bluuebunny/crossref_metadata_2025 huggingface dataset:
The manufacturing of 3D-printed microfluidic chips to analyse the effect upon particle size during the synthesis of lipid nanoparticles
Authors: Weaver Edward , Mathew Essyrose , Caldwell Jay , Hooker Andrew , Uddin Shahid , Lamprou Dimitrios A
Published: December 2022

Objectives

The process of 3D printing to produce microfluidic chips is becoming commonplace, due to its quality, versatility and newfound availability. In this study, a UV liquid crystal display (LCD) printer has been implemented to produce a progression of microfluidic chips for the purpose of liposomal synthesis. The emphasis of this research is to test the limitations of UV LCD printing in terms of resolution and print speed optimisation for the production of microfluidic chips.

Key findings

By varying individual channel parameters such as channel length and internal geometries, the essential channel properties for optimal liposomal formulation are being investigated to act as a basis for future experimentation including the encapsulation of active pharmaceutical ingredients. Using the uniquely designed chips, liposomes of ≈120 nm, with polydispersity index values of ≤0.12 are able to be reproducibly synthesised.

Conclusions

The influence of total flow rates and lipid choice is investigated in depth, to provide further clarification on how a microfluidic setup should be optimised. In-depth explanations of the importance of each channel parameter are also explained throughout, with reference to their importance for the properties of a successful liposome.
Evaluation of OrthoChromic OC-1 films for photon radiotherapy application
Authors: Lim Seng Boh , Tang Grace
Published: December 2022

A new film dosimetry system consists of the new OrthoChromic™ OC-1 film, and a novel calibration procedure was evaluated. Two films, C1 and C2, were exposed simultaneously using the 6FFF beam with a step-wedge pattern of five steps ranging from 590 to 3000 cGy. C1 was used for calibration, and C2 was used for calibration curve validation. The second scan of C2 was done by rotating the film by 90-deg. To evaluate the effectiveness of the non-uniform scanner response correction with the new system, a film was exposed to a 20 × 20 cm2 field. The beam profile measured with the film was compared to the IBA cc04 measurements in water. Films were irradiated to characterize the energy response, dynamic range and temporal growth effect. Open (MLC-defined) and clinical fields were radiated to evaluate the overall performance of the new system. The new calibration procedure was validated with an average dose difference of 1.6% and a gamma (2%,2 mm) passing rate of 100%. With C2 scanned 90-deg rotated, the average dose difference was 1.3%. The average difference between cc04 and film was 0.4%. The St between films and diode/cc04 were within −0.3% difference for 1 × 1 to 14 × 14 cm2 and −2.8% for 0.5 × 0.5 cm2. For clinical fields, the average gamma (3%,2 mm) was 98.8%. These results were consistent with EBT3 film and MapCheck measurements with a dose > 400 cGy. The results have shown that the OC-1 film system can achieve accurate results for QA measurements, but more considerable uncertainty was observed within the low dose range.
A three-step process of manganese acquisition and storage in the microalgaChlorella sorokiniana
Authors: Vojvodić Snežana , Dimitrijević Milena , Žižić Milan , Dučić Tanja , Aquilanti Giuliana , Stanić Marina , Zechmann Bernd , Danilović Luković Jelena , Stanković Dalibor , Opačić Miloš , Morina Arian , Pittman Jon K , Spasojević Ivan
Published: December 2022

Metabolism of metals in microalgae and adaptation to metal excess are of significant environmental importance. We report a three-step mechanism that the green microalga Chlorella sorokiniana activates during the acquisition of and adaptation to manganese (Mn), which is both an essential trace metal and a pollutant of waters. In the early stage, Mn2+ was mainly bound to membrane phospholipids and phosphates in released mucilage. The outer cell wall was reorganized and lipids were accumulated, with a relative increase in lipid saturation. Intracellular redox settings were rapidly altered in the presence of Mn excess, with increased production of reactive oxygen species that resulted in lipid peroxidation and a decrease in the concentration of thiols. In the later stage, Mn2+ was chelated by polyphosphates and accumulated in the cells. The structure of the inner cell wall was modified and the redox milieu established a new balance. Polyphosphates serve as a transient Mn2+ storage ligand, as proposed previously. In the final stage, Mn was stored in multivalent Mn clusters that resemble the structure of the tetramanganese–calcium core of the oxygen-evolving complex. The present findings elucidate the bioinorganic chemistry and metabolism of Mn in microalgae, and may shed new light on water-splitting Mn clusters.
Structural basis of transcription regulation by CNC family transcription factor, Nrf2
Authors: Sengoku Toru , Shiina Masaaki , Suzuki Kae , Hamada Keisuke , Sato Ko , Uchiyama Akiko , Kobayashi Shunsuke , Oguni Asako , Itaya Hayato , Kasahara Kota , Moriwaki Hirotomo , Watanabe Chiduru , Honma Teruki , Okada Chikako , Baba Shiho , Ohta Tsutomu , Motohashi Hozumi , Yamamoto Masayuki , Ogata Kazuhiro
Published: December 2022

