Search

We put forward a dual-mode photonic crystal nanobeam cavity for simultaneous sensing of the refractive index (RI) and temperature (T) designed with the assistance of artificial neural networks (ANNs). We choose the structure of quadratically tapered elliptical holes with a slot to improve the sensitivities of the two modes. To reduce the time consumption of the design, the ANNs are trained to predict the band structure and to inverse design the geometric structure. For the forward prediction and the inverse design neural networks, low mean square errors of 5.1 × 1 0 − 4 and 1.4 × 1 0 − 2 are achieved, respectively. Through a specific design of band properties by the well-trained neural networks, a dual-mode nanobeam sensor with high quality factors of 9.34 × 1 0 4 and 1.55 × 1 0 5 and a small footprint of 23.8 × 0.7 µ m 2 are designed. The RI and T sensitivities of the air mode are 405 nm/RIU and 40 pm/K, respectively, whereas those of the dielectric mode are 531 nm/RIU and 27 pm/K, respectively. The present work shows significance in further research on the design and applications for dual-mode cavities.

Synthesis methods of composites materials can tailor individual materials properties and make the composite possess more superior performance than individual materials. Herein, by combining –NH2 group in graphitic carbon nitride (g-C3N4) and a facile electrolytic route, g-C3N4-bridging reduced graphene oxide nanocomposite (g-C3N4/r-GO) was successfully prepared to construct chemical sensor for detection of Pb2+. Because g-C3N4 contains a large amount of –NH2 group, covalent bonds as bridges between GO and g-C3N4 could be successfully formed by successively electrolyzing, which simultaneously induced removal of electron withdrawing group in r-GO. Such bridges could shorten the planar distance between GO and g-C3N4 in comparison with the conventional π-π stacking, improving the electrochemical performance of r-GO and g-C3N4. Moreover, the above unique chemical structure of g-C3N4/r-GO not only exhibited excellent electrical conductivity but also provided plenty active sites to chelate Pb2+ from solution. Therefore, the prepared g-C3N4/r-GO ensured chemical sensor for Pb2+detection with wide linear range (1.0–300 μg/L) and low detection limit (0.15 μg/L at S/N = 3). This simple method could also be extended to preparation of other elements-contained nanomaterials functionalized oxide graphene for improve its properties and widen its potential applications.

Background Global effort is key to prevent and control infections effectively. Whereas pharmacists’ involvement in the immunization neighborhood, collaborative effort to meet immunization needs of the public, has reduced burden of vaccine-preventable diseases in Western countries, the impact of pharmacist-involved vaccination advocacy and delivery in Asia Pacific remains unclear. Objective To examine the evidence for impact of pharmacists on immunization advocacy and delivery in Asia Pacific and to assess Singaporean pharmacists’ experience in becoming immunizing pharmacists through the American Pharmacists Association’s Pharmacy-based Immunization certificate training program. Methods A mixed-method study consisted of systematic review and survey was conducted. The systematic review was conducted by searching PubMed and Cumulative Index to Nursing and Allied Health databases from inception to March 2021. Randomized controlled trials and observational studies related to pharmacist-involved immunization advocacy and training conducted in Asia Pacific were included. Eligible studies were appraised for quality using CONsolidated Standards of Reporting Trials (CONSORT) and STrengthening the Reporting of OBservational checklists. In addition, a 20-item Likert-scale survey evaluated the pharmacists’ experience in becoming immunizing pharmacists in Singapore. Frequencies of each response to the survey items were analyzed. Results Six studies were eligible for inclusion; 2 assessing impact of pharmacist as immunizer, 3 reporting outcomes of pharmacist-involved vaccine advocacy, and 1 evaluating the structure of pharmacist immunization training. Although study quality was minimal, all studies echoed positive findings as a result of pharmacist-provided immunization advocacy and delivery. Of the 23 pharmacists completing the survey, 91.3% strongly agreed that quality training was important to become immunizing pharmacists. Conclusion Although limited in number, studies conducted in Asia Pacific reported increased vaccination rates when involving pharmacists. Coupled with the enthusiasm to be trained in immunization advocacy and delivery as elucidated by the Singaporean pharmacists, pharmacists in Asia Pacific should also be advocated for their role in the immunization neighborhood as part of the global effort against vaccine-preventable infectious diseases.

Three striking and impactful extreme cold weather events successively occurred across East Asia and North America during the mid-winter of 2020/21. These events open a new window to detect possible underlying physical processes. The analysis here indicates that the occurrences of the three events resulted from integrated effects of a concurrence of anomalous thermal conditions in three oceans and interactive Arctic-lower latitude atmospheric circulation processes, which were linked and influenced by one major sudden stratospheric warming (SSW). The North Atlantic warm blob initiated an increased poleward transient eddy heat flux, reducing the Barents-Kara seas sea ice over a warmed ocean and disrupting the stratospheric polar vortex (SPV) to induce the major SSW. The Rossby wave trains excited by the North Atlantic warm blob and the tropical Pacific La Nina interacted with the Arctic tropospheric circulation anomalies or the tropospheric polar vortex to provide dynamic settings, steering cold polar air outbreaks. The long memory of the retreated sea ice with the underlying warm ocean and the amplified tropospheric blocking highs from the midlatitudes to the Arctic intermittently fueled the increased transient eddy heat flux to sustain the SSW over a long time period. The displaced or split SPV centers associated with the SSW played crucial roles in substantially intensifying the tropospheric circulation anomalies and moving the jet stream to the far south to cause cold air outbreaks to a rarely observed extreme state. The results have significant implications for increasing prediction skill and improving policy decision making to enhance resilience in “One Health, One Future”.

