bluuebunny/crossref_metadata_2025 huggingface dataset:
Polydopamine anchored poly(2-methyl-2-oxazoline)/poly(4-vinyl pyridine) mixed brushes with switchable properties for pepsin adsorption
Authors: He Kang , Hu Fei , Chen Chaoshi , Atif Muhammad , Wang Yanmei
Published: July 2023

Mixed polymer brushes coating based on poly (2-methyl-2-oxazoline)/ poly(4-vinyl pyridine) (PMOXA/P4VP) was prepared by simultaneously grafting amine-terminated PMOXA and thiolterminated P4VP onto poly(dopamine) (PDA)-modified substrates in this work. The coatings were characterized by X-ray photoelectron spectroscopy, ellipsometry, zeta potential measurements, and the static water contact angle tests. The results indicated that it is feasible to control the components of the coating by adjusting the feed ratio of PMOXA to P4VP. Moreover, the zeta potential and the water contact angle of mixed brushes modified surfaces could be tuned by changing the environmental pH value and surface compositions. Finally, fluorescein isothiocyanate-labelled pepsin assay and surface plasmon resonance were performed to investigate the responsive adsorption/desorption of pepsin by PMOXA/P4VP mixed brushes. The results showed that by adjusting the fraction of PMOXA or P4VP, the PMOXA/P4VP mixed brushes coated surfaces could adsorb a high amount of pepsin at pH=3, and achieve a desorption efficiency of over 92% at pH=7.
A fitting program for structural determination of molecular clusters from rotational spectroscopy
Authors: Chen Xinlei , Wang Guanjun , Li Weixing
Published: July 2023

The characterization of the structures of molecular clusters, which serve as building blocks for bulk substances, provides crucial insight into the interactions between constituent units. Chirped-pulse Fourier transform microwave (CP-FTMW) spectroscopy, combined with state-of-the-art quantum chemical calculations, is a powerful tool for characterizing the structures of molecular clusters, as the rotational spectra are directly related to the mass distribution of a molecule or cluster. However, determining the structures of large or complex clusters from experimental rotational spectra remains challenging due to their structural flexibility. Ab initio and density functional theory calculations for searching their stable structures could be significantly time-consuming and method-dependent. To address these challenges, we have developed an approach that relies on the experimental rotational constants to search for potential molecular structures without quantum chemical optimization. Our approach involves creating an initial set of conformers through either a semi-empirical sampling program or the quasi-Monte Carlo method. After-ward, the trust region reflective algorithm is utilized for structure fitting. This procedure enables us to quickly generate potential conformers and gain access to precise structural information. We apply our fitting program to water hexamer and benzaldehyde-water clusters, and the resulting topological structures align extremely well with the experimental results.
The different effects of income and educational level on prosocial behaviour and related ideological variables (Los diversos efectos del nivel de ingresos ynivel educativo en la conducta prosocial yotras variables ideológicas relacionadas)
Authors: Moya Miguel , Alcañiz-Colomer Joaquín
Published: July 2023

Studies on socioeconomic status (SES) have recently increased in social psychology. The most used indicators to measure objective SES are income and educational level (usually standardizing and summing the scores of these variables). However, income and education possibly have different, even opposite effects on certain variables. Across seven studies, using data from previous research and from international databases, we show that this is true both for prosocial behaviour and for variables related to prosocial behaviour. A higher educational level tends to positively predict prosocial behaviour (Studies 1a–1d) and structural attributions of poverty (Studies 2 and 3), and negatively predict scores for meritocratic beliefs (Study 3) and just world beliefs (Study 4). In most cases, income showed a reverse trend or did not predict the outcome. We discuss the broader implications both for the study of prosocial behaviour and social class.
EEG fractal dimensions predict high-level behavioral responses in minimally conscious patients
Authors: Liuzzi Piergiuseppe , Hakiki Bahia , Draghi Francesca , Romoli Anna Maria , Burali Rachele , Scarpino Maenia , Cecchi Francesca , Grippo Antonello , Mannini Andrea
Published: July 2023

Objective. Brain-injured patients may enter a state of minimal or inconsistent awareness termed minimally conscious state (MCS). Such patient may (MCS+) or may not (MCS-) exhibit high-level behavioral responses, and the two groups retain two inherently different rehabilitative paths and expected outcomes. We hypothesized that brain complexity may be treated as a proxy of high-level cognition and thus could be used as a neural correlate of consciousness. Approach. In this prospective observational study, 68 MCS patients (MCS-: 30; women: 31) were included (median [IQR] age 69 [20]; time post-onset 83 [28]). At admission to intensive rehabilitation, 30 min resting-state closed-eyes recordings were performed together with consciousness diagnosis following international guidelines. The width of the multifractal singularity spectrum (MSS) was computed for each channel time series and entered nested cross-validated interpretable machine learning models targeting the differential diagnosis of MCS±. Main results. Frontal MSS widths (p < 0.05), as well as the ones deriving from the left centro-temporal network (C3: p = 0.018, T3: p = 0.017; T5: p = 0.003) were found to be significantly higher in the MCS+ cohort. The best performing solution was found to be the K-nearest neighbor model with an aggregated test accuracy of 75.5% (median [IQR] AuROC for 100 executions 0.88 [0.02]). Coherently, the electrodes with highest Shapley values were found to be Fz and Cz, with four out the first five ranked features belonging to the fronto-central network. Significance. MCS+ is a frequent condition associated with a notably better prognosis than the MCS-. High fractality in the left centro-temporal network results coherent with neurological networks involved in the language function, proper of MCS+ patients. Using EEG-based interpretable algorithm to complement differential diagnosis of consciousness may improve rehabilitation pathways and communications with caregivers.
Research on the application potential of solar energy in rural areas from the perspective of common prosperity
Authors: Liu Yixi , Hu Chun , Yu Anping
Published: July 2023

