An ultra-sensitive biosensor based on surface plasmon resonance and weak value amplification.

An ultra-sensitive phase plasmonic sensor combined with weak value amplification is proposed for the detection of IgG, as a model analyte. Phase detection is accomplished by self-interference between the p-polarization and the s-polarization of the light. With the principles of weak value amplification, a phase compensator is used to modulate the coupling strength and enhance the refractive index sensitivity of the system. On a simple Au-coated prism-coupled surface plasmon resonance (SPR) structure, the scheme, called WMSPR, achieves a refractive index sensitivity of 4.737 × 104 nm/RIU, which is about three times higher than that of the conventional phase-based approach. The proposed WMSPR biosensor gives great characteristics with a high resolution of 6.333 × 10-8 RIU and a low limit of detection (LOD) of 5.3 ng/mL. The results yield a great scope to promote the optimization of other SPR biosensors for high sensitivity.

Targeting and cytotoxicity of chimeric antigen receptor T cells grafted with PD1 extramembrane domain.

BACKGROUND: Immunosuppression induced by programmed cell death protein 1 (PD1) presents a significant constraint on the effectiveness of chimeric antigen receptor (CAR)-T therapy. The potential of combining PD1/PDL1 (Programmed cell death 1 ligand 1) axis blockade with CAR-T cell therapy is promising. However, developing a highly efficient and minimally toxic approach requires further exploration. Our attempt to devise a novel CAR structure capable of recognizing both tumor antigens and PDL1 encountered challenges since direct targeting of PDL1 resulted in systemic adverse effects. METHODS: In this research, we innovatively engineered novel CARs by grafting the PD1 domain into a conventional second-generation (2G) CAR specifically targeting CD19. These CARs exist in two distinct forms: one with PD1 extramembrane domain (EMD) directly linked to a transmembrane domain (TMD), referred to as PE CAR, and the other with PD1 EMD connected to a TMD via a CD8 hinge domain (HD), known as PE8HT CAR. To evaluate their efficacy, we conducted comprehensive assessments of their cytotoxicity, cytokine release, and potential off-target effects both in vitro and in vivo using tumor models that overexpress CD19/PDL1. RESULTS: The findings of our study indicate that PE CAR demonstrates enhanced cytotoxicity and reduced cytokine release specifically towards CD19 + PDL1 + tumor cells, without off-target effects to CD19-PDL1 + tumor cells, in contrast to 2G CAR-T cells. Additionally, PE CAR showed ameliorative differentiation, exhaustion, and apoptosis phenotypes as assessed by flow cytometry, RNA-sequencing, and metabolic parameter analysis, after encountering CD19 + PDL1 + tumor cells. CONCLUSION: Our results revealed that CAR grafted with PD1 exhibits enhanced antitumor activity with lower cytokine release and no PD1-related off-target toxicity in tumor models that overexpress CD19 and PDL1. These findings suggest that our CAR design holds the potential for effectively addressing the PD1 signal.

Analysis of Microbial Diversity and Metabolites in Sauerkraut Products with and without Microorganism Addition.

The microbial compositions and metabolites of fermented sauerkraut with and without the addition of microorganisms have been compared. The OTU clustering, nonvolatile compounds, volatile compounds and associations between bacterial taxa and metabolites were analyzed by 16S rRNA high-throughput sequencing technology, ultra performance liquid chromatography (UPLC), gas chromatography ion mobility mass spectrometry (GC-IMS) and the O2PLS model studies. The results showed that at the phylum level, the microbial species in the four sauerkraut types consisted mainly of the phyla Firmicutes and Proteobacteria, but different modes of microbial addition formed their own unique microbial communities. There were significant differences in the microbial communities among different northeast China sauerkraut samples, and different microbial communities exerted similar effects to inhibit Firmicutes production. At the genus level, sauerkraut without added microorganisms had the lowest microbial diversity. A total of 26 amino acids and 11 organic acids were identified and were more abundant in nonmicrobially fermented sauerkraut; 88 volatile organic compounds were identified in the 4 types of sauerkraut, with the microbially fermented sauerkraut being richer in alcohols, esters and acids. Different brands of sauerkraut contain their own unique flavor compounds. Cystine and tyrosine, ascorbic acid and acetic acid, and alcohols and esters are closely related to a wide range of microorganisms in sauerkraut. Elucidating the correlations among microbiota and metabolites will help guide future improvements in sauerkraut fermentation processes.

Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release.

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in B cell malignancies. However, high tumor burden limits clinical efficacy and increases the risk of cytokine release syndrome and neurotoxicity, which is associated with over-activation of the CAR-T cells. The hinge domain plays an important role in the function of CAR-T cells. We hypothesized that deletion of glycine, an amino acid with good flexibility, may reduce the flexibility of the hinge region, thereby mitigating CAR-T cell over-activation. This study involved generating a novel CAR by deletion of two consecutive glycine residues in the CD8 hinge domain of second-generation (2nd) CAR, thereafter named 2nd-GG CAR. The 2nd-GG CAR-T cells showed similar efficacy of CAR expression but lower hinge flexibility, and its protein affinity to CD19 protein was lower than that of 2nd CAR-T cells. Compared to the 2nd CAR-T cells, 2nd-GG CAR-T cells reduced proinflammatory cytokine secretion without diminishing the specific cytotoxicity toward tumor cells in vitro. Furthermore, 2nd-GG CAR-T cells prolonged overall survival in an immunodeficient mouse model bearing NALM-6 when tumor burden was high. This study demonstrated that a lower-flexibility of CD8α hinge improved survival under high tumor burden and reduced proinflammatory cytokines in preclinical studies. While there is potential for improved safety and efficacy, yet this needs validation with clinical trials.

What Affects Older Adults' Viewing Behaviors in Neighborhood Open Space: A Study in Hong Kong.

Research on older adults' behaviors, living environments, and their quality of life (QoL) has grown rapidly. Viewing behaviors, although broadly acknowledged as critical for older adults' QoL, have not been systematically examined in situ. What affects the viewing behaviors of older adults in neighborhood open space (NOS) is still unclear. This study conducted unobtrusive continuous observations in NOS of two residential estates in Hong Kong. With spatio-temporal analyses with ArcGIS Pro and statistical analyses with SPSS, principal influential factors to viewing behaviors of older adults in NOS were identified, including distances for viewing, landscape attractiveness, body supporting elements, as well as moving and interactive behaviors. How these factors would affect older adults' well-being and QoL is discussed from the perspectives of supportive landscape design, sense of control, prospect and refuge, and social support, etc. Corresponding design implications are proposed to enrich existing NOS design knowledge for older adults' quality of life.

Vitamin D deficiency relation to sepsis, paediatric risk of mortality III score, need for ventilation support, length of hospital stay, and duration of mechanical ventilation in critically ill children: A meta-analysis.

INTRODUCTION: Vitamin D deficiency in children is related to the augmented risk of bone illnesses, but its effect on critically ill children is still conflicting. This meta-analysis study was performed to assess the relationship between vitamin D deficiency in children and sepsis, paediatric risk of mortality III score, need for ventilation support, length of hospital stay, and duration of mechanical ventilation in critically ill children. METHODS: Through a systematic literature search up to June 2020, 16 studies with 2382 children, 1229 children of them with vitamin D deficiency, were found recording relationships between vitamin D deficiency and sepsis, paediatric risk of mortality III score, need for ventilation support, length of hospital stay, and/or duration of mechanical ventilation. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated between vitamin D deficiency children to non-vitamin D deficiency children on the different outcomes in critically ill children using the dichotomous or continuous methods with a random or fixed-effect model. RESULTS: The vitamin D deficiency children category had significantly higher sepsis (OR, 2.35; 95% CI, 1.19-4.63, P = .01); paediatric risk of mortality III score (OR, 2.19; 95% CI, 1.13-4.25, P = .02); higher length of hospital stay (OR, 4.26; 95% CI, 0.81-7.70, P = .02); higher duration of mechanical ventilation (OR, 1.89; 95% CI, 0.22-3.56, P = .03) compared with that in the non-vitamin D deficiency children. However, the need for ventilation support in vitamin D deficiency children did not significantly differ from non-vitamin D deficiency children (OR, 2.00; 95% CI, 0.98-4.07, P = .06) with relatively higher results in vitamin D deficiency children. CONCLUSIONS: Vitamin D deficiency in children might have an independent relationship with higher sepsis, paediatric risk of mortality III score, length of hospital stay, and duration of mechanical ventilation. The relation was relative with a higher risk in need for ventilation support with vitamin D deficiency children. This relationship encouraged us to recommend testing vitamin D levels in all critically ill children and providing them with supplemental vitamin D as prophylaxis.

