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Vaccination has successfully controlled several infectious diseases although better vaccines remain desirable. Host response to vaccination studies have identified correlates of vaccine immunogenicity that could be useful to guide development and selection of future vaccines. However, it remains unclear whether these findings represent mere statistical correlations or reflect functional associations with vaccine immunogenicity. Functional associations, rather than statistical correlates, would offer mechanistic insights into vaccine-induced adaptive immunity. Through a human experimental study to test the immunomodulatory properties of metformin, an anti-diabetic drug, we chanced upon a functional determinant of neutralizing antibodies. Although vaccine viremia is a known correlate of antibody response, we found that in healthy volunteers with no detectable or low yellow fever 17D viremia, metformin-treated volunteers elicited higher neutralizing antibody titers than placebo-treated volunteers. Transcriptional and metabolomic analyses collectively showed that a brief course of metformin, started 3 days prior to YF17D vaccination and stopped at 3 days after vaccination, expanded oxidative phosphorylation and protein translation capacities. These increased capacities directly correlated with YF17D neutralizing antibody titers, with reduced reactive oxygen species response compared to placebo-treated volunteers. Our findings thus demonstrate a functional association between cellular respiration and vaccine-induced humoral immunity and suggest potential approaches to enhancing vaccine immunogenicity. Synopsis: Host response studies have identified multiple correlates of vaccine immunogenicity, yet their functional role in shaping vaccine-induced adaptive responses remain undefined. We demonstrate that mitochondrial activity is functionally involved in live-attenuated yellow fever 17D (YF17D) vaccine immunogenicity. In healthy volunteers, a brief course of metformin given three-days-before to three-days-after live-attenuated YF17D vaccination enhances humoral immune responses in those with low or undetectable viremia. This brief course of metformin expanded oxidative phosphorylation and protein translation capacities without over-activation of antioxidant defenses. In a mouse model, cessation of metformin at Day 3 but not Day 10 post YF17D vaccination enhanced immunogenicity compared to untreated mice. Our findings suggest a way to enhance antibody response to vaccination in patients on long-term metformin treatment. Host response studies have identified multiple correlates of vaccine immunogenicity, yet their functional role in shaping vaccine-induced adaptive responses remain undefined. We demonstrate that mitochondrial activity is functionally involved in live-attenuated yellow fever 17D (YF17D) vaccine immunogenicity. [ABSTRACT FROM AUTHOR]

Background: The biomarkers of immune checkpoint inhibitors in the treatment of non‐small cell lung cancer (NSCLC) patients have limited predictive performance. In this study we aimed to investigate the feasibility of molecular tumor burden index (mTBI) in circulating tumor DNA (ctDNA) as a predictor for immunotherapy in patients with NSCLC. Methods: From February 2017 to November 2020, pretreatment and on‐treatment (3~6 weeks after first cycle of immunotherapy) dynamic plasma ctDNA samples from NSCLC patients receiving immune monotherapy or combination therapy were analyzed by targeted capture sequencing of 1021 genes. PyClone was used to infer the mTBI. The impact of pretreatment mTBI on survival outcomes was verified in the POPLAR/OAK trials. Results: We found that patients without detectable baseline ctDNA had better survival outcomes (median overall survival [OS]: not reached vs. 12.8 months; hazard ratio [HR], 0.15; p = 0.035]). RB1 and SMARCA4 mutations were remarkably associated with worse survival outcomes. Furthermore, lower pretreatment mTBI was associated with superior OS (median: not reached vs. 8.1 months; HR, 0.22; p = 0.024) and PFS (median: 32.9 vs. 5.4 months; HR, 0.35; p = 0.045), but not objective response, which was validated in the POPLAR/OAK cohort, suggesting that baseline mTBI was a prognostic factor for NSCLC immunotherapy. Early dynamic changes of mTBI (ΔmTBI) significantly distinguished responsive patients, and patients with mTBI decrease to more than 68% at the final tumor evaluation had longer OS (median: 38.2 vs. 4.0 months; HR, 0.18; p = 0.017) and PFS (median: not reached vs. 2.3 months; HR, 0.24; p = 0.030). Conclusion: ΔmTBI had a good sensitivity to identify potential beneficial patients based on the best effect CT scans, demonstrating that mTBI dynamics were predictive of benefit from immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