Under the policy background of common prosperity, the Hesheng Town and Yunling Township area of Yongjia County is selected as the research area. The development and application potential of solar energy resources are analyzed, aiming to contribute to wealth and income growth, based on three aspects: resource richness, stability and security, and sunshine time (including effective sunshine time). A comprehensive evaluation of regional microclimate simulation is conducted using the Digital Elevation Model (Abbreviated as DEM). ArcGIS is utilized to generate a potential map for solar energy resource development, which is further divided into five levels based on development potential. The results reveal that the eastern part of Yunling Township, Shiweiyan Community in Hesheng Town, the western and northeastern parts of Donggao Community in Hesheng Town, and the northern part of Xiyuan Community in Hesheng Town exhibit an extremely high abundance of solar energy resources. These areas have the potential for large-scale utilization and development. Moreover, the southwest and southeast regions of the central area of Hesheng Town, along with the northwest area of Xiyuan Community in Hesheng Town, possess a relatively high abundance of solar energy resources. These areas can be developed and utilized on a small-scale and seasonal basis.
Investigation of the dielectric properties and mechanical stability of lignocellulosic biomass based electrical insulation material for high voltage applications
Authors: Rajamanikandan T , Banumathi S , Karthikeyan B
Published: July 2023

The laminated insulation pressboards are used in electrical transformers and they are made from pure wood cellulose fibre. It is used in high-voltage transformers for electrical insulation due to its superior electrical and mechanical properties. Many researchers are searching for alternatives to wood raw materials to reduce deforestation. The banana is one of the lignocellulose-based raw materials; the banana fibre contains 48% cellulose. In this work, different frequencies and temperatures are used to investigate the electrical characteristics of epoxy resin composites reinforced with banana leaf fibres, including their dielectric constant, dissipation factor, and loss factor. At frequencies ranging from 1 to 10 kHz and temperatures ranging from 30 to 150 °C, the dielectric properties of several composites containing banana leaf fibre are studied. The composite’s dielectric properties gradually increased with temperature and decreased with frequency. Correspondingly, the mechanical tests involving a banana leaf fibre epoxy composite are conducted for tensile, bending, impact, and water absorption. The banana leaf fibre has been treated with a 5% sodium hydroxide (NaOH) solution to increase its dielectric and mechanical strength. According to this study, the mechanical strength of biocomposites containing up to 60% treated banana leaf fibre epoxy (TBLFE) composites is greater than that of pure epoxy. A thermogravimetric investigation of composites reinforced with banana fibres has revealed remarkable thermal stability up to 220 °C. In a composite made from chemically treated banana fibre pressboard, there is a good bond between the fibres and the matrix. The FESEM surface analysis shows that treated banana leaf fibril insulation boards have a better texture than composites that have not been treated. The testing results depict that banana leaf fibre is one of the good alternatives to wood cellulose for electrical insulation on pressboard for high-voltage applications.
Hölder classes in the 𝐿^{𝑝} norm on a chord-arc curve in ℝ³
Authors: Alexeeva T. , Shirokov N.
Published: July 2023

The Hölder classes

L
p

α

(
L
)

L_p^{\alpha } (L)

in the

L
p

(
L
)

L_p(L)

norm on a chord-arc curve

L
L

in

R

3

\mathbb {R}^3

are defined and direct and inverse approximation theorems are proved for functions from these classes by functions harmonic in a neighborhood of the curve. The approximation is estimated in the

L
p

(
L
)

L^p(L)

norm, the direct theorem is proved for a certain subclass of

L
p
α

(
L
)

L^\alpha _p(L)

and the inverse theorem covers the entire Hölder class.
The Maxwell system in nonhomogeneous anisotropic waveguides with slowly stabilizing characteristics of the filling medium
Authors: Plamenevskii B. , Poretskii A.
Published: July 2023

In a domain having several cylindrical outlets to infinity, the stationary Maxwell system with perfectly conductive boundary conditions is studied. The dielectric permittivity and magnetic permeability are assumed to be arbitrary positive definite matrix-valued functions that slowly stabilize at infinity. The authors introduce the scattering matrix, establish the unique solvability of the problem with radiation conditions at infinity, and describe the asymptotics of solutions.
A BIVALENT TIM-3/PD-1 BISPECIFIC ANTIBODY FOR THE TREATMENT OF PD-1 ANTIBODY RESISTANT OR REFRACTORY SOLID TUMORS
Authors: Luan Yan , Deng Hongyuan , Wang Fengpo , Wang Cuihui , Zhang Zhen , Liu Xun , Abuduwaili Kahaerjiang , Liu Jiajian
Published: July 2023

Background

Immune checkpoint inhibitors (ICI) PD-1/PD-L1 antibody are key drugs for the treatment of cancer. Bispecific antibody is one of the strategies aimed to meet the clinical needs for cancer patients who are resistant to or refractory from ICI treatment. TIM-3, one of the next generation of ICI targets, co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and TIM-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit for patients who are resistant to or refractory from ICI treatment.

