bluuebunny/crossref_metadata_2025 huggingface dataset:
Orchid seeds are not always short lived in a conventional seed bank!
Authors: Francisqueti Ana Maria , Marin Rafael Rubio , Hengling Mariane Marangoni , Hosomi Silvério Takao , Pritchard Hugh W , Custódio Ceci Castilho , Machado-Neto Nelson Barbosa
Published: February 2024

Background and Aims

Orchid seeds are reputed to be short lived in dry, cold storage conditions, potentially limiting the use of conventional seed banks for long-term ex situ conservation. This work explores whether Cattleya seeds are long lived or not during conventional storage (predried to ~12 % relative humidity, then stored at −18 °C).

Methods

We explored the possible interaction of factors influencing seed lifespan in eight species of the genus Cattleya using physiological (germination and vigour), biochemical (gas chromatography), biophysical (differential scanning calorimetry) and morphometric methods. Seeds were desiccated to ~3 % moisture content and stored at −18 °C for more than a decade, and seed quality was measured via three in vitro germination techniques. Tetrazolium staining was also used to monitor seed viability during storage. The morphometric and germination data were subjected to ANOVA and cluster analysis, and seed lifespan was subjected to probit analysis.

Key Results

Seeds of all Cattleya species were found to be desiccation tolerant, with predicted storage lifespans (P50y) of ~30 years for six species and much longer for two species. Cluster analysis showed that the three species with the longest-lived seeds had smaller (9–11 %) airspaces around the embryo. The post-storage germination method impacted the quality assessment; seeds equilibrated at room temperature for 24 h or in 10 % sucrose solution had improved germination, particularly for the seeds with the smallest embryos. Chromatography revealed that the seeds of all eight species were rich in linoleic acid, and differential scanning calorimetry identified a peak that might be auxiliary to selecting long-lived seeds.

Conclusions

These findings show that not all orchids produce seeds that are short lived, and our trait analyses might help to strengthen prediction of seed longevity in diverse orchid species.
Analyses of high spatial resolution datasets identify genes associated with multi-layered secondary cell wall thickening in Pinus bungeana
Authors: Guo Yu , Jiao Lichao , Wang Jie , Ma Lingyu , Lu Yang , Zhang Yonggang , Guo Juan , Yin Yafang
Published: February 2024

Background and Aims

Secondary cell wall (SCW) thickening is a major cellular developmental stage determining wood structure and properties. Although the molecular regulation of cell wall deposition during tracheary element differentiation has been well established in primary growth systems, less is known about the gene regulatory processes involved in the multi-layered SCW thickening of mature trees.

Methods

Using third-generation [long-read single-molecule real-time (SMRT)] and second-generation [short-read sequencing by synthesis (SBS)] sequencing methods, we established a Pinus bungeana transcriptome resource with comprehensive functional and structural annotation for the first time. Using these approaches, we generated high spatial resolution datasets for the vascular cambium, xylem expansion regions, early SCW thickening, late SCW thickening and mature xylem tissues of 71-year-old Pinus bungeana trees.

Key Results

A total of 79 390 non-redundant transcripts, 31 808 long non-coding RNAs and 5147 transcription factors were annotated and quantified in different xylem tissues at all growth and differentiation stages. Furthermore, using this high spatial resolution dataset, we established a comprehensive transcriptomic profile and found that members of the NAC, WRKY, SUS, CESA and LAC gene families are major players in early SCW formation in tracheids, whereas members of the MYB and LBD transcription factor families are highly expressed during late SCW thickening.