Several basic leucine zipper (bZIP) transcription factors have accessory motifs in their DNA-binding domains, such as the CNC motif of CNC family or the EHR motif of small Maf (sMaf) proteins. CNC family proteins heterodimerize with sMaf proteins to recognize CNC–sMaf binding DNA elements (CsMBEs) in competition with sMaf homodimers, but the functional role of the CNC motif remains elusive. In this study, we report the crystal structures of Nrf2/NFE2L2, a CNC family protein regulating anti-stress transcriptional responses, in a complex with MafG and CsMBE. The CNC motif restricts the conformations of crucial Arg residues in the basic region, which form extensive contact with the DNA backbone phosphates. Accordingly, the Nrf2–MafG heterodimer has approximately a 200-fold stronger affinity for CsMBE than canonical bZIP proteins, such as AP-1 proteins. The high DNA affinity of the CNC–sMaf heterodimer may allow it to compete with the sMaf homodimer on target genes without being perturbed by other low-affinity bZIP proteins with similar sequence specificity.
Wheat EARLY FLOWERING 3 affects heading date without disrupting circadian oscillations
Authors: Wittern Lukas , Steed Gareth , Taylor Laura J , Ramirez Dora Cano , Pingarron-Cardenas Gabriela , Gardner Keith , Greenland Andy , Hannah Matthew A , Webb Alex A R
Published: December 2022

Plant breeders have indirectly selected for variation at circadian-associated loci in many of the world's major crops, when breeding to increase yield and improve crop performance. Using an eight-parent Multiparent Advanced Generation Inter-Cross (MAGIC) population, we investigated how variation in circadian clock-associated genes contributes to the regulation of heading date in UK and European winter wheat (Triticum aestivum) varieties. We identified homoeologues of EARLY FLOWERING 3 (ELF3) as candidates for the Earliness per se (Eps) D1 and B1 loci under field conditions. We then confirmed a single-nucleotide polymorphism within the coding region of TaELF3-B1 as a candidate polymorphism underlying the Eps-B1 locus. We found that a reported deletion at the Eps-D1 locus encompassing TaELF3-D1 is, instead, an allele that lies within an introgression region containing an inversion relative to the Chinese Spring D genome. Using Triticum turgidum cv. Kronos carrying loss-of-function alleles of TtELF3, we showed that ELF3 regulates heading, with loss of a single ELF3 homoeologue sufficient to alter heading date. These studies demonstrated that ELF3 forms part of the circadian oscillator; however, the loss of all homoeologues was required to affect circadian rhythms. Similarly, loss of functional LUX ARRHYTHMO (LUX) in T. aestivum, an orthologue of a protein partner of Arabidopsis (Arabidopsis thaliana) ELF3, severely disrupted circadian rhythms. ELF3 and LUX transcripts are not co-expressed at dusk, suggesting that the structure of the wheat circadian oscillator might differ from that of Arabidopsis. Our demonstration that alterations to ELF3 homoeologues can affect heading date separately from effects on the circadian oscillator suggests a role for ELF3 in cereal photoperiodic responses that could be selected for without pleiotropic deleterious alterations to circadian rhythms.
Predictors of weight loss during the intensive phase of tuberculosis treatment in patients with drug-susceptible pulmonary tuberculosis in South India
Authors: Kalva Jayashree , Babu Senbagavalli P , Narasimhan Prakash B , Raghupathy Kalaivani , Ezhumalai Komala , Knudsen Selby , Horsburgh Charles R , Hochberg Natasha , Salgame Padmini , Roy Gautam , Ellner Jerrold , Sarkar Sonali
Published: December 2022

Background

Tuberculosis (TB) is well-known for causing wasting. Patients on treatment gain weight and weight loss is associated with unfavorable treatment outcomes. There is limited description of weight loss and its predictors during intensive treatment phase. The objective of this study was to assess the predictors of weight loss during intensive phase and to see if there is any association exists with sputum conversion at the end of intensive phase of treatment.

Methods

Data collected as a part of the prospective TB cohort (Regional Prospective Observational Research for TB India Phase 1) conducted in Pondicherry, Cuddalore and Viluppuram districts of Tamil Nadu were used for this study. Sputum smear and body weight comparison were made in the baseline and at the end of second month of treatment.

Results

In all, 726 participants had weight measurements at the two time points and 18.7% had weight loss; mean weight lost being 2.3 kg (SD 3.05). Mean weight loss was more among males (2.4 kg, SD 3.2), diabetics (2.8 kg, SD 3.9) and alcoholics (2.1 kg, SD 2.4). Alcohol consumption was the only predictor of weight loss after adjusting for age, diabetes, marital status and BMI (aRR 1.52, P 0.02). Weight loss was not associated with sputum conversion at the end of second month.

Conclusions

Alcohol use emerged as the major predictor for weight loss during intensive phase.
Finding the common ground: toward an inclusive approach to humanitarian crisis
Authors: Corpuz Jeff Clyde G
Published: December 2022

A recently published correspondence proposed a solution for survival in the context of Indonesia using a spiritual-philosophical perspective to fight the pandemic crisis. However, such principle can be too exclusive and restrictive in its application to the pandemic crisis. One must also consider the alternative approaches in solving the crisis from a multidisciplinary and multisectoral approach. This paper proposes the principle of ‘human dignity’ as an inclusive approach to humanitarian crisis.
Beneficial effects of nintedanib on cardiomyopathy in patients with systemic sclerosis: a pilot study
Authors: Ninagawa Keita , Kato Masaru , Tsuneta Satonori , Ishizaka Suguru , Ujiie Hideyuki , Hisada Ryo , Kono Michihito , Fujieda Yuichiro , Ito Yoichi M , Atsumi Tatsuya
Published: December 2022

Objectives

Nintedanib is an inhibitor of tyrosine kinases that has been shown to slow the progression of interstitial lung disease (ILD), including ILD associated with SSc. The aim of this study was to explore the effect of nintedanib on cardiomyopathy associated with systemic sclerosis (SSc).