Method

A bivalent TIM-3 and PD-1 bispecific antibody (Bis5) was developed, a series of in vitro and in vivo efficacy, preclinical pharmacokinetic and toxicity studies were conducted. A Phase I, multicenter, open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of Bis5 in patients with advanced and/or metastatic solid tumors is ongoing in China.

Results

Bis5 showed affinity of 5-8 nM to both TIM-3 and PD-1, with better cell activity than TIM-3 and PD-1 mAb combination to activated T cell as well as NK and DC, over the other clinical stage reference BsAb. In huPD-1/TIM-3 double knock in mice-CT26 tumor model, Bis5 showed significant tumor inhibition activity and doubled the survival rate, while neither PD-1 mAb, TIM-3 mAb nor PD-1 and TIM-3 antibody combination showed activity. The highest non-severe toxicity dose (HNSTD) was 200mg/kg in monkeys. Nine cohorts (0.001-15 mg/kg) are planned to be enrolled sequentially in the dose escalation part in the Phase I study, as of April 2023, seven cohorts enrollment have completed. No dose limiting toxicity was observed, and the optimal effective dose was not reached. No TRAE higher than grade 2 was observed. The TRAE with ≥10% Incidence was anemia. SD >4 or 2 months were shown in the suboptimal dose levels in NSCLC and CRC (0.3mg/kg, 1mg/kg). The Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in several cohorts including NSCLC, CRC, ESCC etc.

Conclusion

Bis5 showed good preclinical efficacy and safety profile, its clinical performance is expected. Clinical trial information: NCT05357651.
ANTIBODY CO-FORMULATION TOOLBOX AND CAPABILITIES ESTABLISHED IN WUXI BIOLOGICS
Authors: Liu Anyuan , Weng Jingwen , Zhou Fangyuan , Wang Kewei , Wu Hongbing , Wang Shawn , Guo Jeremy
Published: July 2023

Introduction

Co-formulation containing two or more antibodies (mAbs) is deemed to hold distinct merits such as better treatment efficacy, higher efficiency and extended intellectual property right, attracting the demands from both patients and pharmaceutical companies. However, there are only limited numbers of approved drug products, partially due to the technical challenges in formulation development and analytical methods. Herein, we present WuXi Biologics efforts to accelerate the development of co-formulation drug products.

Methodology

We have established an antibody co-formulation specific toolbox with a dedicated team for co-formulation product development addressing the formulation and analytical challenges. Our co-formulation analytical expertise includes size exclusion-high performance liquid chromatography (SE-HPLC), caliper-sodium dodecyl sulfate reduced and non-reduced (Caliper-SDS-R & NR), imaged capillary isoelectric focusing (iCIEF), ion-exchange chromatography (IEC), reverse phase-liquid chromatography (RP-LC), hydrophobic interaction chromatography (HIC), Composition-Gradient Multi-Angle Light Scattering (CG-MALS), differential scanning calorimetry (DSC), enzyme-linked immunosorbent assay (ELISA) based and/or cell based potency, and peptide mapping with mass spectrometry etc.

Results

Remarkably, couple of antibodies co-formulation cases have completed successfully. Take one co-formulation case for instance, specifically, no substantial molecular interactions were observed between the two antibodies according to the results of differential light scattering (DLS) and CG-MALS. Besides, the main peaks of two mAbs were co-eluted in SE-HPLC and Caliper-SDS-NR, respectively. SE-HPLC and Caliper-SDS-NR methods were optimized to evaluate the purity of this co-formulation. As a result, the purity of these two mAbs in this co-formulation was comparable with its individual antibody respectively. Given the isoelectric point of two mAbs in this co-formulation differs by 1.0, iCIEF has been developed to separate the peaks of two mAbs completely. In another case, the isoelectric point of two mAbs differed by just 0.4, CEX has been developed. iCIEF and CEX method were optimized to evaluate the charge variants and determine the concentration ratio of these two mAbs in co-formulation product.
FULLY AI-DRIVEN HUMANOID VHH PHAGE LIBRARY
Authors: Zhao Yangyang , Niu Le , Pan Xuemin , Ye Xingda , Yu Quan , Zhu Yupeng , Chen Yile , Sun Zhiwu , Long Yunfei , Li Yi
Published: July 2023

Background & Significance

VHHs are small and stable fragments that have great potential as therapeutics due to their small size, stability, versatility, and potential for oral administration. The traditional source of VHHs is camelids, but humanization is usually needed for therapeutic development. A human VHH library is highly desirable for the generation of therapeutic VHHs, but natural human VH domains are usually unstable as standalone units. We developed a humanoid VHH library of AI-designed sequences that both resemble camelid VHHs in terms of stability and have such high human content that humanization is no longer needed.

