Theoretical exploration of the stabilities and detonation parameters of nitro-substituted 1H-benzotriazole.

CONTEXT: The nitro group was introduced into the nitrogen heterocycle of 1H-benzotriazole to design a total of 31 derivatives. To estimate the thermal stability of these derivatives, the heat of formation (HOF) is calculated based on the isodesmic reaction. The bond dissociation energy (BDE) was also predicted based on the homolytic reaction to further evaluate the dynamic stability. To evaluate the possibility of utilizing as high energy density compounds (HEDCs), the detonation parameters including the detonation pressure (P), detonation velocity (D), and explosive heat (Q) are predicted by taking advantage of the Kamlet-Jacobs empirical equation. To measure the sensitivity to impact, both the characteristic height (H50) and free space in crystal (∆V) are considered in this paper. Based on our calculations, D-series and E are found to be the candidates for HEDCs. METHODS: The Gaussian 09 software package was used in this paper. The B3PW91 hybrid function with the 6-311 + G(d,p) basis set was chosen to perform the structural optimization, frequency analysis, heat of formation, and bond dissociation energy. The detonation parameters were calculated following the Kamlet-Jacobs equation.

IE1 of Autographa californica Multiple Nucleopolyhedrovirus Activates Low Levels of Late Gene Expression in the Absence of Virus RNA Polymerase.

Early and late gene expressions of baculoviruses have been known to rely on host RNA polymerase II and a virus-encoded RNA polymerase, separately. In this study, we found that Autographa californica multiple nucleopolyhedrovirus (AcMNPV) recombinant bacmids with the individual RNA polymerase subunit genes deleted could support low levels of expression of a reporter gene under the control of the promoter of a typical late gene, vp39, in transfected Sf9 cells. Through multistep subcloning of a genomic library of the virus and transient expression assay analysis, ie1 was identified to be the only viral gene that was responsible for activation of late gene expression in the absence of the viral RNA polymerase. Furthermore, IE1 was found to be capable of activating reporter gene expression from the promoters of additional late genes polh, p6.9, odv-e18, odv-e25, and gp41, independent of any additional viral factors. Deletion of ie1 from the virus genome eliminated late gene expression. The IE1-activated late gene expression was enhanced by the viral hr4b. It was shown to be insensitive to inhibition of α-amanitin and did not appear to have stable transcription start sites. It is proposed that IE1 may serve to recruit newly synthesized viral RNA polymerase to viral DNA by activating low levels of pretranscription of the late genes to create an appropriate DNA conformation. IMPORTANCE The late gene expression of baculovirus has been known to depend on the virus-encoded RNA polymerase, which consists of four subunits. The immediate-early gene ie1 was found to be required for viral early gene expression, late gene expression, and DNA replication. How it functions in late gene expression remains unclear. In this study, we found that AcMNPV IE1 could activate low levels of gene expression from late gene promoters independently of any additional viral factors, with nonspecific transcription start sites. This new finding will shed light on the role of IE1 in the regulation of late gene expression and the understanding of the mechanism of late gene transcription initiation.

Small molecule C381 targets the lysosome to reduce inflammation and ameliorate disease in models of neurodegeneration.

SignificanceNeurodegenerative diseases are poorly understood and difficult to treat. One common hallmark is lysosomal dysfunction leading to the accumulation of aggregates and other undegradable materials, which cause damage to brain resident cells. Lysosomes are acidic organelles responsible for breaking down biomolecules and recycling their constitutive parts. In this work, we find that the antiinflammatory and neuroprotective compound, discovered via a phenotypic screen, imparts its beneficial effects by targeting the lysosome and restoring its function. This is established using a genome-wide CRISPRi target identification screen and then confirmed using a variety of lysosome-targeted studies. The resulting small molecule from this study represents a potential treatment for neurodegenerative diseases as well as a research tool for the study of lysosomes in disease.

Machine learning model to predict the efficacy of antiseizure medications in patients with familial genetic generalized epilepsy.