Methods

Twenty consecutively hospitalized patients with SSc-ILD were enrolled and prospectively followed. The rate of change at 6 months in cardiac magnetic resonance (CMR) parametric mapping, including myocardial extracellular volume, was primarily evaluated. Other endpoints included changes in CMR functional parameters, echocardiographic parameters, modified Rodnan skin score, serum biomarkers and pulmonary function test.

Results

Nintedanib was administered in 10 patients, whereas the other 10 were treated without nintedanib or watched, according to ILD severity and progression. Baseline values of CMR parametric mapping were not different between the two groups. The rate of change at 6 months in myocardial extracellular volume was highly different, almost divergent, between the nintedanib group and the control group (−1.62% vs +2.00%, P = 0.0001). Among other endpoints, the change in right ventricular ejection fraction was significantly different between the two groups (P = 0.02), with a preferential change in the nintedanib group.

Conclusion

Our data indicate beneficial signals of nintedanib on cardiomyopathy associated with SSc. The anti-fibrotic effect of nintedanib might not be limited to the lung.
Lnc-HZ03 promotes TRBP-mediated splicing of pre-miR-hz03 to generate miR-hz03 in human trophoblast cells
Authors: Zhao Jingsong , Cheng Liqin , Liu Qicai , Liang Tingting , Xie Jiayu , Wang Rong , Chen Weina , Ao Lin , Zhang Huidong
Published: December 2022

Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) leads to dysfunctions of human trophoblast cells and further induces miscarriage. In our previous study, we have found that lnc-HZ03 and miR-hz03 are upregulated in BPDE-exposed human trophoblast cells and in recurrent miscarriage tissues; and the upregulated miR-hz03 caused by lnc-HZ03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. However, how lnc-HZ03 upregulates miR-hz03 is completely unknown. In this study, we find that lnc-HZ03 upregulates the expression level of a transcription factor TFIID (a TATA-binding protein) and promotes TFIID-mediated transactivation response element RNA-binding protein (TRBP) transcription. Subsequently, the upregulated TRBP promotes the maturation of miR-hz03 by splicing its precursor pre-miR-hz03 in human trophoblast cells. In BPDE-exposed trophoblast cells or in recurrent miscarriage tissues, lnc-HZ03 was upregulated, which accelerates the TFIID-mediated TRBP transcription and thus promotes TRBP-mediated miR-HZ03 maturation. Subsequently, the upregulated miR-hz03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. This work provides new insights into the regulation of miRNA expression levels by lncRNAs in BPDE-exposed human trophoblast cells.
Constructing a Mixed Simulation With 360° Virtual Reality and a High-Fidelity Simulator
Authors: Kim Sun Kyung , Lee Youngho , Go Younghye
Published: December 2022

Virtual reality technology has been adopted to overcome barriers of conventional simulation. This study was conducted to determine the impact of mixed simulation (a 360° virtual reality and a high-fidelity simulator) on learning how to provide nursing care for patients with arrhythmia. A total of 49 students were randomly assigned to intervention (n = 25) and control (n = 23) groups. They were given four arrhythmia cases with a 360° virtual reality system first followed by a manikin-based simulation. The mixed simulation group showed greater improvement in knowledge, higher decision-making competency in “knowing and acting” (P = .025) and “seeking information from instructors” (P = .049), and lower anxiety in “using resources to gather information” (P = .031). Study participants achieved a good level of empathy (3.28 ± 0.72) and liked the program (4.56 ± 0.60). They were satisfied with the program (4.48 ± 0.65). These findings provide new insight into learning through blending of new technology. When the 360° virtual reality was used with existing manikin-based simulation, they effectively reinforced one another. The 360° virtual reality can be an effective strategy to ensure active participation to gain a comprehensive understanding of and empathy for patients.
Estimation of the Time-Varying Incremental Effect of Low-dose Aspirin on Incidence of Pregnancy
Authors: Rudolph Jacqueline E. , Kim Kwangho , Kennedy Edward H. , Naimi Ashley I.
Published: December 2022

Background:

In many research settings, the intervention implied by the average causal effect of a time-varying exposure is impractical or unrealistic, and we might instead prefer a more realistic target estimand. Instead of requiring all individuals to be always exposed versus unexposed, incremental effects quantify the impact of merely shifting each individual’s probability of being exposed.

Methods:

We demonstrate the estimation of incremental effects in the time-varying setting, using data from the Effects of Aspirin in Gestation and Reproduction trial, which assessed the effect of preconception low-dose aspirin on pregnancy outcomes. Compliance to aspirin or placebo was summarized weekly and was affected by time-varying confounders such as bleeding or nausea. We sought to estimate what the incidence of pregnancy by 26 weeks postrandomization would have been if we shifted each participant’s probability of taking aspirin or placebo each week by odds ratios (OR) between 0.30 and 3.00.

Results:

Under no intervention (OR = 1), the incidence of pregnancy was 77% (95% CI: 74%, 80%). Decreasing women’s probability of complying with aspirin had little estimated effect on pregnancy incidence. When we increased women’s probability of taking aspirin, estimated incidence of pregnancy increased, from 83% (95% confidence interval [CI] = 79%, 87%) for OR = 2 to 89% (95% CI = 84%, 93%) for OR=3. We observed similar results when we shifted women’s probability of complying with a placebo.