Methods

In this study, we present a fully AI-driven approach for the de novo design of a VHH phage library. Firstly, public camelid data and nearly one million private human sequences were collected. Secondly, one autoregressive AI model was trained on human data and another AI model was trained on the mixed data of humans and camels. Thirdly, the CDR1, CDR2, CDR3 regions of VHH were all generated by the mentioned two AI models. Finally, an ultra large quantity (4E10) of VHH sequences generated by AI were utilized to build the Humanoid VHH phage library.

Results

In order to verify the effectiveness of our method, we randomly synthesized and expressed 26 VHH antibodies from our AI based library. At the same time, 3 human VH molecules reported in previous literature were included as positive controls. First of all, the success rate of expression is 96.1%, which is much higher than 72% of Progen and 66% of ESMdesign. Secondly, the average titer is 59.6mg/L, which is 1.5 times the average value of the positive control group. Thirdly, the hydrophobicity of 80% de novo sequences is comparable to the positive control group. Moreover, the immunogenicity of all AI sequences is less than the average value of the positive control group according to our proprietary algorithms. Finally, the diversity and naturalness of the Humanoid VHH phage library are also excellent.

Conclusions

In conclusion, we have developed a fully AI-driven solution that could stably and massively generate human-like VHH sequences satisfying multiple requirements (including high titer, low hydrophobicity, low immunogenicity and ultra high success rate of expression, high diversity, high naturalness) simultaneously. As VHH is a powerful therapeutic fragment, our approach has the potential to accelerate nanobody and bispecific antibody drug development.
YEAST SURFACE DISPLAY OF FULL-LENGTH IGG FOR ENGINEERING MONOCLONAL AND BISPECIFIC ANTIBODIES
Authors: Jiang Youwei
Published: July 2023

The single-chain variable fragment (scFv) and antigen-binding fragment (Fab) are widely used in yeast surface display for antibody engineering. However, these non-IgG antibody fragments are not always well-expressed or functional. We developed a novel approach to display full-length IgG on yeast surfaces for engineering monoclonal and bispecific antibodies.

The yeast surface display of full-length IgG was generated by transforming glycoengineered yeast P. pastoris with plasmids encoding for anchor protein, heavy chains, and light chains. IgG-displaying yeast cells were incubated with the fluorophore antigen and secondary detection antibody for FACS sorting. The displayed antibody with bound antigen and detection antibody was detected by FACS sorting based on both antibody affinity and display level. FACS sorting could eliminate the deviation caused by expression levels. The yeast surface display of IgG-like bispecific antibodies was also constructed, which exhibited specific binding of two distinct fluorophore antigens in flow-cytometry analysis. Thus, our yeast surface display of full-length IgG can be used to screen light chain libraries to isolate common light chains for bispecific antibodies.

To assess antigen-binding efficiency between different displaying formats, an antibody was respectively displayed as full-length IgG or Fab on the surface of yeast cells for flow-cytometry analysis. Cells displaying full-length IgG showed a higher level of fluorescence than those displaying Fab fragments, indicating that yeast surface display of full-length IgG is superior for high-throughput screening.

To test the specificity of the displayed antibody, we performed a demo experiment in which TNF-binding adalimumab-displaying cells were mixed with trastuzumab-displaying cells at a 1 to 1,000,000 ratio, mimicking the immune library. After three consecutive rounds of sorting, the yeast cells with high fluorescence were plated on a selective medium and the individual antibody clones were sequenced. All ten sequenced clones were confirmed to be adalimumab, demonstrating the maintenance of genotype-phenotype linkage for library screening in yeast surface display of full-length IgG.

A mutation library was also generated from the initial hit and displayed at the surface of yeast cells for the screening of higher affinity maturation antibodies by FACS. A pool of high-affinity binders was plated on a selective medium. Individual clones were analyzed by flow cytometry and sequenced to identify unique antibodies with higher affinity.

In summary, full-length IgG antibodies can be displayed on the yeast cell surface, mimicking their native forms in molecular structure and biophysical properties. The technique combines the high throughput of yeast display with mammalian-cell quality control. This novel approach can be used to engineer monoclonal and bispecific antibodies for high affinity and improved developability profiles.
Do executive functions differentiate Iranian children with attention-deficit/hyperactivity disorder with and without comorbid obesity?
Authors: Parhoon Kamal , Aita Stephen L , Mohammadi Azad , Roth Robert M
Published: July 2023

Objective

To compare multiple dimensions of executive function between children with attention-deficit/hyperactivity disorder (ADHD) with and without comorbid obesity.

Method

Participants were 90 Iranian children (ages 8–13, 50% female) who were equally dispersed across three study groups: typically developing (TD), ADHD with obesity (ADHD+O), and ADHD without obesity (ADHD-O). Study participants were administered a comprehensive battery of Iranian-adapted “cool” executive function tasks including Digit Span from the Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V), Victoria Stroop Test (VST), Wisconsin Card Sorting Test (WCST), Tower of London, and dot-probe task (i.e., a task of attentional bias). Parents completed the Children’s Scale for Future Thinking Questionnaire, which assesses future-oriented cognition (e.g., saving, planning, episodic foresight, delay of gratification), aligning more with “hot” executive functions. Groups were compared using multivariate and post-hoc univariate general linear models.