OBJECTIVE: This study aimed to establish a machine learning model that can predict the efficacy of antiseizure medications (ASMs) in patients with familial genetic generalized epilepsy (GGE). METHODS: We prospectively followed up patients with familial GGE for at least 3 years between January 2007 and January 2017. We collected and analyzed the patients' demographic characteristics, medical history, and related auxiliary examinations. The results of the epileptic seizures were divided into two categories: seizure-free and drug-resistant epilepsy. We selected and trained thirteen classification models, i.e., random forest classifier, logistic regression, gradient boosting classifier, light gradient boosting machine, ridge classifier, linear discriminant analysis, support vector machine-linear kernel, extra tree classifier, Ada boost classifier, naive Bayes classifier, decision tree classifier, K neighbors classifier, and quadratic discriminant analysis, to get the best performing classification model. RESULTS: A total of 854 patients with familial GGE were included in the study after excluding 89 who were lost to follow-up. Among them, 631 patients with familial GGE became seizure-free, and 223 developed drug-resistant epilepsy with a 74.89% remission rate. Among the 13 models, the random forest classifier model was the most effective with an accuracy of 91.23% and an F1 score of 84.21%. Among the 18 patient characteristics, the most effective indicators of the final treatment results were the number of seizure types experienced, response to the first drug, prior treatment duration and number of pre-treatment seizures. SIGNIFICANCE: The random forest classifier model can be used to early predict the results of ASM treatment based on the clinical data of patients with familial GGE. This finding can help clinicians make timely adjustments to treatment strategies and improve patients' prognosis.

An oligomeric semiconducting nanozyme with ultrafast electron transfers alleviates acute brain injury.

Artificial enzymes have attracted wide interest in disease diagnosis and biotechnology due to high stability, easy synthesis, and cost effectiveness. Unfortunately, their catalytic rate is limited to surface electron transfer, affecting the catalytic and biological activity. Here, we report an oligomeric nanozyme (O-NZ) with ultrafast electron transfer, achieving ultrahigh catalytic activity. O-NZ shows electron transfer of 1.8 nanoseconds in internal cores and 1.2 picoseconds between core and ligand molecule, leading to ultrahigh superoxidase dismutase­like and glutathione peroxidase­like activity (comparable with natural enzyme, Michaelis constant = 0.87 millimolars). Excitingly, O-NZ can improve the 1-month survival rate of mice with acute brain trauma from 50 to 90% and promote the recovery of long-term neurocognition. Biochemical experiments show that O-NZ can decrease harmful peroxide and superoxide via in vivo catalytic chain reaction and reduce acute neuroinflammation via nuclear factor erythroid-2 related factor 2­mediated up-regulation of heme oxygenase-1 expression.

Acute and late administration of colony stimulating factor 1 attenuates chronic cognitive impairment following mild traumatic brain injury in mice.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability. Currently there is no effective pharmacological treatment for patients suffering from the long-lasting symptoms of TBI. We recently discovered that colony stimulating factor 1 (CSF1), an essential regulator of macrophage homeostasis, is neuroprotective and reduces neuroinflammation in two models of neurological disease in mice. Here we used a mouse model of repetitive mild TBI (mTBI) to examine whether CSF1 would attenuate cognitive deficits and improve pathological outcomes in two paradigms. In the acute paradigm, a single bolus treatment of CSF1 administered 24 h after injury significantly reduces memory impairment and astrocyte reactivity assessed 3 months later. In the chronic paradigm, the mice were tested 3 months after mTBI when they showed cognitive deficits. The mice were then randomly assigned to receive CSF1 or PBS (as control) treatment. After one month of treatment, the PBS-treated mice remained cognitively impaired, but the CSF1-treated showed significant improvements in cognitive function. RNA-seq and Ingenuity Pathway Analysis reveals CSF1 treatment alters cognition- and memory-related transcriptomic changes and pathways. The results of this study show that acute as well as delayed CSF1 treatment attenuate chronically impaired cognitive functions and improve pathological outcomes long after mTBI. The wide therapeutic time window of CSF1, together with the fact that CSF1 is approved for human use in clinical trials, strongly supports the potential clinical usefulness of this treatment in patients with mTBI.

Comparative genomic analysis of three geographical isolates from China reveals high genetic stability of Plutella xylostella granulovirus.