Conclusions

Our results provide new molecular insights into the regulation of multi-layered SCW thickening in conifers. The high spatial resolution datasets provided can serve as important gene resources for improving softwoods.
Non-compensable regulation and regulatory expropriation: where is the line?
Authors: Riazantsev Mikhail
Published: February 2024

Having examined the police powers doctrine and clarified expropriation clauses, this study concludes that neither of the two instruments can draw the line between non-compensable regulation and regulatory expropriation in a predictable and consistent manner. The outcome of expropriation cases depends significantly on tribunals’ discretion and their ex post interpretation of State actions. In this paradigm, investors and States cannot assess their risks at the time of investment or regulation. Every decision to invest or to regulate becomes a gamble. There is a need for more objective and clear rules to distinguish expropriation and regulation in international investment law.
FEOpti-ACVP: identification of novel anti-coronavirus peptide sequences based on feature engineering and optimization
Authors: Jiang Jici , Pei Hongdi , Li Jiayu , Li Mingxin , Zou Quan , Lv Zhibin
Published: February 2024

Anti-coronavirus peptides (ACVPs) represent a relatively novel approach of inhibiting the adsorption and fusion of the virus with human cells. Several peptide-based inhibitors showed promise as potential therapeutic drug candidates. However, identifying such peptides in laboratory experiments is both costly and time consuming. Therefore, there is growing interest in using computational methods to predict ACVPs. Here, we describe a model for the prediction of ACVPs that is based on the combination of feature engineering (FE) optimization and deep representation learning. FEOpti-ACVP was pre-trained using two feature extraction frameworks. At the next step, several machine learning approaches were tested in to construct the final algorithm. The final version of FEOpti-ACVP outperformed existing methods used for ACVPs prediction and it has the potential to become a valuable tool in ACVP drug design. A user-friendly webserver of FEOpti-ACVP can be accessed at http://servers.aibiochem.net/soft/FEOpti-ACVP/.
scEVOLVE: cell-type incremental annotation without forgetting for single-cell RNA-seq data
Authors: Zhai Yuyao , Chen Liang , Deng Minghua
Published: February 2024

The evolution in single-cell RNA sequencing (scRNA-seq) technology has opened a new avenue for researchers to inspect cellular heterogeneity with single-cell precision. One crucial aspect of this technology is cell-type annotation, which is fundamental for any subsequent analysis in single-cell data mining. Recently, the scientific community has seen a surge in the development of automatic annotation methods aimed at this task. However, these methods generally operate at a steady-state total cell-type capacity, significantly restricting the cell annotation systems'capacity for continuous knowledge acquisition. Furthermore, creating a unified scRNA-seq annotation system remains challenged by the need to progressively expand its understanding of ever-increasing cell-type concepts derived from a continuous data stream. In response to these challenges, this paper presents a novel and challenging setting for annotation, namely cell-type incremental annotation. This concept is designed to perpetually enhance cell-type knowledge, gleaned from continuously incoming data. This task encounters difficulty with data stream samples that can only be observed once, leading to catastrophic forgetting. To address this problem, we introduce our breakthrough methodology termed scEVOLVE, an incremental annotation method. This innovative approach is built upon the methodology of contrastive sample replay combined with the fundamental principle of partition confidence maximization. Specifically, we initially retain and replay sections of the old data in each subsequent training phase, then establish a unique prototypical learning objective to mitigate the cell-type imbalance problem, as an alternative to using cross-entropy. To effectively emulate a model that trains concurrently with complete data, we introduce a cell-type decorrelation strategy that efficiently scatters feature representations of each cell type uniformly. We constructed the scEVOLVE framework with simplicity and ease of integration into most deep softmax-based single-cell annotation methods. Thorough experiments conducted on a range of meticulously constructed benchmarks consistently prove that our methodology can incrementally learn numerous cell types over an extended period, outperforming other strategies that fail quickly. As far as our knowledge extends, this is the first attempt to propose and formulate an end-to-end algorithm framework to address this new, practical task. Additionally, scEVOLVE, coded in Python using the Pytorch machine-learning library, is freely accessible at https://github.com/aimeeyaoyao/scEVOLVE.
EvoAug-TF: extending evolution-inspired data augmentations for genomic deep learning to TensorFlow
Authors: Yu Yiyang , Muthukumar Shivani , Koo Peter K
Published: February 2024