Visual interpretation is considered the gold standard for amyloid scans in clinical practice. However, dichotomous classification of amyloid deposition by visual reading always results in bias due to rater experience. Therefore, there is a need for a more lenient and flexible amyloid‐equivocal classification in clinical practice. A total of 461 participants were included in this study. Amyloid and glucose positron‐emission tomography was performed, and neuropsychological tests were evaluated. A disease‐specific deep‐learning method was used to identify amyloid equivocality. Amyloid deposition, glucose metabolism, and cognitive performance were analyzed and compared among amyloid‐positive, amyloid‐negative, and amyloid‐equivocal groups. Clinically diagnosed Alzheimer's disease individuals and subjects with normal cognition were used to create amyloid biomarker cut points to support the definition of equivocal amyloid deposition. A total of 139 amyloid‐equivocal individuals were identified by deep learning methods. They displayed intermediate amyloid deposition between that of amyloid‐positive (standardized uptake value ratio [SUVr]: 1.25 ± 0.10 vs. 1.47 ± 0.20, p < 0.001) and amyloid‐negative (SUVr: 1.25 ± 0.10 vs. 1.18 ± 0.07, p < 0.001) individuals. No difference in glucose metabolism or cognitive performance was observed between amyloid negativity and equivocality. Furthermore, the SUVr for the whole cortex, the precuneus, and the frontal lobe served as auxiliary criteria supporting the diagnosis of equivocal amyloid deposition. We also established a guide to assist in the interpretation of amyloid equivocality by visual reading with auxiliary criteria including two cut points and deep learning methods. [ABSTRACT FROM AUTHOR]

Longitudinal changes in the white matter/functional brain networks of semantic dementia (SD), as well as their relations with cognition remain unclear. Using a graph‐theoretic method, we examined the neuroimaging (T1, diffusion tensor imaging, functional MRI) network properties and cognitive performance in processing semantic knowledge of general and six modalities (i.e., object form, color, motion, sound, manipulation and function) from 31 patients (at two time points with an interval of 2 years) and 20 controls (only at baseline). Partial correlation analyses were carried out to explore the relationships between the network changes and the declines of semantic performance. SD exhibited aberrant general and modality‐specific semantic impairment, and gradually worsened over time. Overall, the brain networks showed a decreased global and local efficiency in the functional network organization but a preserved structural network organization with a 2‐year follow‐up. With disease progression, both structural and functional alterations were found to be extended to the temporal and frontal lobes. The regional topological alteration in the left inferior temporal gyrus (ITG.L) was significantly correlated with general semantic processing. Meanwhile, the right superior temporal gyrus and right supplementary motor area were identified to be associated with color and motor‐related semantic attributes. SD manifested disrupted structural and functional network pattern longitudinally. We proposed a hub region (i.e., ITG.L) of semantic network and distributed modality‐specific semantic‐related regions. These findings support the hub‐and‐spoke semantic theory and provide targets for future therapy. [ABSTRACT FROM AUTHOR]

The synthesis of layered nanorod arrays with a core‐shell structure is considered to be a viable strategy to improve the electrochemical property of electrode materials. Herein, we have successfully designed and fabricated layered MoO3‐MnNi LDH@Cu(OH)2/CF(MO‐MN LDH@COH) core‐shell nanorods through a handy in‐situ oxidation reaction followed by a hydrothermal synthesis, which consist of ordered Cu(OH)2 nanorods and ultra‐thin MoO3‐MnNi LDHs nanosheets. The MO‐MN LDH@COH which is utilized as the cathode in three electrodes exhibits superior electrochemical property. The specific capacity of prepared electrode is 16913 mF cm−2 under a current density of 2 mA cm−2, which is superior to its counterparts of COH, MN LDH@COH‐0, MO‐MN LDH@COH‐0.5 and MO‐MN LDH@COH‐2. What's more, the cycling stability reaches 83.33 % capacitance retention after 5000 cycles under the current density of 30 mA cm−2. When a solid‐state asymmetric supercapacitor (ASC) device (MO‐MN LDH@COH//AC) is fabricated, it could keep a household LED screen running for 27 minutes, verifying the immense commercial potential. Overall, this unique MO‐MN LDH@COH nanocomposite with excellent electrochemical performance should envision great practical application potential. [ABSTRACT FROM AUTHOR]