In this study, the genomes of three Plutella xylostella granulovirus (PlxyGV) isolates, PlxyGV-W and PlxyGV-Wn from near Wuhan and PlxyGV-B from near Beijing, China were completely sequenced and comparatively analyzed to investigate genetic stability and diversity of PlxyGV. PlxyGV-W, PlxyGV-B and PlxyGV-Wn consist of 100,941bp, 100,972bp and 100,999bp in length with G + C compositions of 40.71-40.73%, respectively, and share nucleotide sequence identities of 99.5-99.8%. The three individual isolates contain 118 putative protein-encoding ORFs in common. PlxyGV-W, PlxyGV-B and PlxyGV-Wn have ten, nineteen and six nonsynonymous intra isolate nucleotide polymorphisms (NPs) in six, fourteen and five ORFs, respectively, including homologs of five DNA replication/late expression factors and two per os infectivity factors. There are seventeen nonsynonymous inter isolate NPs in seven ORFs between PlxyGV-W and PlxyGV-B, seventy three nonsynonymous NPs in forty seven ORFs between PlxyGV-W and PlxyGV-Wn, seventy seven nonsynonymous NPs in forty six ORFs between PlxyGV-B and PlxyGV-Wn. Alignment of the genome sequences of nine PlxyGV isolates sequenced up to date shows that the sequence homogeneity between the genomes are over 99.4%, with the exception of the genome of PlxyGV-SA from South Africa, which shares a sequence identity of 98.6-98.7% with the other ones. No events of gene gain/loss or translocations were observed. These results suggest that PlxyGV genome is fairly stable in nature. In addition, the transcription start sites and polyadenylation sites of thirteen PlxyGV-specific ORFs, conserved in all PlxyGV isolates, were identified by RACE analysis using mRNAs purified from larvae infected by PlxyGV-Wn, proving the PlxyGV-specific ORFs are all genuine genes.

CAS Calculation of the Excited States of the Methylthio Neutral Radical and Its Ions.

The complete active space (CASSCF) and the multiconfiguration second-order perturbation theory (CASPT2) calculations with 6-311++G(3df,3pd) gauss basis sets are performed for several electronic states of the methylthio neutral radical and its cation and anion. Twenty-two electronic states are optimized in the C s point group. Through the vertical promotion calculations, the absorption spectral is simulated for the neutral radical. Furthermore, through the energy comparison between the neutral radical and relative ions, the ionization energy and the electronic absorption energy are understood adiabatically.

Computational study about the thermal stability and the detonation performance of nitro-substituted thymine.

By replacing hydrogen atoms in thymine molecules with nitro groups, a series of new high-energy-density molecules are designed. To explore the thermal stability, the heats of formation (HOF) are calculated at the B3PW91-D3/6-311++G(2df,2p) level. The bond dissociation energy and the bond order are also calculated to predict the kinetic stability at the same level. Based on our calculations, excellent stability is confirmed for title molecules. To confirm the possibility of application as high-energy-density compounds, the molecular density (ρ), explosive heats (Q), detonation velocity (D), detonation pressure (P), free space per molecule in crystal lattice (ΔV), and characteristic drop height (H50) are calculated. On the consideration of the stability and the detonation characters, E1 is confirmed as the candidates of high-energy-density compounds.

Physiological blood-brain transport is impaired with age by a shift in transcytosis.

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

Theoretical exploration about the thermal stability and detonation properties of nitro-substituted hypoxanthine.

Nitro-substituted derivatives of hypoxanthine are designed by substituting the hydrogen atoms by nitro groups. The heats of formation (HOF) are calculated at the G3MP2 level to confirm the thermal stability. Also, the bond dissociation energy (BDE) accompanied by the bond order is calculated at the same level to explore kinetic stability. To evaluate the potential application as high-energy density materials, the explosive heat, the molecular density, the detonation pressure, and detonation velocity are estimated by using the Kamlet-Jacobs (K-J) equation. Furthermore, the molecular sensitivities are considered by calculating the character height (H50) and the amount of free space per molecule in the crystal lattice (ΔV). Based on our calculations, the trinitro-substituted hypoxanthine (C) is screened out as the potential high-energy density compounds for further study.

Atomic-Precision Gold Clusters for NIR-II Imaging.

Near-infrared II (NIR-II) imaging at 1100-1700 nm shows great promise for medical diagnosis related to blood vessels because it possesses deep penetration and high resolution in biological tissue. Unfortunately, currently available NIR-II fluorophores exhibit slow excretion and low brightness, which prevents their potential medical applications. An atomic-precision gold (Au) cluster with 25 gold atoms and 18 peptide ligands is presented. The Au25 clusters show emission at 1100-1350 nm and the fluorescence quantum yield is significantly increased by metal-atom doping. Bright gold clusters can penetrate deep tissue and can be applied in in vivo brain vessel imaging and tumor metastasis. Time-resolved brain blood-flow imaging shows significant differences between healthy and injured mice with different brain diseases in vivo. High-resolution imaging of cancer metastasis allows for the identification of the primary tumor, blood vessel, and lymphatic metastasis. In addition, gold clusters with NIR-II fluorescence are used to monitor high-resolution imaging of kidney at a depth of 0.61 cm, and the quantitative measurement shows 86% of the gold clusters are cleared from body without any acute or long-term toxicity at a dose of 100 mg kg-1 .