Results

Significant group effects were observed for all executive function variables, broadly with the gradient pattern of TD > ADHD-O > ADHD+O. ADHD+O had poorer performances than ADHD-O for WISC-V Digit Span (d = −0.84), WCST Categories Completed (d = −0.55) and Perseverative Responses (d = 1.15), VST Interference Errors (d = 0.83) and Interference Time (d = 1.38), and Dot-Probe Task (d = 0.84). Relative to the ADHD-O group, ADHD+O had also poorer parent-reported Prospective Memory (d = −0.62), Episodic Foresight (d = −0.63), and Delay of Gratification (d = −0.54).

Conclusions

Children with ADHD-O have poorer executive functioning than those without obesity. We observed stronger effects for “cool” rather than “hot” domains of executive function, though this could be due to the former being performance-based and the latter parent-reported.
The Emerging Role of Injectable Weight Loss Medications in Plastic Surgery: A Systematic Review
Authors: Shridharani Sachin M , Kohan Joshua
Published: July 2023

Obesity is a multifactorial disease that represents a substantial global health concern. As of 2016, the World Health Organization (WHO) estimated that over 650 million adults were obese, and more than 1.9 billion were overweight. Surgical interventions or lifestyle changes are typically suggested to patients who experience comorbidities as a result of their weight; however, more recently, antidiabetic medications have been proposed, specifically sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs). This is the first systematic review to evaluate the safety, efficacy, and future role of SGLT-2 inhibitors and GLP-1RAs for weight loss in the world of aesthetic plastic surgery. Sixteen randomized controlled trials were identified that met the eligibility criteria for this systematic review and comprised data from 10,492 patients. All studies reported a decline in body weight following treatment with SGLT-2 inhibitors or GLP-1RAs, ranging from 1.5 to 5 kg. Although adverse events were reported in a large proportion of patients, primarily gastrointestinal manifestations, the literature reports that these were mild to moderate in severity and tended to subside following treatment adjustment. Future research is warranted to determine the ideal SGLT-2 inhibitor or GLP-1RA for weight loss management, and additional randomized controlled trials (RCTs) are needed to determine the efficacy and tolerability of potential combination therapies with SGLT-2 inhibitors and GLP-1RAs.

Level of Evidence: 3
quickBAM: a parallelized BAM file access API for high-throughput sequence analysis informatics
Authors: Pitman Anders , Huang Xiaomeng , Marth Gabor T , Qiao Yi
Published: July 2023

Motivation

In time-critical clinical settings, such as precision medicine, genomic data needs to be processed as fast as possible to arrive at data-informed treatment decisions in a timely fashion. While sequencing throughput has dramatically increased over the past decade, bioinformatics analysis throughput has not been able to keep up with the pace of computer hardware improvement, and consequently has now turned into the primary bottleneck. Modern computer hardware today is capable of much higher performance than current genomic informatics algorithms can typically utilize, therefore presenting opportunities for significant improvement of performance. Accessing the raw sequencing data from BAM files, e.g. is a necessary and time-consuming step in nearly all sequence analysis tools, however existing programming libraries for BAM access do not take full advantage of the parallel input/output capabilities of storage devices.

Results

In an effort to stimulate the development of a new generation of faster sequence analysis tools, we developed quickBAM, a software library to accelerate sequencing data access by exploiting the parallelism in commodity storage hardware currently widely available. We demonstrate that analysis software ported to quickBAM consistently outperforms their current versions, in some cases finishing an analysis in under 3 min while the original version took 1.5 h, using the same storage solution.

Availability and implementation

Open source and freely available at https://gitlab.com/yiq/quickbam/, we envision that quickBAM will enable a new generation of high-performance informatics tools, either directly boosting their performance if they are currently data-access bottlenecked, or allow data-access to keep up with further optimizations in algorithms and compute techniques.
Association of atrial fibrillation with survival in patients with low-flow low-gradient aortic stenosis with preserved ejection fraction undergoing TAVI
Authors: Nakase Masaaki , Tomii Daijiro , Heg Dik , Praz Fabien , Stortecky Stefan , Lanz Jonas , Reineke David , Windecker Stephan , Pilgrim Thomas
Published: July 2023

Aims

There is limited evidence on the prognostic significance of atrial fibrillation (AF) in patients with low flow, low-gradient aortic stenosis with preserved ejection fraction (LFLG-pEF AS). We aimed to evaluate the recovery of stroke volume after transcatheter aortic valve implantation (TAVI) and clinical outcomes in patients with LFLG-pEF AS stratified by presence or absence of AF.

Methods and results

In a prospective TAVI registry, patients with preserved left ventricular ejection fraction (LVEF ≥ 50%) were stratified according to flow-gradient status and presence of AF. Among 2259 TAVI patients with preserved LVEF between August 2007 and June 2021, 765 had high-gradient AS (HG AS) and 444 had LFLG-pEF AS. AF was observed in 199 patients with HG AS (26.0%) and 190 patients with LFLG-pEF AS (42.8%). At 1 year, stroke volume index (SVi) was significantly improved in LFLG-pEF AS patients without AF, while SVi remained low in patients with AF (from 25.9 ± 8.5 mL/m2 to 37.2 ± 9.9 mL/m2 and from 26.8 ± 5.1 mL/m2 to 26.1 ± 9.1 mL/m2, respectively). LFLG-pEF AS patients with AF had an increased risk of 1-year all-cause mortality compared with those without AF (adjusted hazard ratio (HRadjusted) 2.57; 95% confidence interval [CI] 1.44–4.59). LFLG-pEF AS patients without AF had similar mortality compared with HG AS patients without AF (HRadjusted 0.85; 95% CI 0.49–1.46).