Conclusions:

These results estimated that realistic interventions to increase women’s probability of taking aspirin would have yielded little to no impact on the incidence of pregnancy, relative to similar interventions on placebo.
Comparative In Vitro Activity of New Lipoglycopeptides and Vancomycin Against Ocular Staphylococci and Their Toxicity on the Human Corneal Epithelium
Authors: André Camille , Islam Mohammad Mirazul , Paschalis Eleftherios , Bispo Paulo J. M.
Published: December 2022

Purpose:

The purpose of this study was to assess the potential of new lipoglycopeptides as novel topical therapies for improved treatment of recalcitrant ocular infections. We evaluated the in vitro antimicrobial activity of oritavancin, dalbavancin, and telavancin compared with vancomycin (VAN) against a large collection of ocular staphylococcal isolates and their cytotoxicity on human corneal epithelial cells (HCECs).

Methods:

Antimicrobial susceptibility testing was performed by broth microdilution against 223 Staphylococcus spp. clinical isolates. Time–kill kinetics were determined for methicillin-resistant strains of Staphylococcus aureus (MRSA) (n = 2) and Staphylococcus epidermidis (MRSE) (n = 1). In vitro cytotoxicity assays were performed with AlamarBlue and live/dead staining on HCECs.

Results:

All new lipoglycopeptides showed strong in vitro potency against ocular staphylococci, including multidrug-resistant MRSA strains, with dalbavancin showing a slightly higher potency overall [minimum inhibitory concentration (MIC)90 0.06 μg/mL] compared with telavancin and oritavancin (MIC90 0.12 μg/mL), whereas VAN had the lowest potency (MIC90 2 μg/mL). Oritavancin exerted rapid bactericidal activity within 1 h for MRSA and 2 h for MRSE. All other drugs were bactericidal within 24 h. At a concentration commonly used for topical preparations (25 mg/mL), cytotoxicity was observed for VAN after 5 min of incubation, whereas reduction in HCEC viability was not seen for telavancin and was less affected by oritavancin and dalbavancin. Cytotoxicity at 25 mg/mL was seen for all drugs at 30 and 60 min but was significantly reduced or undetected for lower concentrations.

Conclusions:

Our study demonstrates that new lipoglycopeptides have substantially better in vitro antimicrobial activity against ocular staphylococcal isolates compared with VAN, with a similar or improved toxicity profile on HCECs.
The Use of Metaverse in Nursing Education
Authors: De Gagne Jennie C. , Randall Paige S. , Rushton Sharron , Park Hyeyoung K. , Cho Eunji , Yamane Sandra S. , Jung Dukyoo
Published: December 2022

Background:

Given the wide range of metaverse technologies, there is a need to synthesize evidence of metaverse pedagogy used effectively for nursing education.

Purpose:

This umbrella review synthesized systematic reviews on the use of metaverse in nursing education.

Methods:

A search was performed in MEDLINE, EMBASE, CINAHL, Web of Science, and Education Full Text. This umbrella review was conducted with reference to the Joanna Briggs Institute (JBI) Reviewer's Manual and reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The JBI Critical Appraisal Checklist for Systematic Review was used to assess the quality of studies.

Results:

The final review comprised 15 articles published between 2013 and 2021, most of which indicate that metaverse interventions support increased knowledge, self-confidence, engagement, satisfaction, and performance in nursing students. Several articles in this review presented mixed findings related to certain learning outcomes.

Conclusion:

This umbrella review supports the viability and effectiveness of metaverse in nursing education.
Development of a Community Advisory Board to Guide Research About Cancer Disparities in the Black and African American Community
Authors: Hirschey Rachel , Getachew Berhan , Coleman Karia , Lea Deirdre , Milner John , Bryant Ashley L. , Carlisle Veronica
Published: December 2022

Background

Researchers who aim to serve a community (i.e., racial, gender, ethnic group) of which they are not a part must do foundational work to understand that community and build intentional, thoughtful collaborations with the community to guide their work.

Objectives

This article aims to share a case exemplar of the formation period of a community advisory board (CAB) that conducts research focused on improving health equity in the Black and African American community.

Methods

CAB development has three phases: formation, operation, and maintenance. Previous work has described and provided best practices for each phase. This article focused on the first phase, formation. Guided by critical race theory, with guidance from her mentor, a researcher partnered with a research assistant and a community health educator to develop a CAB. Details of their processes—which apply to the formation of other CABs—are presented.

Discussion

During the board formation period, the major focus has been relationship building and developing a shared mission: “To work in partnership with researchers at the University of North Carolina to reduce cancer disparities in Black/African American communities by informing research and program development. As a liaison between the community and researchers, the Community Advisory Board will identify community needs, promote evidence-based interventions and information, raise awareness about health disparities in communities, and educate researchers.” CAB formation is nuanced and unique, dependent upon the nature of the research to be conducted and the characteristics of the community and researchers. This case exemplar provides valuable insights to other researchers working to build community partnerships.
THE ROLE OF OBESITY AND PLASMA ADIPOCYTOKINES IN IMMUNE DYSREGULATION IN SEPSIS PATIENTS
Authors: de Nooijer Aline H. , Antonakos Nikolaos , Markopoulou Dimitra , Grondman Inge , Kox Matthijs , Pickkers Peter , Giamarellos-Bourboulis Evangelos J. , Netea Mihai G.
Published: December 2022