The inclusion of fiber in cemented paste backfill (CPB) can significantly alter the mechanical response of the CPB body. The intrinsic defects in CPB and the potential dynamic loading condition make it necessary to investigate the fracture properties of fiber‐reinforced CPB (FR‐CPB). The mode‐I fracture behavior and properties are crucial to the successful engineering application of FR‐CPB technology used in underground mines. The contribution of fiber length and content to the evolutive mode‐I fracture behavior and properties of FR‐CPB was examined in this study. The results show that the addition of fiber reduces the prepeak stiffness but improves the mode I fracture toughness (KIc), and the improvement in KIc increases with fiber length. In contrast, the initial increase in fiber content (from 0% to 0.5%) benefits the KIc acquisition, while a further increase in fiber content from 0.5% to 0.75% poses a negative influence on the KIc development. Moreover, with the adoption of the cement hydration model, four predictive functions are proposed to describe the contribution of fiber length and content to the development of fracture properties. In addition, KIc is identified as a more reliable fracture property for assessing the immediate ground support role played by the FR‐CPB structure. The findings are helpful when it comes to the determination of the fiber length and content in FR‐CPB design. [ABSTRACT FROM AUTHOR]

In total patients, low bTMB (bTMB-L, optimal cutoff = 4) showed significantly longer OS ( I p i = .019) compared with high bTMB (bTMB-H) (Figure 1A and B), and bTMB was significantly associated with disease control rate (DCR) (Figure 1C and D), but not objective response rate (ORR) (Supplementary Figure S4A). Patients with bMSAF-H and bTMB-H (n = 11) are indicated in red, patients with bMSAF-L and bTMB-H (n = 21) are indicated in blue, and those with bMSAF-L and bTMB-L (n = 10) are indicated in green. BMSAF is a prognostic predictor for advanced hepatocellular carcinoma patients treated with immune checkpoint inhibitor camrelizumab and anti-angiogenic agent apatinib combination therapy. [Extracted from the article]

Background: For detecting mild cognitive impairment (MCI), brief cognitive screening tools are increasingly required for the advantage of time saving and no need for special equipment or trained raters. We aimed to develop a modified Chinese version of Mini‐Addenbrooke's Cognitive Examination (C‐MACE) and further evaluate its validation in detecting MCI. Methods: A total of 716 individuals aged from 50 to 90 years old were recruited, including 431 cognitively normal controls (NC) and 285 individuals with MCI. The effect size of Cramer's V was used to explore which items in the Chinese version of Addenbrooke's Cognitive Examination‐III (ACE‐III‐CV) best associated with MCI and to form the C‐MACE. Receiver operating characteristic (ROC) analyses were carried out to explore the ability of C‐MACE, ACE‐III‐CV, Chinese version of Montreal Cognitive Assessment‐Basic (MoCA‐BC), and Mini‐Mental State Examination (MMSE) in discriminating MCI from NC. Results: Five items with greatest effect sizes of Cramer's V were selected from ACE‐III‐CV to form the C‐MACE: Memory Immediate Recall, Memory Delayed Recall, Memory Recognition, Verbal Fluency Animal and Language Naming. With a total score of 38, the C‐MACE had a satisfactory classification accuracy in detecting MCI (area under the ROC curve, AUC = 0.892), superior to MMSE (AUC = 0.782) and comparable to ACE‐III‐CV (AUC = 0.901) and MoCA‐BC (AUC = 0.916). In the subgroup of Age > 70 years, Education ≤ 12 years, the C‐MACE got a highest classification accuracy (AUC = 0.958) for detecting MCI. Conclusion: In the Chinese‐speaking population, C‐MACE derived from ACE‐III‐CV may identify MCI with a good classification accuracy, especially in aged people with low education. [ABSTRACT FROM AUTHOR]