In this study, a biomass pretreatment strategy with a recyclable cosolvent (toluene sulfonic acid/ethanol) was developed. The low boiling point solvent (78.15 °C), ethanol, was employed to replace water in the cosolvent system for reducing energy consumption of solvent evaporation. Under a mild temperature (80 °C), the lignin removal and enzymatic saccharification yield of glucan reached to 49.27% and 93.28%, respectively. The obtained lignin was characterized with fourier transform infrared spectroscopy, 31P nuclear magnetic resonance spectroscopy, gel permeation chromatography, and two-dimensional H–C heteronuclear single quantum coherence nuclear magnetic resonance spectroscopy. Meanwhile, the interaction mechanism of lignin and cosolvent molecules was explored by density functional theory calculation and molecular dynamics simulations. The results showed that water molecules significantly enhanced the noncovalent interactions, mainly the C–H⋯π and H–O···H bonding, as revealed by an increase of interaction energy ΔE. By disrupting the natural hydrogen bonds, the fractionated lignin was thereby dissolved out from wood material.

An overarching goal of aging and age-related neurodegenerative disease research is to discover effective therapeutic strategies applicable to a broad spectrum of neurodegenerative diseases. Little is known about the extent to which targetable pathogenic mechanisms are shared among these seemingly diverse diseases. Translational control is critical for maintaining proteostasis during aging. Gaining control of the translation machinery is also crucial in the battle between viruses and their hosts. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic. Here, we show that overexpression of SARS-CoV-2–encoded nonstructural protein 1 (Nsp1) robustly rescued neuromuscular degeneration and behavioral phenotypes in Drosophila models of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. These diseases share a common mechanism: the accumulation of aberrant protein species due to the stalling and collision of translating ribosomes, leading to proteostasis failure. Our genetic and biochemical analyses revealed that Nsp1 acted in a multipronged manner to resolve collided ribosomes, abort stalled translation, and remove faulty translation products causative of disease in these models, at least in part through the ribosome recycling factor ABCE1, ribosome-associated quality-control factors, autophagy, and AKT signaling. Nsp1 exhibited exquisite specificity in its action, as it did not modify other neurodegenerative conditions not known to be associated with ribosome stalling. These findings uncover a previously unrecognized mechanism of Nsp1 in manipulating host translation, which can be leveraged for combating age-related neurodegenerative diseases that are affecting millions of people worldwide and currently without effective treatment.

The serine/threonine kinase STK33 has been implicated in cancer cell proliferation. Abnormal expression of STK33 is closely related to malignant tumors of many cancers. Here, we provide evidence of a critical role for STK33 in the pathogenesis and metastatic progression of esophageal squamous cell carcinoma (ESCC). In human ESCC specimens, STK33 was overexpressed and associated with poor prognosis. Silencing STK33 expression inhibited ESCC proliferation, migration, invasion, and tumor growth. Furthermore, STK33 was also involved in angiogenesis, TGFB, and inflammatory response in ESCC. Mechanistic investigations showed that STK33 regulated ESCC through multiple complex pathways. In showing that dysregulated STK33 signaling promotes ESCC growth and progression, our results suggest STK33 as a candidate therapeutic target to improve ESCC treatment.

Sequencing of Congenital Heart Disease (CHD) patients identified variants in many histone modifying genes, suggesting that histone modification plays important roles in heart development and disease. However, how these histone modifying genes perform their epigenetic regulation function during heart development remain elusive, and whether these novel genetic variants identified from CHD patients are causal remain unclear. We found that most histone modifying genes are highly conserved from Drosophila to humans, and many are expressed in the developing heart in both systems. Using a high-throughput functional validation system that we generated for providing the “gene-level” disease association for candidate CHD genes, we screened lots of histone-modifying genes and identified many that are required for heart development in Drosophila. Among them, genes involved in histone H3K4 mono- and dimethylation are particularly important for heart development and appear to regulate evolutionarily conserved targets during heart development from Drosophila to mammals. We also generated Drosophila models for CHD patient-derived variants in histone-modifying genes to study how these variants affect the function of the human genes in the context of the fly heart development, to provide the “variant-level” evidence for their causal association with CHD.