Introduction: The dysregulated immune response in sepsis is highly variable, ranging from hyperinflammation to immunoparalysis. Obesity is associated with the release of inflammatory mediators from adipose tissue, known as adipocytokines, causing a chronic inflammatory state. Perhaps counterintuitively, obesity is also associated with lower mortality in sepsis patients. We investigated the association between obesity, circulating adipocytokine concentrations, immune dysregulation, and outcome in sepsis patients. Methods In this secondary analysis of a prospective study, plasma concentrations of the adipocytokines leptin, adiponectin, and resistin were assessed in 167 patients at diagnosis of sepsis due to pneumonia, bacteremia, or acute cholangitis. Adipocytokines were compared between patients with normal weight (body mass index [BMI], 18.5–24.9 kg/m2; n = 67), overweight (BMI, 25.0–29.9 kg/m2; n = 56), and obesity (BMI ≥30 kg/m2; n = 42), as well as between immunological endotypes: hyperinflammation (n = 40), immunoparalysis (n = 62), and unclassified (n = 55). Results: Higher circulating concentrations of leptin were observed in patients with obesity compared with patients with normal weight (P = 0.008) and overweight (P = 0.02), whereas adiponectin and resistin plasma concentrations were not different (P = 0.08 and P = 0.85, respectively). Resistin concentrations were associated with immunological endotypes, with the highest levels found in hyperinflammatory patients (P < 0.001). Furthermore, resistin concentrations were predictive for 28-day mortality (adjusted odds ratio, 1.03 per 10 ng/mL; P = 0.04). These associations were not found for leptin and adiponectin. Conclusion: Obesity and BMI-related adipocytokines are not related to the development of a hyperactive or suppressed immune response as defined by ferritin and mHLA-DR expression in sepsis patients. Although resistin is related to the immune response and an increased risk of adverse clinical outcomes, these associations are similar in patients with normal weight, overweight, and obesity. This implies that the relationship between resistin and clinical outcome is likely driven by the inflammatory response and not by obesity itself. Taken together, although there exists a strong association between inflammation and sepsis mortality, our results do not point toward a role for obesity and BMI-related adipocytokines in immune dysregulation in sepsis patients.
Efflux-mediated tolerance to cationic biocides, a cause for concern?
Authors: Wand Matthew E. , Sutton J. Mark
Published: December 2022

Abstract

With an increase in the number of isolates resistant to multiple antibiotics, infection control has become increasingly important to help combat the spread of multi-drug-resistant pathogens. An important component of this is through the use of disinfectants and antiseptics (biocides). Antibiotic resistance has been well studied in bacteria, but little is known about potential biocide resistance genes and there have been few reported outbreaks in hospitals resulting from a breakdown in biocide effectiveness. Development of increased tolerance to biocides has been thought to be more difficult due to the mode of action of biocides which affect multiple cellular targets compared with antibiotics. Very few genes which contribute towards increased biocide tolerance have been identified. However, the majority of those that have are components or regulators of different efflux pumps or genes which modulate membrane function/modification. This review will examine the role of efflux in increased tolerance towards biocides, focusing on cationic biocides and heavy metals against Gram-negative bacteria. As many efflux pumps which are upregulated by biocide presence also contribute towards an antimicrobial resistance phenotype, the role of these efflux pumps in cross-resistance to both other biocides and antibiotics will be explored.
A prospective evaluation of breast thermography enhanced by a novel machine learning technique for screening breast abnormalities in a general population of women presenting to a secondary care hospital
Authors: Bansal Richa , Collison Sathiakar , Aggarwal Bharat
Published: December 2022

Objective

Artificial intelligence-enhanced breast thermography is being evaluated as an ancillary modality in the evaluation of breast disease. The objective of this study was to evaluate the clinical performance of Thermalytix, a CE-marked, AI-based thermal imaging test, with respect to conventional mammography.

Methods

A prospective, comparative study performed between 15 December 2018 and 06 January 2020 evaluated the performance of Thermalytix in 459 women with both dense and nondense breast tissue. Both symptomatic and asymptomatic women, aged 30 to 80 years, presenting to the hospital underwent Thermalytix followed by 2-D mammography and appropriate confirmatory investigations to confirm malignancy. The radiologist interpreting the mammograms and the technician using the Thermalytix tool were blinded to the others’ findings. The statistical analysis was performed by a third party.

Results

A total of 687 women were recruited, of whom 459 fulfilled the inclusion criteria. Twenty-one malignancies were detected (21/459, 4.6%). The overall sensitivity of Thermalytix was 95.24% (95% CI, 76.18-99.88), and the specificity was 88.58% (95% CI, 85.23-91.41). In women with dense breasts (n=168, 36.6%), the sensitivity was 100% (95% CI, 69.15-100), and the specificity was 81.65% (95% CI, 74.72-87.35). Among these 168 women, 37 women (22%) were reported as BI-RADS 0 on mammography; in this subset, the sensitivity of Thermalytix was 100% (95% CI, 69.15-100), and the specificity was 77.22% (95% CI, 69.88-83.50).

Conclusion

Thermalytix showed acceptable sensitivity and specificity with respect to mammography in the overall patient population. Thermalytix outperformed mammography in women with dense breasts and those reported as BI-RADS 0.

Key points

Compared with mammography as the reference, Thermalytix showed acceptable sensitivity and specificity of 95.24% and 88.58%, respectively, in the overall patient population (N=459).

Among women with dense breasts (n=168), 37 women (22%) were reported as BI-RADS 0 (incomplete examination) on mammograms, whereas Thermalytix identified all malignancies.

