantial change of the charge‐transfer resistance in the sloping region of the voltage profile indicates the intercalation of sodium ions into hard carbon, whereas the low‐voltage plateau is associated with the pore‐filling process. In situ Raman analysis at low frequencies reveals that the pore filling is progressed via formation of small sodium clusters in closed pores. Prolonged cycling demonstrates that intercalation is stable and consistent throughout multiple charge–discharge cycles. The transition from intercalation to pore filling strongly affects the diffusion behavior, leading to considerably slower diffusivity at low voltage. The EIS effectively differentiates the contribution of adsorption to charge storage. The gradual growth of the solid‐electrolyte interphase layer affects the rise of the interfacial resistance as cycling progresses. In combination with the slower diffusivity, the low‐voltage plateau region strictly impedes fast de/sodiation and eventually causes capacity fade.
Hard carbon (de)sodiation is comprehensively studied by means of in situ Raman spectroscopy, Electrochemical impedance spectroscopy, and other electrochemical methods. All methods justify “intercalation‐pore filling” mechanism and indicate gradual SEI growth upon extensive cycling. SEI growth‐associated charge transfer and diffusion deceleration is decisive for hard carbon performance fade.
Formalin fixing with paraffin embedding (FFPE) has been a standard sample preparation method for decades, and archival FFPE samples are still very useful resources. Nonetheless, the use of FFPE ...samples in cancer genome analysis using next-generation sequencing, which is a powerful technique for the identification of genomic alterations at the nucleotide level, has been challenging due to poor DNA quality and artificial sequence alterations. In this study, we performed whole-exome sequencing of matched frozen samples and FFPE samples of tissues from 4 cancer patients and compared the next-generation sequencing data obtained from these samples. The major differences between data obtained from the 2 types of sample were the shorter insert size and artificial base alterations in the FFPE samples. A high proportion of short inserts in the FFPE samples resulted in overlapping paired reads, which could lead to overestimation of certain variants; >20% of the inserts in the FFPE samples were double sequenced. A large number of soft clipped reads was found in the sequencing data of the FFPE samples, and about 30% of total bases were soft clipped. The artificial base alterations, C>T and G>A, were observed in FFPE samples only, and the alteration rate ranged from 200 to 1,200 per 1M bases when sequencing errors were removed. Although high-confidence mutation calls in the FFPE samples were compatible to that in the frozen samples, caution should be exercised in terms of the artifacts, especially for low-confidence calls. Despite the clearly observed artifacts, archival FFPE samples can be a good resource for discovery or validation of biomarkers in cancer research based on whole-exome sequencing.
Highlights • Over 30% of Pseudomonas aeruginosa isolated in 8 Korean hospitals were carbapenem-resistant. • All metallo-β-lactamase-producing isolates belonged to ST235, a worldwide high-risk clone. ...• Of 33 IMP-6-producing ST235 isolates, 9 were colistin-resistant and exhibited resistance to all antimicrobials tested.
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•SARS-CoV-2 has a high viral load from 5 days before symptoms onset to 10 days after symptoms onset.•rRT-PCR results are converted to negative approximately 3 weeks after the onset of ...symptoms.•Ct values for 6 weeks or longer were repeated negative and positive.•It is necessary to consider the expansion of the scope of epidemiological investigations.•Consider the release of isolation 10 days after symptom onset in limited resource situations.
It is necessary to know the viral kinetics and conduct epidemiological investigations of confirmers to prevent the spread of the new infectious disease COVID-19 to the community. To date, no study has been published on viral kinetics during the preclinical and clinical periods of SARS-CoV-2.
A confirmed case was defined as a patient with positive results by real-time reverse transcription polymerase chain reaction (RT-PCR) assay for SARS-CoV-2. Both specimen types were collected over the whole clinical course in all patients. Asymptomatic patients who had been screened for COVID-19 due to a strong epidemiological link were also enrolled. The study population included 54 hospitalized patients with confirmed COVID-19.
COVID-19 shows a very high viral load on the day of symptom development, which then decreases overall. Rapid viral proliferation was observed 0–5 days before symptoms developed. Cycle threshold (Ct) value was the lowest in the clinical course from 5 days before symptoms to 10 days after symptoms occurred (Ct < 30). The rRT-PCR results were negative approximately 3 weeks after the onset of symptoms. However, there was a continuous pattern that was negative and positive for up to 6 weeks and more.
Considering the characteristic that COVID-19 has a high viral load before symptoms appear, it is necessary to consider to expand the scope of epidemiological investigations. As there is a very low possibility of transmission after 10 days of symptom occurrence, it may be considered to release isolation after 10 days of symptom occurrence in limited resource situations. This study allows for the planning of epidemiological investigations, patient's ward supply, and follow-up of patients through sequential changes in viral loads over the entire clinical course. In addition, it is possible to estimate the clinical time at which the patient is present.