Thermal stability and detonation character of nitro-substituted derivatives of imidazole.

A series of nitro-imidazole derivatives were designed by replacing hydrogen atoms on imidazole ring with nitro group one by one. In order to investigate the thermodynamic stability, heat of formation (HOF), and bond dissociation energy (BDE) are calculated at the B3PW91/6-311+G(d,p) level. In order to investigate the impact sensitivity and detonation property, the drop height (H50), free space per molecule in crystal lattice (ΔV), detonation velocity (D), and detonation pressure (P) are calculated by using the empirical Kamlet-Jacobs (K-J) equation. The results show that the thermal stabilities of title molecules are determined by whether nitro group is associated to 1-position or not and accompanied with the steric hindrance between nitro groups and the charge population on the carbon atoms of imidazole ring. The excellent impact sensitivity and detonation performance of title molecules are also evaluated. On the consideration both of stability and detonation characters, 2,4,5-trinitro-1H-imidazole (D = 8.98 km/s, P = 36.70 GPa) is screened out as the potential high-energy-density molecule for further research.

Light-sheet microscopy in the near-infrared II window.

Non-invasive deep-tissue three-dimensional optical imaging of live mammals with high spatiotemporal resolution is challenging owing to light scattering. We developed near-infrared II (1,000-1,700 nm) light-sheet microscopy with excitation and emission of up to approximately 1,320 nm and 1,700 nm, respectively, for optical sectioning at a penetration depth of approximately 750 µm through live tissues without invasive surgery and at a depth of approximately 2 mm in glycerol-cleared brain tissues. Near-infrared II light-sheet microscopy in normal and oblique configurations enabled in vivo imaging of live mice through intact tissue, revealing abnormal blood flow and T-cell motion in tumor microcirculation and mapping out programmed-death ligand 1 and programmed cell death protein 1 in tumors with cellular resolution. Three-dimensional imaging through the intact mouse head resolved vascular channels between the skull and brain cortex, and allowed monitoring of recruitment of macrophages and microglia to the traumatic brain injury site.

CD22 blockade restores homeostatic microglial phagocytosis in ageing brains.

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-ß oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.

Theoretical calculations about nitro-substituted pyridine as high-energy-density compounds (HEDCs).

A series of derivatives of pyridine were designed through substituting hydrogen atoms by nitro groups systematically. By using the density functional theory at B3PW91/6-311++G(d,p)//MP2/311++G(d,p) level, heats of formation, bond orders, and bond dissociation energies were calculated to explore the thermodynamic stabilities of title molecules. Furthermore, the regularity of stability was explained based on the electronic population. Our results indicated that title molecules had enough stability to exist. To evaluate the potential usage as a high-energy-density molecule, the detonation pressure and detonation velocity were explored by using the semi-empirical Kamlet-Jacobs equation and excellent detonation character was confirmed. Overall consideration of the thermal stability and energetic character, four molecules (2,3,4,5-tetranitropyridine, 2,3,5,6-tetranitropyridine, 2,4,5,6-tetranitrop-pyridine, 2,3,4,5,6-pentanitropyridine) were confirmed to be better than RDX and filtered as potential energetic molecules.

Photonic band engineering in absorbing media for spectrally selective optoelectronic films.

Spectrally selective materials are of great interest for optoelectronic devices in which wavelength-selectivity of the photoactive material is necessary for applications such as multi-junction solar cells, narrow-band photodetectors, transparent photovoltaics, and tailored emission sources. Achieving controlled transparency or opacity within multiple wavelength bands in the absorption, reflection, and transmission spectra are difficult to achieve in traditional semiconductors that typically absorb at all energies above their electronic band gap and is generally realized by the use of external bandpass filters. Here, we propose an alternate method for achieving spectral selectivity in optoelectronic thin films: the use of photonic band engineering within the absorbing region of a semiconductor in which resonant photonic bands are strongly coupled to the external reflectivity and transmission spectra. As a first step, we use optical simulations to systematically study the effect of material absorption on the properties of the photonic bands in a photonic crystal slab structure. We find that adding a weak loss to the materials model does not appreciably change the frequencies of the photonic bands but does reduce the quality factor of the associated photonic modes. Critically, the radiating photonic bands induce strong Fano resonance features in the transmission and reflection spectra, even in the presence of material absorption, due to coupling between the bands and external electromagnetic plane waves. These resonances can be tuned by adjusting the photonic crystal structural properties to induce spectral selectivity in the absorbing region of semiconductors. Lastly, we demonstrate this tuning method experimentally by fabricating a proof-of-principle photonic structure consisting of a self-assembled polystyrene bead monolayer infiltrated with PbS CQDs that displays both near-infrared absorption enhancement and visible transparency enhancement over a homogeneous control film, qualitatively matching predictions and showing promise for optoelectronic applications.