Thermalytix identified all malignancies among premenopausal women and women younger than 50 years of age.

Summary Statement

Thermalytix, an AI-based thermal imaging tool, showed acceptable sensitivity and specificity when mammography was used as the reference in the overall patient population and in women with dense breast tissue.
In-channel cancellation: a model of early auditory processing
Authors: Alain de Cheveigné
Published: December 2022

A model of early auditory processing is proposed in which each peripheral channel is processed by a delay-and-subtract cancellation filter, tuned independently for each channel with a criterion of minimum power. For a channel dominated by a pure tone or a resolved partial of a complex tone, the optimal delay is its period. For a channel responding to harmonically-related partials, the optimal delay is their common fundamental period. Each peripheral channel is thus split into two subchannels, one that is cancellation-filtered and the other not. Perception can involve either or both, depending on the task. The model is illustrated by applying it to the masking asymmetry between pure tones and narrowband noise: a noise target masked by a tone is more easily detectable than a tone target masked by noise. The model is one of a wider class of models, monaural or binaural, that cancel irrelevant stimulus dimensions so as to attain invariance to competing sources. Similar to occlusion in the visual domain, cancellation yields sensory evidence that is incomplete, thus requiring Bayesian inference of an internal model of the world along the lines of Helmholtz’s doctrine of unconscious inference.
Head-to-head comparison between plasma p-tau217 and Flortaucipir-PET in amyloid-positive patients with cognitive impairment
Authors: Mundada Nidhi S. , Rojas Julio C. , Vandevrede Lawren , Thijssen Elisabeth H. , Iaccarino Leonardo , Okoye Obiora C. , Shankar Ranjani , Soleimani-Meigooni David N. , Lago Argentina L. , Miller Bruce L. , Teunissen Charlotte E. , Heuer Hillary , Rosen Howie J. , Dage Jeffrey L. , Jagust William J. , Rabinovici Gil D. , Boxer Adam L. , La Joie Renaud
Published: December 2022

Background and Objective

Plasma phosphorylated tau (p-tau) has emerged as a promising biomarker for Alzheimer’s disease (AD). Studies have reported strong associations between p-tau and tau-PET that are mainly driven by differences between amyloid-positive and amyloid-negative patients. However, the relationship between p-tau and tau-PET is less characterized within cognitively impaired patients with a biomarker-supported diagnosis of AD. We conducted a head-to-head comparison between plasma p-tau217 and tau-PET in patients at the clinical stage of AD and further assessed their relationships with demographic, clinical, and biomarker variables.

Methods

We retrospectively included 87 amyloid-positive patients diagnosed with MCI or AD dementia who underwent structural MRI, amyloid-PET (11C-PIB), tau-PET (18F-flortaucipir, FTP), and blood draw assessments within one year (age=66±10, 48% female). Amyloid-PET was quantified in Centiloids (CL) while cortical tau-PET binding was measured using Standardized Uptake Value Ratios (SUVRs) referenced against inferior cerebellar cortex. Plasma p-tau217 concentrations were measured using an electrochemiluminescence-based assay on the Meso Scale Discovery platform. MRI-derived cortical volume was quantified with FreeSurfer. Mini-Mental State Examination (MMSE) scores were available at baseline (n=85) and follow-up visits (n=28; 1.5±0.7 years).

Results

Plasma p-tau217 and cortical FTP-SUVR were correlated (r=0.61, p<.001), especially in temporo-parietal and dorsolateral frontal cortices. Both higher p-tau217 and FTP-SUVR values were associated with younger age, female sex, and lower cortical volume, but not with APOE-ε4 carriership. PIB-PET centiloids were weakly correlated with FTP-SUVR (r=0.26, p=0.02), but not with p-tau217 (r=0.10, p=0.36). Regional PET-plasma associations varied with amyloid burden, with p-tau217 being more strongly associated with tau-PET in temporal cortex among patients with moderate amyloid-PET burden, and with tau-PET in primary cortices among patients with high amyloid-PET burden. Higher p-tau217 and FTP-SUVR values were independently associated with lower MMSE scores cross-sectionally, while only baseline FTP-SUVR predicted longitudinal MMSE decline when both biomarkers were included in the same model.

Discussion

Plasma p-tau217 and tau-PET are strongly correlated in amyloid-PET-positive patients with MCI and AD, and they exhibited comparable patterns of associations with demographic variables and with markers of downstream neurodegeneration.
An Effective Automated Algorithm to Isolate Patient Speech from Conversations with Clinicians
Authors: Jaquenoud Theo , Keene Sam , Shlayan Neveen , Federman Alex , Pandey Gaurav
Published: December 2022