Deep neural networks (DNNs) have been widely applied to predict the molecular functions of the non-coding genome. DNNs are data hungry and thus require many training examples to fit data well. However, functional genomics experiments typically generate limited amounts of data, constrained by the activity levels of the molecular function under study inside the cell. Recently, EvoAug was introduced to train a genomic DNN with evolution-inspired augmentations. EvoAug-trained DNNs have demonstrated improved generalization and interpretability with attribution analysis. However, EvoAug only supports PyTorch-based models, which limits its applications to a broad class of genomic DNNs based in TensorFlow. Here, we extend EvoAug’s functionality to TensorFlow in a new package, we call EvoAug-TF. Through a systematic benchmark, we find that EvoAug-TF yields comparable performance with the original EvoAug package.

Availability and implementation

EvoAug-TF is freely available for users and is distributed under an open-source MIT license. Researchers can access the open-source code on GitHub (https://github.com/p-koo/evoaug-tf). The pre-compiled package is provided via PyPI (https://pypi.org/project/evoaug-tf) with in-depth documentation on ReadTheDocs (https://evoaug-tf.readthedocs.io). The scripts for reproducing the results are available at (https://github.com/p-koo/evoaug-tf_analysis).
Insular evolution from an archaeological perspective: a case study of Orkney house mouse
Authors: Romaniuk Andrzej A , Renaud Sabrina , Bendrey Robin , Searle Jeremy B , Owen Olwyn , Herman Jeremy
Published: February 2024

Archaeological material adds a temporal dimension to evolutionary studies that is valuable for elucidating long-term population stability and evolutionary shifts for species closely associated with humans. Here, a two-dimensional geometric morphometrics approach on first upper molars was applied to modern and archaeological samples to assess the evolution of house mice in Orkney, an archipelago north of Scotland. Modern populations included localities in Orkney, north Scotland, and France. Two archaeological sites in Orkney represented the Norse period: Birsay Beachview (Mainland) and Tuquoy (Westray) (10th–14th/15th centuries AD). The archaeological specimens were larger than modern specimens from similar settings, suggesting processes leading to a recent decline in the size of Orkney house mice. Molar morphology and associated non-metric traits distinct to the Orkney lineage were already established in the Norse period, as indicated by morphological similarity of the Birsay samples to modern Orkney and north Scotland populations. Stability of human settlement is likely to influence morphological evolution in house mice. The Birsay site, located in Birsay village, which has been inhabited since Norse times, might represent the ancestral house mouse population in Orkney. Tuquoy, a settlement abandoned by the end of the medieval period, provided samples different from modern house mouse populations in Westray and neighbouring isles.
A critique of the use of colour lightness in animal studies
Authors: Lopez Vinicius M , Datto-Liberato Felipe , Gorb Stanislav N , Guillermo-Ferreira Rhainer
Published: February 2024

Colour lightness has received considerable attention owing to its diverse functional aspects, such as in thermoregulation, pathogen resistance, and photoprotection. However, the theoretical basis underlying the function of colour lightness is closely related to melanin pigments. Therefore, here we discuss that neglecting other colour-producing mechanisms may bias interpretation of the results. In general, colour lightness is indiscriminately employed as a measure of melanization. Nevertheless, animals may exhibit colours that derive from several pigmentary and structural mechanisms other than melanin. Our primary argument is that colour lightness should not be used indiscriminately before knowing the colour-producing mechanism and validating correlated physiological parameters. For instance, the use of colour lightness as a proxy for thermal or photoprotection function must be validated for pterins, ommochromes, and structural colours.
Robust data integration from multiple external sources for generalized linear models with binary outcomes
Authors: Choi Kyuseong , Taylor Jeremy M G , Han Peisong
Published: February 2024