Background Stroke is the leading cause of disability worldwide, resulting in severe damage to the central nervous system and disrupting neurological functions. There is no effective therapy for promoting neurological recovery. Growing evidence suggests that the composition of exosomes from different microenvironments may benefit stroke. Therefore, it is reasonable to assume that exosomes secreted in response to infarction microenvironment could have further therapeutic effects. Methods In our study, cerebral infarct tissue extracts were used to pretreat umbilical cord mesenchymal stem cells (UCMSC). Infarct-preconditioned exosomes were injected into rats via tail vein after middle cerebral artery occlusion (MCAO). The effect of infarct-preconditioned exosomes on the neurological recovery of rats was examined using Tunel assay, 2,3,5-triphenyltetrazolium chloride (TTC) assay, magnetic resonance imaging (MRI) analyses, modified Neurological Severity Score (mNSS), Morris water maze (MWM), and vascular remodeling analysis. Mi-RNA sequencing and functional enrichment analysis were used to validate the signal pathway involved in the effect of infarct-preconditioned exosomes. Human umbilical vein endothelial cells (HUVECs) were co-cultured with the isolated exosomes. Cell Counting Kit-8 (CCK-8) assay, scratch healing, and Western blot analysis were used to detect the biological behavior of HUVECs. Results The results showed that compared with normal exosomes, infarct-preconditioned exosomes further promoted vascular remodeling and recovery of neurological function after stroke. The function of upregulated miRNAs and their target genes which is beneficial to vascular smooth muscle cells verified the importance of vascular remodeling in improving stroke. Better resistance to oxygen–glucose deprivation/reoxygenation (OGD/R), reduced apoptosis, and enhanced migration were observed in infarct-preconditioned exosomes-treated umbilical vein endothelial cells. Conclusions Our results demonstrated that infarct-preconditioned exosomes promoted neurological recovery after stroke by enhancing vascular endothelial remodeling, suggested that infarct-preconditioned exosomes could be a novel way to alleviate brain damage following a stroke.

With the advent of the molecular era, the diagnosis and treatment systems of glioma have also changed. A single histological type cannot be used for prognosis grade. Only by combining molecular diagnosis can precision medicine be realized.To develop an automatic integrated gene detection system (AIGS) for intraoperative detection in glioma and to explore its positive role in intraoperative diagnosis and treatment.We analyzed the isocitrate dehydrogenase 1 (IDH1) mutation status of 105 glioma samples and evaluated the product's potential value for diagnosis; 37 glioma samples were detected intraoperatively to evaluate the feasibility of using the product in an actual situation. A blinding method was used to evaluate the effect of the detection technology on the accuracy of intraoperative histopathological diagnosis by pathologists. We also reviewed the current research status in the field of intraoperative molecular diagnosis.Compared with next-generation sequencing, the accuracy of AIGS in detecting IDH1 was 100% for 105 samples and 37 intraoperative samples. The blind diagnostic results were compared between the 2 groups, and the molecular information provided by AIGS increased the intraoperative diagnostic accuracy of glioma by 16.2%. Using the technical advantages of multipoint synchronous detection, we determined the tumor molecular margins for 5 IDH-positive patients and achieved accurate resection at the molecular level.AIGS can quickly and accurately provide molecular information during surgery. This methodology not only improves the accuracy of intraoperative pathological diagnosis but also provides an important molecular basis for determining tumor margins to facilitate precision surgery.

CO2 hydrogenation to methanol is becoming a potential route for reducing CO2 emission, benefiting from the worldwide growth of renewable energy for H2 production. In this work, the ZnO-ZrO2 solid solution catalysts with ordered mesoporous structure were constructed by the evaporation-induced self-assembly (EISA) process using triblock copolymer P123 as the template. The 20% ZnO-ZrO 2 catalyst prepared by the evaporation-induced self-assembly process shows a methanol formation rate of 22.1 mmol·h-1·gcat-1 at 320°C, 5.5 MPa, which is 1.35 times that of the catalyst prepared by co-precipitation. Characterizations prove that the EISA catalysts have larger specific surface areas and more sites for the activation of CO2 and H2, which are related to the higher CO2 conversion.

By replacing multiplication with XNOR operation, Binarized Neural Networks (BNN) are hardware-friendly and extremely suitable for FPGA acceleration. Previous researches highlighted the potential exploitation of BNNs performance. However, most of the present researches targeted at minimizing chip areas. They achieved excellent energy and resource efficiency in small FPGA while the results in larger FPGA were unsatisfying. Thus, we proposed a scalable fully pipelined BNN architecture, which targeted on maximizing throughput and keeping energy and resource efficiency in large FPGA. By exploiting multi-levels parallelism and balancing pipeline stages, it achieved excellent performance. Moreover, we shared on-chip memory and balanced the computation resources to further utilizing the resource. Then a methodology is proposed that explores design space for the optimal configuration. This work is evaluated based on Xilinx UltraScale XCKU115. The results show that the proposed architecture achieves 2.24×–11.24× performance and 2.43×–11.79× resource efficiency improvement compared with other BNN accelerators.

Background Potassium levels regulate multiple physiologic processes. The heritability of serum potassium level is moderate, with published estimates varying from 17% to 60%, suggesting genetic influences. However, the genetic determinants of potassium levels are not generally known. Methods A whole-exome sequencing association study of serum potassium levels in 5812 subjects of the Old Order Amish was performed. A dietary salt intervention in 533 Amish subjects estimated interaction between p.R642G and sodium intake. Results A cluster of variants, spanning approximately 537 kb on chromosome 16q13, was significantly associated with serum potassium levels. Among the associated variants, a known pathogenic variant of autosomal recessive Gitelman syndrome (p.R642G SLC12A3) was most likely causal; there were no homozygotes in our sample. Heterozygosity for p.R642G was also associated with lower chloride levels, but not with sodium levels. Notably, p.R642G showed a novel association with lower serum BUN levels. Heterozygotes for p.R642G had a two-fold higher rate of self-reported bone fractures and had higher resting heart rates on a low-salt diet compared with noncarriers. Conclusions This study provides evidence that heterozygosity for a pathogenic variant in SLC12A3 causing Gitelman syndrome, a canonically recessive disorder, contributes to serum potassium concentration. The findings provide insights into SLC12A3 biology and the effects of heterozygosity on electrolyte homeostasis and related subclinical phenotypes that may have implications for personalized medicine and nutrition.