Conclusion

Patients with LFLG-pEF AS and AF experienced no relevant recovery of stroke volume after TAVI, but a more than two-fold increased risk of death compared to patients with HG AS or LFLG-pEF AS without AF.

Clinical Trial Registration

https://www.clinicaltrials.gov. NCT01368250.
The Forward-Looking Effect of Increasing the Full Retirement Age
Authors: Carta Francesca , De Philippis Marta
Published: July 2023

This paper analyses the effects of increasing the statutory retirement age for claiming full pension benefits on the labour force participation of middle-aged individuals and their partners. Identification relies on a difference-in-differences setting that exploits the heterogeneous increase in age eligibility for retirement caused by an unexpected pension reform. We detect a rise in the participation rate of middle-aged women that spills over into the labour supply of their husbands, who choose to postpone their retirement. The overall labour supply response has important implications for the extent of the fiscal externality associated with pension reforms that increase the retirement age.
PCR-based gene targeting in Hanseniaspora uvarum
Authors: Badura Jennifer , van Wyk Niël , Zimmer Kerstin , Pretorius Isak S , von Wallbrunn Christian , Wendland Jürgen
Published: July 2023

Lack of gene-function analyses tools limits studying the biology of Hanseniaspora uvarum, one of the most abundant yeasts on grapes and in must. We investigated a rapid PCR-based gene targeting approach for one-step gene replacement in this diploid yeast. To this end, we generated and validated two synthetic antibiotic resistance genes, pFA-hygXL and pFA-clnXL, providing resistance against hygromycin and nourseothricin, respectively, for use with H. uvarum. Addition of short flanking-homology regions of 56–80 bp to these selection markers via PCR was sufficient to promote gene targeting. We report here the deletion of the H. uvarum LEU2 and LYS2 genes with these marker genes via two rounds of consecutive transformations, each resulting in the generation of auxotrophic strains (leu2/leu2; lys2/lys2). The hereby constructed leucine auxotrophic leu2/leu2 strain was subsequently complemented in a targeted manner, thereby further validating this approach. PCR-based gene targeting in H. uvarum was less efficient than in Saccharomyces cerevisiae. However, this approach, combined with the availability of two marker genes, provides essential tools for directed gene manipulations in H. uvarum.
Computational Modeling of Substrate-Dependent Mitochondrial Respiration and Bioenergetics in the Heart and Kidney Cortex and Outer Medulla
Authors: Sadri Shima , Zhang Xiao , Audi Said H , Cowley Jr. Allen W , Dash Ranjan K
Published: July 2023

Integrated computational modeling provides a mechanistic and quantitative framework to characterize alterations in mitochondrial respiration and bioenergetics in response to different metabolic substrates in-silico. These alterations play critical roles in the pathogenesis of diseases affecting metabolically active organs such as heart and kidney. Therefore, the present study aimed to develop and validate thermodynamically constrained integrated computational models of mitochondrial respiration and bioenergetics in the heart and kidney cortex and outer medulla (OM). The models incorporated the kinetics of major biochemical reactions and transport processes as well as regulatory mechanisms in the mitochondria of these tissues. Intrinsic model parameters such as Michaelis–Menten constants were fixed at previously estimated values, while extrinsic model parameters such as maximal reaction and transport velocities were estimated separately for each tissue. This was achieved by fitting the model solutions to our recently published respirometry data measured in isolated rat heart and kidney cortex and OM mitochondria utilizing various NADH- and FADH2-linked metabolic substrates. The models were validated by predicting additional respirometry and bioenergetics data, which were not used for estimating the extrinsic model parameters. The models were able to predict tissue-specific and substrate-dependent mitochondrial emergent metabolic system properties such as redox states, enzyme and transporter fluxes, metabolite concentrations, membrane potential, and respiratory control index under diverse physiological and pathological conditions. The models were also able to quantitatively characterize differential regulations of NADH- and FADH2-linked metabolic pathways, which contribute differently toward regulations of oxidative phosphorylation and ATP synthesis in the heart and kidney cortex and OM mitochondria.
Modeling Recombination Rate as a Quantitative Trait Reveals New Insight into Selection in Humans
Authors: Drury Austin L , Gout Jean-Francois , Dapper Amy L
Published: July 2023