We aim to estimate parameters in a generalized linear model (GLM) for a binary outcome when, in addition to the raw data from the internal study, more than 1 external study provides summary information in the form of parameter estimates from fitting GLMs with varying subsets of the internal study covariates. We propose an adaptive penalization method that exploits the external summary information and gains efficiency for estimation, and that is both robust and computationally efficient. The robust property comes from exploiting the relationship between parameters of a GLM and parameters of a GLM with omitted covariates and from downweighting external summary information that is less compatible with the internal data through a penalization. The computational burden associated with searching for the optimal tuning parameter for the penalization is reduced by using adaptive weights and by using an information criterion when searching for the optimal tuning parameter. Simulation studies show that the proposed estimator is robust against various types of population distribution heterogeneity and also gains efficiency compared to direct maximum likelihood estimation. The method is applied to improve a logistic regression model that predicts high-grade prostate cancer making use of parameter estimates from 2 external models.
A generalized phase 1-2-3 design integrating dose optimization with confirmatory treatment comparison
Authors: Zang Yong , Thall Peter F , Yuan Ying
Published: February 2024

A generalized phase 1-2-3 design, Gen 1-2-3, that includes all phases of clinical treatment evaluation is proposed. The design extends and modifies the design of Chapple and Thall (2019), denoted by CT. Both designs begin with a phase 1-2 trial including dose acceptability and optimality criteria, and both select an optimal dose for phase 3. The Gen 1-2-3 design has the following key differences. In stage 1, it uses phase 1-2 criteria to identify a set of candidate doses rather than 1 dose. In stage 2, which is intermediate between phase 1-2 and phase 3, it randomizes additional patients fairly among the candidate doses and an active control treatment arm and uses survival time data from both stage 1 and stage 2 patients to select an optimal dose. It then makes a Go/No Go decision of whether or not to conduct phase 3 based on the predictive probability that the selected optimal dose will provide a specified substantive improvement in survival time over the control. A simulation study shows that the Gen 1-2-3 design has desirable operating characteristics compared to the CT design and 2 conventional designs.
Group work enhances student performance in biology: A meta-analysis
Authors: Driessen Emily P , Wilson Alan E , Hall Ian , Brewer Peyton , Odom Sara , Ramsey Sara Beth , Wood Sara , Ballen Cissy J
Published: February 2024

We conducted a meta-analysis to test the impacts of one active learning teaching strategy, group work, on student performance by calculating estimates across 91 studies from 53 articles. Our overall estimate indicates that the implementation of group work in biology classrooms increased student performance by 1.00 standard deviation, which we contextualized as a change greater than one letter grade. Moderator analyses revealed that this increase in performance held across all group sizes, class sizes, biology and life science majors and nonmajors, and whether the groups were assigned by the instructor. However, we did not observe increased performance in graduate level courses, in cases where group work was incorporated for only part of the course term (e.g., less than a semester or quarter) or when the group work was not graded. These results demonstrate that group work leads to impressive boosts in student performance and underscores the value of studying specific active learning strategies.
A Bayesian approach for investigating the pharmacogenetics of combination antiretroviral therapy in people with HIV
Authors: Jin Wei , Ni Yang , Spence Amanda B , Rubin Leah H , Xu Yanxun
Published: February 2024