Hydrogenation of CO2 into methanol using the H2 produced from renewable energy is a promising way for carbon capture and utilization. Therefore, the methanol synthesis catalysts with high methanol selectivity are highly desired. In this work, we found that the methanol selectivity of In2O3 catalyst can be significantly enhanced by introducing a small amount of Pt. Methanol selectivity can be increased from 72.2% (In2O3) to 91.1% (0.58 wt.% Pt/In2O3) at 220 °C. The introduced Pt atoms are doped into the In2O3, forming atomically dispersed Ptn+ species, most of which are stable under working conditions. It is proposed that the atomically dispersed Ptn+ species are responsible for the enhanced methanol selectivity, while Pt nanoparticles on In2O3 mainly boost the reverse water-gas shift reaction (CO2 + H2 → CO + H2O).

We investigated in larval and adult Drosophila models whether loss of the mitochondrial chaperone Hsc70-5 is sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we studied an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displayed ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of dj-1β, Lrrk, DCTN2-p50, DCTN1-p150, Atg1, Atg101, Atg5, Atg7, and Atg12. The knockdown of components of the macroautophagy/autophagy machinery or overexpression of human HSPA9 broadly rescued larval and adult phenotypes, while disease-associated HSPA9 variants did not. Overexpression of Pink1 or promotion of autophagy exacerbated defects.Abbreviations: AEL: after egg laying; AZ: active zone; brp: bruchpilot; Csp: cysteine string protein; dlg: discs large; eEJPs: evoked excitatory junctional potentials; GluR: glutamate receptor; H2O2: hydrogen peroxide; mEJP: miniature excitatory junctional potentials; MT: microtubule; NMJ: neuromuscular junction; PD: Parkinson disease; Pink1: PTEN-induced putative kinase 1; PSD: postsynaptic density; SSR: subsynaptic reticulum; SV: synaptic vesicle; VGlut: vesicular glutamate transporter.

An efficient indium-mediated cascade annulation reaction of 2-azidoaryl aldehydes with propargyl bromides is reported. The aromatic 5/6/6-fused heterocycles, [1,2,3]triazolo[1,5-a]quinoline derivatives, could be constructed in one pot in moderate yields with a broad substrate scope. Mechanistic studies indicated that the reaction proceeded through allenol formation, azide–allene [3 + 2] cycloaddition, and dehydration. The synthetic potential of the products including the denitrogenative functionalization and the Pd-catalyzed coupling reactions has also been explored.

MicroRNA-363-3 p (miR-363–3 p) has been reported to play a crucial role in tumor development and progression, and function as a tumor suppressor in many types of cancer. In our previous studies, we found that miRNA-363–3 p inhibited papillary thyroid carcinoma (PTC) progression by targeting PIK3CA. Meanwhile, we found that NIN1/RPN12 binding protein 1 (NOB1) was significantly upregulated in thyroid carcinoma tissue and downregulation of NOB1 expression significantly inhibited cell proliferation, migration and invasion in PTC. However, the correlation of NOB1 and miR-363–3 p has not been investigated. Here, we performed bioinformatic analysis to explore miRNA targeting NOB1. We found that NOB1 was a target of miR-363–3 p and miR-363–3 p regulated NOB1 expression at the translational and transcriptional levels by targeting its 3’ untranslated region (3′-UTR). Further, we showed that miR-363–3 p inhibited tumor progression by targeting NOB1 in vitro and in vivo. We found that overexpression miR-363–3 p or silencing NOB1 significantly increased G0/G1-phase and decreased S-phase in the human papillary thyroid cells, which led to a significant delay in cell proliferation, indicating miR-363–3 p and NOB1 are crucial for human papillary thyroid cancer tumorigenesis. Collectively, our data unveil that miR-363–3 p negatively regulates NOB1 activity by reducing its stability. This study provides a new therapeutic target for regulation of NOB1 stability to modulate human papillary thyroid cancer progression.

Pteridium aquilinum (L.) Kuhn (Pteridaceae family) has been widely used as a food and medicine in China and Korea. Previous studies indicate that P. aquilinum contains a variety of bioactive chemical components such as flavonoids, phenols, terpenoids, saponins, polysaccharides, and so on. In the present study, a novel polysaccharide (named as PAP-3) with average molecular weight of 2.14 × 105 Da was obtained from P. aquilinum. The structure was studied through physicochemical and spectroscopic analysis. The results indicated that PAP-3 consists of arabinose, rhamnose, fucose, galactose, mannose, and xylose in a molar ratio of 1.58:1.00:3.26:4.57:4.81:3.33. The polysaccharide is mainly composed of (1→2)-linked xylose and (1→3,6)-linked mannose on the main chain, with (1→2)-linked xylose, (1→6)-linked mannose, and (1→6)- and (1→3,6)-linked galactose as side chains. Galactose, fucose, and xylose are located at the end of the side chains. The in vitro immunomodulatory and antioxidant activities were assayed. PAP-3 has strong free-radical scavenging activity on DPPH and ABTS radicals and significant immunomodulatory activity on RAW264.7 cells. These data provide useful information for further study on the polysaccharides of P. aquilinum and their applications in the food and medical industries.

SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection. By expressing individual SARS-CoV-2 proteins in the Drosophila heart we demonstrated interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1). Complementing transcriptomic data from the fly heart revealed that this interaction blocks the antagonistic MGA/MAX complex, which shifts the balance towards MYC/MAX and activates glycolysis—with similar findings in mouse cardiomyocytes. Further, the Nsp6-induced glycolysis disrupted cardiac mitochondrial function, known to increase reactive oxygen species (ROS) in heart failure; this could explain COVID-19-associated cardiac pathology. Furthermore, inhibiting the glycolysis pathway by 2-deoxy-D-glucose (2DG) treatment attenuated the Nsp6-induced cardiac phenotype in fly and mice; thus, suggesting glycolysis as a potential pharmacological target for treating COVID-19-associated heart failure.

Aim: To assess whether periodic fasting reduces albuminuria and activates nephropathy-driven pathways in patients with type 2 diabetes and diabetic nephropathy. Methods: Forty patients with type 2 diabetes (HbA1c 7.8±0.2% [62.1±2.3 mmol/mol]) and increased albumin-to-creatinine ratio (ACR) were randomized to fasting-mimicking diet (FMD) (n=21) or Mediterranean diet (n=19) for six months with three-month follow-up. Primary endpoint was the difference of the change in ACR from baseline to after six months between groups. Subgroup analysis for patients with micro- versus macroalbuminuria at baseline was performed. Secondary endpoints comprised HOMA-IR, circulating markers of dicarbonyl detoxification (MG-H1, glyoxalase-1 and hydroxyacetone) , lipid oxidation (acylcarnitines AC) , DNA-damage/repair, (yH2Ax) and senescence (suPAR) . Comparison was done by ANCOVA adjusted for age, sex, weight loss and baseline values of the respective outcome. Results: Difference of change in ACR between FMD and control group after six months was 110.3mg/g (95% CI 99.2, 121.5mg/g; P=0.45) in all patients, -30.3mg/g (95% CI -35.7, -24.9mg/g; P≤0.05] in patients with microalbuminuria, and 434.0mg/g (95% CI 404.7, 463.4mg/g; P=0.23) in those with macroalbuminuria at baseline. FMD led to change in HOMA-IR of -3,8 (95% CI -5,6, -2.0; P≤0.05) and in suPAR of -156.6pg/ml (95% CI -172.9, -140.4pg/ml; P≤0.05) after six months, while no change was observed in markers of dicarbonyl detoxification or DNA-damage/repair. Change in AC profile was related to patient responsiveness to ACR improvement. At follow-up only HOMA-IR reduction (-1.9 [95% CI -3.7, -0.1], P≤0.05) was sustained. Conclusions: When accompanied by intensive diabetes care, FMD improves microalbuminuria, HOMA-IR and suPAR. Lack of changes in markers of dicarbonyl detoxification and DNA-damage/repair might explain the relapse of albuminuria at follow-up. Disclosure A.Sulaj: None. Z.Han: None. V.Kumar: None. V.Longo: Stock/Shareholder; L-Nutra Inc. A.Teleman: None. J.G.Okun: None. J.Morgenstern: None. T.H.Fleming: None. J.M.Szendroedi: Consultant; Boehringer Ingelheim International GmbH. S.Herzig: None. S.Kopf: Board Member; Novo Nordisk, Speaker's Bureau; AstraZeneca, Recordati S.p.A. E.V.Rauchhaupt: None. E.Kliemank: None. M.Brune: None. Z.Kender: None. H.Bartl: None. F.Garcia-cortizo: None. K.Klepac: None. Funding German Research Foundation DFG (236360313 and 255156212) German Center for Diabetes Research DZD (82DZD07C2G)

In this work, we propose a slotted photonic crystal nanobeam cavity (PCNC) to trap and sort the 120 nm and 30 nm nanoparticles. The simulation shows that the maximum optical trapping force of the 120 nm particle is 38.7 pN/mW, and that of the 30 nm particle is 10.8 pN/mW. It is calculated that the trapping threshold power of the 120 nm particle is 35.3 µW, and that of the 30 nm particle is 41.6 µW. Because the width of the slot is 100 nm, when the input power is between 35.3 µW and 41.6 µW, only the 120 nm particle can be trapped in the upper cladding of the slotted-PCNC. When the input power is greater than 41.6 µW, the 120 nm particle is still trapped in the upper cladding of the slotted-PCNC, while the 30 nm particle is trapped inside the slot of the slotted-PCNC. By properly controlling the input power and the direction of flow in the microfluidic channel, the sorting of particles can be achieved. In addition, trapping of the particles causes different redshifts of peak wavelengths. Thus, the proposed slotted-PCNC can detect particle trapping and sorting by monitoring the resonant wavelength shifts. What is the most important, compared with previous reported single particle trapping work, is that the proposed work can realize both trapping and sorting. Therefore, provided with the ultra-compact footprint and excellent performance, the proposed slotted-PCNC shows great potential for a multifunctional lab-on-a-chip system.