A growing number of algorithms are being developed to automatically identify disorders or disease biomarkers from digitally recorded audio of patient speech. An important step in these analyses is to identify and isolate the patient’s speech from that of other speakers or noise that are captured in a recording. However, current algorithms, such as diarization, only label the identified speech segments in terms of non-specific speakers, and do not identify the specific speaker of each segment, e.g., clinician and patient. In this paper, we present a novel algorithm that not only performs diarization on clinical audio, but also identifies the patient among the speakers in the recording and returns an audio file containing only the patient’s speech. Our algorithm first uses pretrained diarization algorithms to separate the input audio into different tracks according to nonspecific speaker labels. Next, in a novel step not conducted in other diarization tools, the algorithm uses the average loudness (quantified as power) of each audio track to identify the patient, and return the audio track containing only their speech. Using a practical expert-based evaluation methodology and a large dataset of clinical audio recordings, we found that the best implementation of our algorithm achieved near-perfect accuracy on two validation sets. Thus, our algorithm can be used for effectively identifying and isolating patient speech, which can be used in downstream expert and/or data-driven analyses.
Correlates of protection against SARS-CoV-2 Omicron variant and anti-spike antibody responses after a third/booster vaccination or breakthrough infection in the UK general population
Authors: Wei Jia , Matthews Philippa C. , Stoesser Nicole , Newton John N , Diamond Ian , Studley Ruth , Taylor Nick , Bell John I , Farrar Jeremy , Kolenchery Jaison , Marsden Brian D. , Hoosdally Sarah , Jones E Yvonne , Stuart David I , Crook Derrick W. , Peto Tim E. A. , Walker A. Sarah , Pouwels Koen B. , Eyre David W. ,   the COVID-19 Infection Survey team
Published: December 2022

Following primary SARS-CoV-2 vaccination, understanding the relative extent of protection against SARS-CoV-2 infection from boosters or from breakthrough infections (i.e. infection in the context of previous vaccination) has important implications for vaccine policy. In this study, we investigated correlates of protection against Omicron BA.4/5 infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18y from the United Kingdom general population. We found that higher anti-spike IgG antibody levels were associated with increased protection against Omicron BA.4/5 infection and that breakthrough infections were associated with higher levels of protection at any given antibody level than booster vaccinations. Breakthrough infections generated similar antibody levels to third/booster vaccinations, and the subsequent declines in antibody levels were similar to or slightly slower than those after third/booster vaccinations. Taken together our findings show that breakthrough infection provides longer lasting protection against further infections than booster vaccinations. For example, considering antibody levels associated with 67% protection against infection, a third/booster vaccination did not provide long-lasting protection, while a Delta/Omicron BA.1 breakthrough infection could provide 5-10 months of protection against Omicron BA.4/5 reinfection. 50-60% of the vaccinated UK population with a breakthrough infection would still be protected by the end of 2022, compared to <15% of the triple-vaccinated UK population without previous infection. Although there are societal impacts and risks to some individuals associated with ongoing transmission, breakthrough infection could be an efficient immune-boosting mechanism for subgroups of the population, including younger healthy adults, who have low risks of adverse consequences from infection.
A Minimal Model of CD95 Signal Initiation Revealed by Advanced Super-resolution and Multiparametric Fluorescence Microscopy
Authors: Bartels Nina , van der Voort Nicolaas T M , Greife Annemarie , Bister Arthur , Wiek Constanze , Seidel Claus A M , Monzel Cornelia
Published: December 2022

Unraveling the spatiotemporal organization and dynamical interactions of receptors in the plasma membrane remains a key challenge for our mechanistic understanding of cell signal initiation. A paradigm of such process is the oligomerization of TNF receptor CD95 during apoptosis signaling, where molecular configurations are yet to be defined. Here, we scrutinize proposed oligomerization models in live cells, establishing a molecular sensitive imaging toolkit including time-resolved FRET spectroscopy, quantitative STED microscopy, confocal Photobleaching Step Analysis and FCS. CD95 interactions were probed over molecular concentrations of few to ∼ 1000 molecules/µm2, over ns to hours, and molecular to cellular scales. We further established high-fidelity monomer and dimer controls for quantitative benchmarking. Efficient apoptosis was already observed when ∼ 8 to 17% monomeric CD95 oligomerize to dimers/trimers after ligand binding. Our multiscale study highlights the importance of molecular concentrations, of the native environment, and reveals a minimal oligomerization model of CD95 signal initiation.
Targeted photodynamic neutralization of SARS-CoV-2 mediated by singlet oxygen
Authors: Yao Ruhui , Hou Jian , Zhang Xin , Li Yi , Lai Junhui , Wu Qinqin , Liu Qinglian , Zhou Lei
Published: December 2022

The SARS-CoV-2 virus has been on a rampage for more than two years. Vaccines in combination with neutralizing antibodies (NAbs) against SARS-CoV-2 carry great hope in the treatment and final elimination of COVID-19. However, the relentless emergence of variants of concern (VOC), including the most recent Omicron variants, presses for novel measures to counter these variants that often show immune evasion. Hereby we developed a targeted photodynamic approach to neutralize SARS-CoV-2 by engineering a genetically encoded photosensitizer (SOPP3) to a diverse list of antibodies targeting the WT spike protein, including human antibodies isolated from a 2003 SARS patient, potent monomeric and multimeric nanobodies targeting RBD, and non-neutralizing antibodies (non-NAbs) targeting the more conserved NTD region. As confirmed by pseudovirus neutralization assay, this targeted photodynamic approach significantly increased the efficacy of these antibodies, especially that of non-NAbs, against not only the WT but also the Delta strain and the heavily immune escape Omicron strain (BA.1). Subsequent measurement of infrared phosphorescence at 1270 nm confirmed the generation of singlet oxygen (1O2) in the photodynamic process. Mass spectroscopy assay uncovered amino acids in the spike protein targeted by1O2. Impressively, Y145 and H146 form an oxidization “hotspot”, which overlaps with the antigenic “supersite” in NTD. Taken together, our study established a targeted photodynamic approach against the SARS-CoV-2 virus and provided mechanistic insights into the photodynamic modification of protein molecules mediated by1O2.
FMRP phosphorylation modulates neuronal translation through YTHDF1
Authors: Zou Zhongyu , Wei Jiangbo , Chen Yantao , Kang Yunhee , Shi Hailing , Yang Fan , Chen Shijie , Zhou Ying , Sepich-Poore Caraline , Zhuang Xiaoxi , Zhou Xiaoming , Jiang Hualiang , Wen Zhexing , Jin Peng , Luo Cheng , He Chuan
Published: December 2022