Background: Suction cups are widely used in applications such as in measurement of mechanical properties of skin in vivo, in drug delivery devices or in acupuncture treatment. Understanding mechanical response of skin under hypobaric pressure is of great importance for users of suction cups. The aim of this work is to predict the hypobaric pressure induced 3D stretching of the skin. Methods: Experimental skin tensile tests were carried out for mechanical property characterization. Both linear elasticity and hyperelasticity parameters were determined and implemented in Finite Element modelling. Skin suction tests were performed in both experiments and FEM simulations for model validation. 3D skin stretching is then visualized in detail in FEM simulations. Results: The simulations showed that the skin was compressed consistently along the thickness direction, leading to reduced thickness. At the center of the dome, the radial and angular strain decreases from the top surface to the bottom surface, although always in tension. Hyperelasticity modelling showed superiority over linear elasticity modelling while predicting the strain distribution because the stretch ratio reaches values exceeding the initial linear elastic stage of the stress‐strain curve for skin. Conclusion: Hyperelasticity modelling is an effective approach to predict the 3D strain distribution, which paves a way to accurately design safe commercial products that interface with the skin. [ABSTRACT FROM AUTHOR]

Aims: Mild cognitive impairment due to semantic dementia represents the preclinical stage, involving cognitive decline dominated by semantic impairment below the semantic dementia standard. Therefore, studying mild cognitive impairment due to semantic dementia may identify changes in patients before progression to dementia. However, whether changes in local functional activity occur in preclinical stages of semantic dementia remains unknown. Here, we explored local functional changes in patients with mild cognitive impairment due to semantic dementia using resting‐state functional MRI. Methods: We administered a battery of neuropsychological tests to twenty‐two patients with mild cognitive impairment due to semantic dementia (MCI‐SD group) and nineteen healthy controls (HC group). We performed structural MRI to compare gray matter volumes, and resting‐state functional MRI with multiple sub‐bands and indicators to evaluate functional activity. Results: Neuropsychological tests revealed a significant decline in semantic performance in the MCI‐SD group, but no decline in other cognitive domains. Resting‐state functional MRI revealed local functional changes in multiple brain regions in the MCI‐SD group, distributed in different sub‐bands and indicators. In the normal band, local functional changes were only in the gray matter atrophic area. In the other sub‐bands, more regions with local functional changes outside atrophic areas were found across various indicators. Among these, the degree centrality of the left precuneus in the MCI‐SD group was positively correlated with general semantic tasks (oral sound naming, word‐picture verification). Conclusion: Our study revealed local functional changes in mild cognitive impairment due to semantic dementia, some of which were located outside the atrophic gray matter. Driven by functional connectivity changes, the left precuneus might play a role in preclinical semantic dementia. The study proved the value of frequency‐dependent sub‐bands, especially the slow‐2 and slow‐3 sub‐bands. [ABSTRACT FROM AUTHOR]

In the title compound, C13H10O3, the pyran-one and benzene rings are almost coplanar, making a dihedral angle of 1.9 (1)°. The cyclo-hexenone ring adopts an envelope conformation, with a methyl-ene C atom located at the flap and displaced by 0.639 (3) Å from the mean plane of the other five atoms. In the crystal, pairs of weak C-H⋯π inter-actions occur between inversion-related mol-ecules.

In the crystal structure of the title compound, C(8)H(6)N(2)O(3), the mol-ecules are linked by a pairs of inter-molecular N-H⋯O hydrogen bonds, forming inversion dimers. The aldehyde group is in the same plane as the pyrimidine ring [with a maximum deviation of 0.083 (2) Å for the O atom), and the linear propargyl group [C-C-C = 178.99 (19)°] makes a dihedral angle of 74.36 (13)° with the ring.