In contrast to the homeokinesis of mitosis, asymmetric division of cytoplasm is the conspicuous feature of meiosis in mammalian oocytes. Protein regulator of cytokinesis 1 (PRC1) is an important regulator during mitotic spindle assembly and cytoplasmic division, but its functions in oocyte meiosis and early embryo development have not been fully elucidated. In this study, we detected PRC1 expression and localization and revealed a nuclear, spindle midzone-related dynamic pattern throughout meiotic and mitotic progressions. Treatment of oocytes with the reagents taxol or nocodazole disturbed the distribution of PRC1 in metaphase II oocytes. Further, PRC1 depletion led to failure of first polar body (PB1) extrusion and spindle migration, aneuploidy and defective kinetochore-microtubule attachment and spindle assembly. Overexpression of PRC1 resulted in PB1 extrusion failure, aneuploidy and serious defects of spindle assembly. To investigate PRC1 function in early embryos, we injected Prc1 morpholino into zygotes and 2-cell stage embryos. Depletion of PRC1 in zygotes impaired 4-cell, morula and blastocyst formation. Loss of PRC1 in single or double blastomeres in 2-cell stage embryos significantly impaired cell division, indicating its indispensable role in early embryo development. Co-immunoprecipitation showed that PRC1 interacts with polo-like kinase 1 (PLK1), and functional knockdown and rescue experiments demonstrated that PRC1 recruits PLK1 to the spindle midzone to regulate cytoplasmic division during meiosis. Finally, kinesin family member 4 knockdown downregulates PRC1 expression and leads to PRC1 localization failure. Taken together, our data suggest PRC1 plays an important role during oocyte maturation and early embryonic development by regulating chromosome dynamics and cytoplasmic division.

Density functional theory calculations were performed to understand the distinctly different reactivities of o-carboxylate-substituted aryl halides and pristine aryl halides toward the PdII-catalyzed γ-C(sp3)-H arylation of secondary alkylamines. It is found that, when 2-iodobenzoic acid (a representative of o-carboxylate-substituted aryl halides) is used as an aryl transfer agent, the arylation reaction is energetically favorable, while when the pristine aryl halide iodobenzene is used as the aryl transfer reagent, the reaction is kinetically difficult. Our calculations showed an operative PdII/PdIV/PdII redox cycle, which differs in the mechanistic details from the cycle proposed by the experimental authors. The improved mechanism emphasizes that (i) the intrinsic role of the o-carboxylate group is facilitating the C(sp3)-C(sp2) bond reductive elimination from PdIV rather than facilitating the oxidative addition of the aryl iodide on PdII, (ii) the decarboxylation occurs at the PdII species instead of the PdIV species, and (iii) the 1,2-arylpalladium migration proceeds via a stepwise mechanism where the reductive elimination occurs before decarboxylation, not via a concerted mechanism that merges the three processes decarboxylation, 1,2-arylpalladium migration, and C(sp3)-C(sp2) reductive elimination into one. The experimentally observed exclusive site selectivity of the reaction was also rationalized well.

Subsurface soil acidity in conjunction with aluminium (Al3+) toxicity is a major limitation to agricultural production globally. The conventional use of surface-applied lime is often insufficient at correcting subsurface acidity; therefore, new practices and ameliorants are required. This 3-month leaching experiment investigated whether animal wastes and other novel ameliorants in combination with lime could improve alkalinity movement, leading to greater amelioration of acid subsurface soil layers compared with lime alone. Five ameliorants (mature dairy compost, vegetable garden compost, poultry litter, potassium humate and gypsum) were added at a rate of 18 mg dry matter g−1 to the topsoil layer either without or with lime (target pH 5.5). All ameliorants with lime improved alkalinity movement below the amended layer (0–10 cm), with pH increases of 0.03–0.10 units at 1 month and 0.02–0.20 units at 3 months. In comparison, the Al3+ concentrations in 10–12-cm and 12–15-cm layers were significantly decreased by 2–5.5 μg g−1. With lime, the improvements in alkalinity movement with ameliorants were in the order of gypsum > vegetable garden compost > potassium humate > poultry litter > mature dairy compost. Without lime, each amendment increased soil pH in the subsoil, with their effectiveness decreasing in the order of poultry litter > vegetable garden compost > mature dairy compost > gypsum > potassium humate. Some organic amendments are effective in addressing subsoil acidity. When combined with lime, their additive effects are limited.

Current approaches in bridge valuation mostly focus on engineering construction costs while neglecting other values generated by the bridge's functionality and utilization, along with other indirect economic values of a bridge. Such limitations prevent public agencies from capturing the true asset value of their bridges to make informed management decisions. The objective of this paper is to develop a comprehensive bridge asset valuation methodology that is based on the utility theory concept to better represent the asset value of a bridge. Various factors featuring the bridge asset value are characterized and considered in the model including physical condition, safety, mobility, average annual daily traffic (AADT), direct time savings, and so on. These factors are categorized into economic value and utility-based value and quantified with specific performance measures. The applicability of the proposed methodology is demonstrated through a case study using five real-world bridges in Austin, Texas. The results show that the integrated, comprehensive model is able to effectively evaluate the overall asset value of a bridge. Finally, the paper discusses how public agencies can take advantage of the evaluation results to better understand bridge asset value and make more insightful decisions in bridge management practice.