Background
No tick‐borne pathogens (TBPs) causing haemolytic anaemia in cattle have been reported, except Theileria orientalis and complete blood count (CBC) profile is the only haematological ...parameter to determine the severity of regenerative haemolytic anaemia.
Objectives
To identify the causative agents of TBP‐induced haemolytic anaemia and determine haematological parameters that indicate haemolytic anaemia in grazing cattle.
Methods
Eighty‐two Korean indigenous cattle (Hanwoo) were divided into two groups: grazing (n = 67) and indoor (n = 15) groups. CBC and serum biochemistry were performed. PCR was conducted using whole blood‐extracted DNA to investigate the prevalence of TBPs.
Results
TBP‐induced haemolytic anaemia was observed in the grazing group. In grazing cattle, co‐infection (43.3%, 29/67) was most frequently detected, followed by T. orientalis (37.6%, 25/67) and Anaplasma phagocytophilum infections (1.5%, 1/67). In indoor cattle, only co‐infection (20%, 3/15) was identified. Grazing cattle exhibited regenerative haemolytic anaemia with marked monocytosis, mild neutropenia, and thrombocytopenia. According to grazing frequency, the 1st‐time grazing group had more severe anaemia than the 2nd‐time grazing group. Elevations in indirect bilirubin and L‐lactate due to haemolytic anaemia were identified, and correlations with the respective markers were determined in co‐infected grazing cattle.
Conclusions
Quantitative evaluation of haematocrit, mean corpuscular volume, and reticulocytes (markers of regenerative haemolytic anaemia in cattle) was performed for the first time. Our results show that, in addition to T. orientalis, A. phagocytophilum is strongly associated with anaemia. The correlation between haemolytic anaemia severity and haematological parameters (indirect bilirubin, reticulocytes, and L‐lactate) was confirmed.
In grazing Korean indigenous cattle, haemolytic anaemia caused by Theileria orientalis and Anaplasma phagocytophilum has been observed.
Reticulocytosis, a marker of regeneration, was quantitatively expressed with an increase in indirect bilirubin and a decrease in haptoglobin.
In addition, indirect bilirubin, L‐lactate and reticulocytes were correlated with the severity of anaemia after HCT.
Poly(methyl methacralyate) (PMMA) has long been used in dentistry as a base polymer for dentures, and it is recently being used for the 3D printing of dental materials. Despite its many advantages, ...its susceptibility to microbial colonization remains to be overcome. In this study, the interface between 3D-printed PMMA specimens and oral salivary biofilm was studied following the addition of zwitterionic materials, 2-methacryloyloxyethyl phosphorylcholine (MPC) or sulfobetaine methacrylate (SB). A significant reduction in bacterial and biofilm adhesions was observed following the addition of MPC or SB, owing to their protein-repellent properties, and there were no significant differences between the two test materials. Although the mechanical properties of the tested materials were degraded, the statistical value of the reduction was minimal and all the properties fulfilled the requirements set by the International Standard, ISO 20795-2. Additionally, both the test materials maintained their resistance to biofilm when subjected to hydrothermal fatigue, with no further deterioration of the mechanical properties. Thus, novel 3D-printable PMMA incorporated with MPC or SB shows durable oral salivary biofilm resistance with maintenance of the physical and mechanical properties.
DynOmics (dynomics.pitt.edu) is a portal developed to leverage rapidly growing structural proteomics data by efficiently and accurately evaluating the dynamics of structurally resolved systems, from ...individual molecules to large complexes and assemblies, in the context of their physiological environment. At the core of the portal is a newly developed server, ENM 1.0, which permits users to efficiently generate information on the collective dynamics of any structure in PDB format, user-uploaded or database-retrieved. ENM 1.0 integrates two widely used elastic network models (ENMs)-the Gaussian Network Model (GNM) and the Anisotropic Network Model (ANM), extended to take account of molecular environment. It enables users to assess potentially functional sites, signal transduction or allosteric communication mechanisms, and protein-protein and protein-DNA interaction poses, in addition to delivering ensembles of accessible conformers reconstructed at atomic details based on the global modes of motions predicted by the ANM. The 'environment' is defined in a flexible manner, from lipid bilayer and crystal contacts, to substrate or ligands bound to a protein, or surrounding subunits in a multimeric structure or assembly. User-friendly interactive features permit users to easily visualize how the environment alter the intrinsic dynamics of the query systems. ENM 1.0 can be accessed at http://enm.pitt.edu/ or http://dyn.life.nthu.edu.tw/oENM/.
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