Meiotic recombination is both a fundamental biological process required for proper chromosomal segregation during meiosis and an important genomic parameter that shapes major features of the genomic landscape. However, despite the central importance of this phenotype, we lack a clear understanding of the selective pressures that shape its variation in natural populations, including humans. While there is strong evidence of fitness costs of low rates of recombination, the possible fitness costs of high rates of recombination are less defined. To determine whether a single lower fitness bound can explain the variation in recombination rates observed in human populations, we simulated the evolution of recombination rates as a sexually dimorphic quantitative trait. Under each scenario, we statistically compared the resulting trait distribution with the observed distribution of recombination rates from a published study of the Icelandic population. To capture the genetic architecture of recombination rates in humans, we modeled it as a moderately complex trait with modest heritability. For our fitness function, we implemented a hyperbolic tangent curve with several flexible parameters to capture a wide range of existing hypotheses. We found that costs of low rates of recombination alone are likely insufficient to explain the current variation in recombination rates in both males and females, supporting the existence of fitness costs of high rates of recombination in humans. With simulations using both upper and lower fitness boundaries, we describe a parameter space for the costs of high recombination rates that produces results consistent with empirical observations.
Dynamics of nucleic acid mobility
Authors: Singh Shailja , Hu Xinyi , Dixelius Christina
Published: July 2023

Advances in sequencing technologies and bioinformatic analyses are accelerating the quantity and quality of data from all domains of life. This rich resource has the potential to reveal a number of important incidences with respect to possible exchange of nucleic acids. Ancient events have impacted species evolution and adaptation to new ecological niches. However, we still lack a full picture of processes ongoing within and between somatic cells, gametes, and different organisms. We propose that events linked to acceptance of alien nucleic acids grossly could be divided into 2 main routes in plants: one, when plants are exposed to extreme challenges and, the second level, a more everyday or season-related stress incited by biotic or abiotic factors. Here, many events seem to comprise somatic cells. Are the transport and acceptance processes of alien sequences random or are there specific regulatory systems not yet fully understood? Following entrance into a new cell, a number of intracellular processes leading to chromosomal integration and function are required. Modification of nucleic acids and possibly exchange of sequences within a cell may also occur. Such fine-tune events are most likely very common. There are multiple questions that we will discuss concerning different types of vesicles and their roles in nucleic acid transport and possible intracellular sequence exchange between species.
Cannabis sativa: origin and history, glandular trichome development, and cannabinoid biosynthesis
Authors: Xie Ziyan , Mi Yaolei , Kong Lingzhe , Gao Maolun , Chen Shanshan , Chen Weiqiang , Meng Xiangxiao , Sun Wei , Chen Shilin , Xu Zhichao
Published: July 2023

Is Cannabis a boon or bane? Cannabis sativa has long been a versatile crop for fiber extraction (industrial hemp), traditional Chinese medicine (hemp seeds), and recreational drugs (marijuana). Cannabis faced global prohibition in the twentieth century because of the psychoactive properties of ∆9-tetrahydrocannabinol; however, recently, the perspective has changed with the recognition of additional therapeutic values, particularly the pharmacological potential of cannabidiol. A comprehensive understanding of the underlying mechanism of cannabinoid biosynthesis is necessary to cultivate and promote globally the medicinal application of Cannabis resources. Here, we comprehensively review the historical usage of Cannabis, biosynthesis of trichome-specific cannabinoids, regulatory network of trichome development, and synthetic biology of cannabinoids. This review provides valuable insights into the efficient biosynthesis and green production of cannabinoids, and the development and utilization of novel Cannabis varieties.
What Does Queer IR Want? A Queer Psychoanalytic Critique
Authors: Valle Luiz
Published: July 2023

This article presents a sympathetic critique of the concept of “queer” operative in the subfield of Queer International Relations from a psychoanalytic perspective. I first reconstruct queer International Relations (IR) in relation to disciplinary IR and queer theory, and offer an appraisal of the current state of the field's division between LGBT+ theorists and queer theorists. I then consider Cynthia Weber’s recent work and suggest that the boundary between the two camps of queer IR is precarious in that both require and presuppose an opposition to some concept of the straight world. I suggest that, thus construed, the form of the queer/straight distinction approximates that of the mirror stage Jacques Lacan theorized in the 1930s. Read through Lacan, the notion of “queer” in queer IR can be shown to reduce the concept of desire to that of identity, which precludes understanding of the political import of queerness in respect of the LGBT+ group. Finally, I apply the Freudian–Lacanian reflection on narcissism, group formation, and desire to the debate on LGBT+ rights, and conclude that attending to the Lacanian concept of pure desire (via queer readings of Antigone) may be productive for queer IR's rethinking of the deadlocks it has run into in its brief history.
Beyond “Sing Hallelujah to the Lord”: Diffused Religion and Religious Co-Optations in Hong Kong
Authors: Guo Ting
Published: July 2023