The scattering center (SC) model provides a concise, explicit description of the object electromagnetic characteristics, significantly improves the efficiency of radar signal simulations, and plays an important role in model-based automatic target recognition. The existing models are mainly developed for conducting objects, and few are developed for dielectric ones. The SC models of dielectric objects are essentially different from those of their conducting counterparts due to the different scattering mechanisms. In this article, the backscattering mechanisms of canonical dielectric structures are studied, and their corresponding SC models are proposed. More importantly, the parametric SC models of the composite objects of canonical structures are first presented. These SC models are validated by comparing the radar cross section (RCS), the time–frequency representation (TFR), and the high-resolution range profile (HRRP) from the SC model with the results of the full-wave numerical method.

Drosophila has been extensively used to model the human blood-immune system, as both systems share many developmental and immune response mechanisms. However, while many human blood cell types have been identified, only three were found in flies: plasmatocytes, crystal cells and lamellocytes. To better understand the complexity of fly blood system, we used single-cell RNA sequencing technology to generate comprehensive gene expression profiles for Drosophila circulating blood cells. In addition to the known cell types, we identified two new Drosophila blood cell types: thanacytes and primocytes. Thanacytes, which express many stimulus response genes, are involved in distinct responses to different types of bacteria. Primocytes, which express cell fate commitment and signaling genes, appear to be involved in keeping stem cells in the circulating blood. Furthermore, our data revealed four novel plasmatocyte subtypes (Ppn+, CAH7+, Lsp+ and reservoir plasmatocytes), each with unique molecular identities and distinct predicted functions. We also identified cross-species markers from Drosophila hemocytes to human blood cells. Our analysis unveiled a more complex Drosophila blood system and broadened the scope of using Drosophila to model human blood system in development and disease.

Background Studies have linked mutations in genes encoding the eight-protein exocyst protein complex to kidney disease, but the underlying mechanism is unclear. Because Drosophila nephrocytes share molecular and structural features with mammalian podocytes, they provide an efficient model for studying this issue. Methods We silenced genes encoding exocyst complex proteins specifically in Drosophila nephrocytes and studied the effects on protein reabsorption by lacuna channels and filtration by the slit diaphragm. We performed nephrocyte functional assays, carried out super-resolution confocal microscopy of slit diaphragm proteins, and used transmission electron microscopy to analyze ultrastructural changes. We also examined the colocalization of slit diaphragm proteins with exocyst protein Sec15 and with endocytosis and recycling regulators Rab5, Rab7, and Rab11. Results Silencing exocyst genes in nephrocytes led to profound changes in structure and function. Abolition of cellular accumulation of hemolymph proteins with dramatically reduced lacuna channel membrane invaginations offered a strong indication of reabsorption defects. Moreover, the slit diaphragm's highly organized surface structure-essential for filtration-was disrupted, and key proteins were mislocalized. Ultrastructural analysis revealed that exocyst gene silencing led to the striking appearance of novel electron-dense structures that we named "exocyst rods," which likely represent accumulated membrane proteins following defective exocytosis or recycling. The slit diaphragm proteins partially colocalized with Sec15, Rab5, and Rab11. Conclusions Our findings suggest that the slit diaphragm of Drosophila nephrocytes requires balanced endocytosis and recycling to maintain its structural integrity and that impairment of the exocyst complex leads to disruption of the slit diaphragm and nephrocyte malfunction. This model may help identify therapeutic targets for treating kidney diseases featuring molecular defects in vesicle endocytosis, exocytosis, and recycling.

Minichromosome maintenance 10 (MCM10) plays an important role in DNA replication and is expressed in a variety of tumors, including glioma. However, its role and mechanism in glioma remain elusive. The purpose of this study was to examine the molecular function of MCM10 in glioblastoma cell lines in vitro and to further investigate the molecular mechanisms in the network mediated by MCM10. Cell proliferation, invasion, and migration were investigated in the absence of MCM10 mediated by RNA interference (RNAi) in U87 and U251 cell lines. Microarray data were obtained from U87 cells infected with a lentivirus expressing a small interfering RNA (siRNA) targeting MCM10, and ingenuity pathway analysis (IPA) was performed. Molecular signaling pathways, gene functions, and upstream and downstream regulatory genes and networks were analyzed. MCM10 was positively stained in human glioblastoma multiforme (GBM) samples according to immunohistochemistry. Silencing MCM10 in U87 and U251 cells significantly reduced cell proliferation, migration, and invasion. In U87 cells transfected with MCM10, 274 genes were significantly upregulated, while 313 genes were downregulated. IPA revealed that MCM10 is involved in the IGF-1 signaling pathway, and calcitriol appears to be a significant upstream regulator of MCM10. Other factors, such as TWIST1 and Stat3, also interact within the MCM10-mediated network. Our data indicate that MCM10 is involved in the regulation of GBM in vitro and may provide more evidence for understanding the molecular mechanisms of this fatal disease.