Translation activation of local synaptic mRNAs is critical to learning and memory1-3. Despite extensive studies on how phosphorylation of ribosomal proteins and translation factors enables timely response to exogenous stimuli4,our knowledge on molecular pathways utilized by RNA binding proteins (RBPs) to control translation of specific mRNAs remains incomplete. We have previously found that YTHDF1 regulates depolarization-induced protein synthesis by promoting translation ofN6-methyladenosine (m6A)-modified transcripts5. Here we report an unexpected mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Phosphorylation of FMRP serine 499 induced by neuronal depolarization alters the condensing behavior of prion-like protein YTHDF1. Unphosphorylated FMRP sequesters YTHDF1 away from the translation initiation complex, whereas the stimulation-induced FMRP phosphorylation releases YTHDF1 to form translational active condensates with the ribosome to activate translation of YTHDF1 target transcripts. In fragile X syndrome (FXS) models characterized by low FMRP expression, we observed YTHDF1-mediated hyperactive translation, which notably impacts FXS pathophysiology. Developmental defects in an FXS forebrain organoid model could be reversed by a selective small-molecule inhibitor of YTHDF1 which acts by suppressing its condensation in neurons. We characterized transcriptome-wide mRNA translation with inhibitor treatment in organoids and identified targets that explain alleviated FXS pathology. Our study thus reveals FMRP and its phosphorylation as an important regulator of the activity-dependent translation during neuronal development and stimulation, and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.
Transposable elements drive the evolution of metazoan zinc finger genes
Authors: Wells Jonathan N. , Chang Ni-Chen , McCormick John , Coleman Caitlyn , Ramos Nathalie , Jin Bozhou , Feschotte Cédric
Published: December 2022

Cys2-His2 Zinc finger genes (ZNFs) form the largest family of transcription factors in metazoans. ZNF evolution is highly dynamic and characterized by the rapid expansion and contraction of numerous subfamilies across the animal phylogeny. The forces and mechanisms underlying rapid ZNF evolution remain poorly understood, but there is growing evidence that the targeting and repression of lineage-specific transposable elements (TEs) plays a major role in the diversification of the Kruppel-associated box ZNF (KZNF) subfamily, which predominates in tetrapod genomes. At present, it is unknown whether this function and co-evolutionary relationship is unique to KZNFs, or a broader feature of metazoan ZNFs. Here, we present evidence that genomic conflict with TEs has been a central driver in the diversification of ZNFs in animals. Sampling from more than 4000 animal genome assemblies, we show that the copy number of retroelements correlates with that of ZNFs across at least 750 million years of metazoan evolution, both within and between major taxonomic groups. Using computational predictions, we show that ZNFs preferentially bind TEs in a diverse set of representative animal species. We further investigate one of the most expansive ZNF subfamilies found in cyprinid fish, which are characterized by a conserved domain we dubbed theFishN-terminalZinc-finger associated (FiNZ) domain. FiNZ-ZNFs have dramatically expanded in several fish species, including the zebrafish in which we predict ~700 FiNZ-ZNF genes. Almost all are located on the long arm of chromosome 4, and recent duplicates are evolving adaptively under positive selection. Like mammalian KZNFs, the bulk of zebrafish FiNZ-ZNFs are expressed in waves at the onset of zygotic genome activation. Blocking FiNZ-ZNF translation using morpholinos during early zebrafish embryogenesis results in a global de-repression of young, transcriptionally active TEs, likely driven by the failure to establish heterochromatin over these elements. Together, these data suggest that ZNF diversification has been intimately connected to TE expansion throughout animal evolution and that families of ZNFs have been deployed independently in fish and mammals to repress TEs during early embryogenesis.
Translation-dependent downregulation of Cas12a mRNA by an anti-CRISPR protein
Authors: Marino Nicole D. , Talaie Alexander , Carion Héloïse , Johnson Matthew C. , Zhang Yang , Silas Sukrit , Li Yuping , Bondy-Denomy Joseph
Published: December 2022

Bacteria have evolved multiple defense systems, including CRISPR-Cas, to cleave the DNA of phage and mobile genetic elements (MGE). In turn, phage have evolved anti-CRISPR (Acr) proteins that use novel and co-opted mechanisms to block DNA binding or cleavage. Here, we report that an anti-CRISPR (AcrVA2) unexpectedly inhibits Cas12a biogenesis by triggering translation-dependent destruction of its mRNA. AcrVA2 specifically clears the mRNA of Cas12a by recognizing and binding its N-terminal polypeptide. Mutating conserved N-terminal amino acids in Cas12a prevents binding and inhibition by AcrVA2 but also decreases Cas12a anti-phage activity. This mechanism therefore enables AcrVA2 to specifically inhibit divergent Cas12a orthologs while constraining its ability to escape inhibition. AcrVA2 homologs are found on diverse MGEs across numerous bacterial classes, typically in the absence of Cas12a, suggesting that this protein family may induce similar molecular outcomes against other targets. These findings reveal a new gene regulatory strategy in bacteria and create opportunities for polypeptide-specific gene regulation in prokaryotes and beyond.