Most discussions on religious activism in Hong Kong focus on Christianity. Building on C. K. Yang’s classic theory of diffused religion, this article first distinguishes Chinese religious institutions from less institutional religious practices and expressions and argues beyond this popular assumption and representation of Christianity by considering elements of Buddhism, Daoism, and Chinese folk religions in recent activism, revealing a more complex religious ecology. Second, this paper uncovers a longer historical trajectory whereby colonial forces attempted to co-opt Christianity to legitimize their power, which explains why assumptions concerning Christian domination exist in the first place. Furthermore, colonial policies, Cold War politics, and Chinese regimes have all co-opted institutional religious elites in Hong Kong for ideological purposes, resulting in institutional Chinese religions in Hong Kong, such as Buddhism and Daoism, being connected with the Chinese Communist Party, whereas the linkage between Christianity and liberty is reinforced. At the same time, without secularizing forces from Mainland China, religions in Hong Kong, including Christianity, institutional Chinese religions, and less institutional folk religions, have all diffused into secular institutions and with each other, contributing to the foundation of the Chinese community in the past and the pursuit of democracy, justice, and freedom today on a grassroots, non-institutional level. In this way, this article not only offers critical insight into the role of religion in Hong Kong activism and the often neglected history of religious co-optations under British colonialism and in the Cold War but also provides a theoretical contribution in terms of furthering our understanding of the relationship among religious institutions, state apparatuses, and diffused religion on the ground.
A genome assembly for the southern Pacific rattlesnake, Crotalus oreganus helleri, in the western rattlesnake species complex
Authors: Westeen Erin P , Escalona Merly , Holding Matthew L , Beraut Eric , Fairbairn Colin , Marimuthu Mohan P A , Nguyen Oanh , Perri Ralph , Fisher Robert N , Toffelmier Erin , Shaffer H Bradley , Wang Ian J
Published: July 2023

Rattlesnakes play important roles in their ecosystems by regulating prey populations, are involved in complex coevolutionary dynamics with their prey, and exhibit a variety of unusual adaptations, including maternal care, heat-sensing pit organs, hinged fangs, and medically-significant venoms. The western rattlesnake (Crotalus oreganus) is one of the widest ranging rattlesnake species, with a distribution from British Columbia, where it is listed as threatened, to Baja California and east across the Great Basin to western Wyoming, Colorado and New Mexico. Here, we report a new reference genome assembly for one of six currently recognized subspecies, C. oreganus helleri, as part of the California Conservation Genomics Project (CCGP). Consistent with the reference genomic sequencing strategy of the CCGP, we used Pacific Biosciences HiFi long reads and Hi-C chromatin-proximity sequencing technology to produce a de novo assembled genome. The assembly comprises a total of 698 scaffolds spanning 1,564,812,557 base pairs, has a contig N50 of 64.7 Mb, a scaffold N50 of 110.8 Mb, and BUSCO complete score of 90.5%. This reference genome will be valuable for studies on the genomic basis of venom evolution and variation within Crotalus, in resolving the taxonomy of C. oreganus and its relatives, and for the conservation and management of rattlesnakes in general.
2021 Elizabeth Colson Lecture, Refugee Studies Centre, Oxford
Authors: Cabot Heath
Published: July 2023

This article features a long-term refugee in Greece who decided to return to his home country in the face of severe illness. I ask what his illness and treatment in Greece, and ultimately his return to Sudan, reveal about protection regimes: as he sought care, respite from pain, and a good—or at least dignified—death. His return enabled him to be among family again, in once-familiar places, and to be laid to rest among ancestors. Yet rather than reading his return as a form of closure or resolution, I probe its afterlives: the frayed, tangled, still-unfurling edges of the story, which speak to the ongoing nature of displacement.
Third-Generation Sequencing Reveals the Adaptive Role of the Epigenome in Three Deep-Sea Polychaetes
Authors: Perez Maeva , Aroh Oluchi , Sun Yanan , Lan Yi , Juniper Stanley Kim , Young Curtis Robert , Angers Bernard , Qian Pei-Yuan
Published: July 2023

The roles of DNA methylation in invertebrates are poorly characterized, and critical data are missing for the phylum Annelida. We fill this knowledge gap by conducting the first genome-wide survey of DNA methylation in the deep-sea polychaetes dominant in deep-sea vents and seeps: Paraescarpia echinospica, Ridgeia piscesae, and Paralvinella palmiformis. DNA methylation calls were inferred from Oxford Nanopore sequencing after assembling high-quality genomes of these animals. The genomes of these worms encode all the key enzymes of the DNA methylation metabolism and possess a mosaic methylome similar to that of other invertebrates. Transcriptomic data of these polychaetes support the hypotheses that gene body methylation strengthens the expression of housekeeping genes and that promoter methylation acts as a silencing mechanism but not the hypothesis that DNA methylation suppresses the activity of transposable elements. The conserved epigenetic profiles of genes responsible for maintaining homeostasis under extreme hydrostatic pressure suggest DNA methylation plays an important adaptive role in these worms.
The surgical management of diffuse gliomas: Current state of neurosurgical management and future directions
Authors: Young Jacob S , Morshed Ramin A , Hervey-Jumper Shawn L , Berger Mitchel S
Published: July 2023

After recent updates to the World Health Organization pathological criteria for diagnosing and grading diffuse gliomas, all major North American and European neuro-oncology societies recommend a maximal safe resection as the initial management of a diffuse glioma. For neurosurgeons to achieve this goal, the surgical plan for both low- and high-grade gliomas should be to perform a supramaximal resection when feasible based on preoperative imaging and the patient’s performance status, utilizing every intraoperative adjunct to minimize postoperative neurological deficits. While the surgical approach and technique can vary, every effort must be taken to identify and preserve functional cortical and subcortical regions. In this summary statement on the current state of the field, we describe the tools and technologies that facilitate the safe removal of diffuse gliomas and highlight intraoperative and postoperative management strategies to minimize complications for these patients. Moreover, we discuss how surgical resections can go beyond cytoreduction by facilitating biological discoveries and improving the local delivery of adjuvant chemo- and radiotherapies.