Hatching out from the zona pellucida (ZP) is a crucial step for blastocyst implantation and development. However, it is still unknown whether the location of the hatching site relative to the inner cell mass (ICM) affects embryo implantation and foetal development. Here, we classified hatching blastocysts into three categories, 0° ≤ θ ≤ 30°, 30°

Phosphodiesterase (PDE)-mediated reduction of cyclic adenosine monophosphate (cAMP) activity can initiate germinal vesicle (GV) breakdown in mammalian oocytes. It is crucial to maintain oocytes at the GV stage for a long period to analyze meiotic resumption in vitro. Meiotic resumption can be reversibly inhibited in isolated oocytes by cAMP modulator forskolin, cAMP analog dibutyryl cAMP (dbcAMP), or PDE inhibitors, milrinone (Mil), Cilostazol (CLZ), and 3-isobutyl-1-methylxanthine (IBMX). However, these chemicals negatively affect oocyte development and maturation when used independently. Here, we used ICR mice to develop a model that could maintain GV-stage arrest with minimal toxic effects on subsequent oocyte and embryonic development. We identified optimal concentrations of forskolin, dbcAMP, Mil, CLZ, IBMX, and their combinations for inhibiting oocyte meiotic resumption. Adverse effects were assessed according to subsequent development potential, including meiotic resumption after washout, first polar body extrusion, early apoptosis, double-strand DNA breaks, mitochondrial distribution, adenosine triphosphate levels, and embryonic development. Incubation with a combination of 50.0 μM dbcAMP and 10.0 μM IBMX efficiently inhibited meiotic resumption in GV-stage oocytes, with low toxicity on subsequent oocyte maturation and embryonic development. This work proposes a novel method with reduced toxicity to effectively arrest and maintain mouse oocytes at the GV stage.

Hyperuricemia (HUA) is a metabolic disease characterized by elevated serum uric acid (SUA). Empagliflozin, a kind of sodium-glucose cotransporter 2 inhibitors, has recently emerged as a new antidiabetic agent by facilitating glucose excretion in urine. Moreover, there was evidence of SUA reduction following treatment with empagliflozin in addition to glycaemic control, while the molecular mechanisms remain unknown. To investigate the potential mechanisms, the model of type 2 diabetes (T2DM) with HUA was established by combination of peritoneal injection of potassium oxonate and intragastric administration of hypoxanthine in KK-Ay mice. A series of method such as RT-PCR, western blot, immunochemistry, immunofluorescence were conducted to explore the mechanism. Our results showed that empagliflozin significantly ameliorated the levels of SUA and blood glucose in T2DM mice with HUA. Furthermore, in both kidney and ileum, empagliflozin obviously promoted protein expression of uric acid (UA) transporter ABCG2, p-AMPK, p-AKT and p-CREB. The same trend was observed in human tubular epithelial (HK-2) cells. Additionally, through application of an AMPK inhibitor (Compound C), it was further confirmed empagliflozin exerted its anti-hyperuricemic effects in an AMPK dependent manner. Meanwhile, with the help of ChIP assay and luciferase reporter gene assay, we found that CREB further activated ABCG2 via binding to the promoter of ABCG2 to induce transcription. Taken together, our study demonstrated that empagliflozin treatment played an essential role in attenuating HUA by upregulation of ABCG2 via AMPK/AKT/CREB signaling pathway.

DNA data storage is a rapidly developing technology with great potential due to its high density, long-term durability, and low maintenance cost. The major technical challenges include various errors, such as strand breaks, rearrangements, and indels that frequently arise during DNA synthesis, amplification, sequencing, and preservation. In this study, a de novo strand assembly algorithm (DBGPS) is developed using de Bruijn graph and greedy path search to meet these challenges. DBGPS shows substantial advantages in handling DNA breaks, rearrangements, and indels. The robustness of DBGPS is demonstrated by accelerated aging, multiple independent data retrievals, deep error-prone PCR, and large-scale simulations. Remarkably, 6.8 MB of data is accurately recovered from a severely corrupted sample that has been treated at 70 °C for 70 days. With DBGPS, we are able to achieve a logical density of 1.30 bits/cycle and a physical density of 295 PB/g.

Current evidence supporting antimicrobial stewardship programs focused largely in inpatient setting. With the shift in cancer management from inpatient to ambulatory setting, it is crucial to examine the prevalence and predictors of inappropriate antibiotics prescribing. This is a retrospective cross-sectional study conducted at the National Cancer Centre Singapore (NCCS). Patients at least 21 years, with an active or past cancer diagnosis and prescribed with at least one oral antibiotic by a NCCS physician from 1st July to 30th September 2019 were included. Antibiotic appropriateness was assessed using institutional antibiotic guidelines or published clinical practice guidelines. For cases where antibiotics appropriateness cannot be ascertained using these guidelines, an independent three-member expert panel was consulted. A total of 815 patients were screened; 411 (59.4% females) were included with mean age of 62.4 years. The top three cancer diagnoses were breast (26.5%), lung (15.6%) and head and neck (13.6%). More than half (58.6%) received appropriate antibiotic choice. Of which, 235 (97.5%), 238 (98.8%) and 194 (80.5%) received appropriate dose, frequency and duration respectively. The presence of non-oncologic immunosuppressive comorbidities (OR 4.890, 95% CI 1.556-15.369, p-value = 0.007), antibiotic allergy (OR 2.352, 95% CI 1.178-4.698, p-value = 0.015) and skin and soft tissue infections (OR 2.004, 95% CI 1.276-3.146, p-value = 0.003) were associated with a higher incidence of inappropriate antibiotic choice. This study highlighted that inappropriate antibiotic prescribing is prevalent in the ambulatory oncology setting. Predicators identified can aid in the design of targeted strategies to optimise antibiotic use in ambulatory oncology patients.