A bright organic NIR-II nanofluorophore for three-dimensional imaging into biological tissues.

Fluorescence imaging of biological systems in the second near-infrared (NIR-II, 1000-1700 nm) window has shown promise of high spatial resolution, low background, and deep tissue penetration owing to low autofluorescence and suppressed scattering of long wavelength photons. Here we develop a bright organic nanofluorophore (named p-FE) for high-performance biological imaging in the NIR-II window. The bright NIR-II >1100 nm fluorescence emission from p-FE affords non-invasive in vivo tracking of blood flow in mouse brain vessels. Excitingly, p-FE enables one-photon based, three-dimensional (3D) confocal imaging of vasculatures in fixed mouse brain tissue with a layer-by-layer imaging depth up to ~1.3 mm and sub-10 µm high spatial resolution. We also perform in vivo two-color fluorescence imaging in the NIR-II window by utilizing p-FE as a vasculature imaging agent emitting between 1100 and 1300 nm and single-walled carbon nanotubes (CNTs) emitting above 1500 nm to highlight tumors in mice.

Autographa californica multiple nucleopolyhedrovirus ac75 is required for egress of nucleocapsids from the nucleus and formation of de novo intranuclear membrane microvesicles.

In this study, Autographa californica multiple nucleopolyhedrovirus ac75 was functionally characterized. Ac75 has homologs in all sequenced genomes of alphabaculoviruses, betabaculoviruses, and gammabaculoviruses. It was determined to encode a protein that is associated with the nucleocapsid of budded virus and with both envelope and nucleocapsids of occlusion-derived virus. Sf9 cells transfected by an ac75-knockout bacmid resulted in the infection being restricted to single cells. No budded virus were detected although viral DNA replication and late gene expression were unaffected. Electron microscopy revealed that the virogenic stroma, nucleocapsids and occlusion bodies appeared normal in the cells transfected by an ac75-knockout bacmid. However, the nucleocapsids were unenveloped, the occlusion bodies did not contain any virions or nucleocapsids, and no nucleocapsids were found outside the nucleus or spanning the nuclear membrane. In addition, de novo intranuclear membrane microvesicles that are the precursor of occlusion-derived virus envelopes were absent in the nuclei of transfected cells. Confocal microscopy showed that AC75 protein appeared in the cytoplasm as early as 6 hours post infection. It localized to the ring zone at the periphery of the nucleus from 15 to 24 hours post infection and demonstrated light blocky cloud-like distribution in the center of the nucleus. AC75 was found to co-immunoprecipitate with BV and ODV associated envelope protein ODV-E25. The data from this study suggest that ac75 is essential for induction of the intranuclear membrane microvesicles, it appears to be required for the intranuclear envelopment of nucleocapsids, and is also essential for egress of nucleocapsids from the nuclei, in infected cells.

Deficiency in Neuronal TGF-ß Signaling Leads to Nigrostriatal Degeneration and Activation of TGF-ß Signaling Protects against MPTP Neurotoxicity in Mice.

Transforming growth factor-ß (TGF-ß) plays an important role in the development and maintenance of embryonic dopaminergic (DA) neurons in the midbrain. To study the function of TGF-ß signaling in the adult nigrostriatal system, we generated transgenic mice with reduced TGF-ß signaling in mature neurons. These mice display age-related motor deficits and degeneration of the nigrostriatal system. Increasing TGF-ß signaling in the substantia nigra through adeno-associated virus expressing a constitutively active type I receptor significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and motor deficits. These results suggest that TGF-ß signaling is critical for adult DA neuron survival and that modulating this signaling pathway has therapeutic potential in Parkinson disease.SIGNIFICANCE STATEMENT We show that reducing Transforming growth factor-ß (TGF-ß) signaling promotes Parkinson disease-related pathologies and motor deficits, and increasing TGF-ß signaling reduces neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a parkinsonism-inducing agent. Our results provide a rationale to pursue a means of increasing TGF-ß signaling as a potential therapy for Parkinson's disease.