miRNA-10a-5p Alleviates Insulin Resistance and Maintains Diurnal Patterns of Triglycerides and Gut Microbiota in High-Fat Diet-Fed Mice.

miRNA-10a is rhythmically expressed and regulates genes involved in lipid and glucose metabolism. However, the effects of miRNA-10a on obesity and glucose intolerance, as well as on the diurnal pattern of expression of circadian clock genes, remain unknown. We explored the effects of miRNA-10a-5p on insulin resistance and on the diurnal patterns of serum triglycerides and gut microbiota in high-fat diet- (HFD-) fed mice. The results showed that oral administration of miRNA-10a-5p significantly prevented body weight gain and improved glucose tolerance and insulin sensitivity in HFD-fed mice. Administration of miRNA-10a-5p also maintained the diurnal rhythm of Clock, Per2, and Cry1 expression, as well as serum glucose and triglyceride levels. Surprisingly, the diurnal oscillations of three genera of microbes, Oscillospira, Ruminococcus, and Lachnospiraceae, disrupted by HFD feeding, maintained by administration of miRNA-10a-5p. Moreover, a strong positive correlation was found between hepatic Clock expression and relative abundance of Lachnospiraceae, both in control mice (r = 0.877) and in mice administered miRNA-10a-5p (r = 0.853). Furthermore, we found that along with changes in Lachnospiraceae abundance, butyrate content in the feces maintained a diurnal rhythm after miRNA-10a-5p administration in HFD-fed mice. In conclusion, we suggest that miRNA-10a-5p may improve HFD-induced glucose intolerance and insulin resistance through the modulation of the diurnal rhythm of Lachnospiraceae and its metabolite butyrate. Therefore, miRNA-10a-5p may have preventative properties in subjects with metabolic disorders.

A Generalized Chirp-Scaling Algorithm for Geosynchronous Orbit SAR Staring Observations.

Geosynchronous Orbit Synthetic Aperture Radar (GEO SAR) has recently received increasing attention due to its ability of performing staring observations of ground targets. However, GEO SAR staring observation has an ultra-long integration time that conventional frequency domain algorithms cannot handle because of the inaccurately assumed slant range model and existing azimuth aliasing. To overcome this problem, this paper proposes an improved chirp-scaling algorithm that uses a fifth-order slant range model where considering the impact of the "stop and go" assumption to overcome the inaccuracy of the conventional slant model and a two-step processing method to remove azimuth aliasing. Furthermore, the expression of two-dimensional spectrum is deduced based on a series of reversion methods, leading to an improved chirp-scaling algorithm including a high-order-phase coupling function compensation, range and azimuth compression. The important innovations of this algorithm are implementation of a fifth-order order slant range model and removal of azimuth aliasing for GEO SAR staring observations. A simulation of an L-band GEO SAR with 1800 s integration time is used to demonstrate the validity and accuracy of this algorithm.

Projective multiview structure and motion from element-wise factorization.

The Sturm-Triggs type iteration is a classic approach for solving the projective structure-from-motion (SfM) factorization problem, which iteratively solves the projective depths, scene structure, and camera motions in an alternated fashion. Like many other iterative algorithms, the Sturm-Triggs iteration suffers from common drawbacks, such as requiring a good initialization, the iteration may not converge or may only converge to a local minimum, and so on. In this paper, we formulate the projective SfM problem as a novel and original element-wise factorization (i.e., Hadamard factorization) problem, as opposed to the conventional matrix factorization. Thanks to this formulation, we are able to solve the projective depths, structure, and camera motions simultaneously by convex optimization. To address the scalability issue, we adopt a continuation-based algorithm. Our method is a global method, in the sense that it is guaranteed to obtain a globally optimal solution up to relaxation gap. Another advantage is that our method can handle challenging real-world situations such as missing data and outliers quite easily, and all in a natural and unified manner. Extensive experiments on both synthetic and real images show comparable results compared with the state-of-the-art methods.