Combination antiretroviral therapy (ART) with at least three different drugs has become the standard of care for people with HIV (PWH) due to its exceptional effectiveness in viral suppression. However, many ART drugs have been reported to associate with neuropsychiatric adverse effects including depression, especially when certain genetic polymorphisms exist. Pharmacogenetics is an important consideration for administering combination ART as it may influence drug efficacy and increase risk for neuropsychiatric conditions. Large-scale longitudinal HIV databases provide researchers opportunities to investigate the pharmacogenetics of combination ART in a data-driven manner. However, with more than 30 FDA-approved ART drugs, the interplay between the large number of possible ART drug combinations and genetic polymorphisms imposes statistical modeling challenges. We develop a Bayesian approach to examine the longitudinal effects of combination ART and their interactions with genetic polymorphisms on depressive symptoms in PWH. The proposed method utilizes a Gaussian process with a composite kernel function to capture the longitudinal combination ART effects by directly incorporating individuals’ treatment histories, and a Bayesian classification and regression tree to account for individual heterogeneity. Through both simulation studies and an application to a dataset from the Women’s Interagency HIV Study, we demonstrate the clinical utility of the proposed approach in investigating the pharmacogenetics of combination ART and assisting physicians to make effective individualized treatment decisions that can improve health outcomes for PWH.
A multicentre randomized double-blind placebo-controlled phase III study of the efficacy and safety of xeligekimab (GR1501) in patients with moderate-to-severe plaque psoriasis
Authors: Cai Lin , Jiang Congjun , Zhang Guoqiang , Fang Hong , Wang Jinyan , Li Yumei , Xu Hui , Xiao Rong , Ding Yangfeng , Huang Kun , Zhang Chunlei , Zhang Litao , Chen Bin , Duan Xinsuo , Pan Weili , Han Guangming , Chen Rongyi , Liu Lunfei , Zhang Shoumin , Tao Juan , Pang Xiaowen , Yu Jianbin , Wang Huiping , Zhao Yi , Li Chengxin , Kang Xiaojing , Qin Lanying , Zhu Xiaofang , Su Juan , Li Shanshan , Yang Chunjun , Feng Wenli , Lei Tiechi , Jiang Shan , Fang Ruihua , Lin Mao , Lu Qianjin , Xu Chunxing , Wang Wei , Zhang Jianzhong
Published: February 2024

Background

Xeligekimab (GR1501) is a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A and has shown potential efficacy in treating moderate-to-severe psoriasis in preliminary trials.

Objectives

To evaluate the efficacy and safety of xeligekimab in Chinese patients with moderate-to-severe psoriasis.

Methods

A total of 420 Chinese patients were randomized to 200 mg xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by an extension of the treatment schedule to xeligekimab every 4 weeks for a further 40 weeks. Efficacy was assessed by evaluating achievement of Physician Global Assessment (PGA) 0/1 and 75%, 90% and 100% improvement in Psoriasis Area and Severity Index (PASI 75, PASI 90 and PASI 100, respectively). The safety profile was also evaluated.

Results

At week 12, PASI 75, PASI 90 and PASI 100 were achieved in 90.7%, 74.4% and 30.2% of patients in the xeligekimab group vs. 8.6%, 1.4% and 0% of patients in the placebo group, respectively. PGA 0/1 was achieved in 74.4% patients in the xeligekimab group and 3.6% of patients in the placebo group. PASI 75 and PGA 0/1 were maintained until week 52. No unexpected adverse events were recorded.

Conclusions

Xeligekimab showed high efficacy and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.
Acceptability of ‘as needed’ biologic therapy in psoriasis: insights from a multistakeholder mixed-methods study
Authors: Gleeson David , Naveed Maneeha , Moorhead Lucy , McAteer Helen , Sewell Georgia , McGuire Arlene , Weinman John , Barker Jonathan N W N , Norton Sam , Chapman Sarah C E , Smith Catherine H , Mahil Satveer K
Published: February 2024

Background

Biologic therapies have led to increasing numbers of patients with psoriasis who have clear or nearly clear skin. It is current practice to continue biologic therapy indefinitely in these patients, which contributes to a substantial long-term drug and healthcare burden. ‘As needed’ biologic therapy in psoriasis may address this; however, our understanding of patient and clinician perceptions of this strategy is limited.

Objectives

The aim of this mixed-methods study was to gain insight into the perspectives of both patients and clinicians regarding the acceptability of an ‘as needed’ approach to biologic therapy in psoriasis, including potential barriers and enablers to implementation in routine care.

Methods

We first conducted UK-wide online scoping surveys of patients with psoriasis and dermatology clinicians to explore their views on ‘as needed’ biologic therapy. Using topic guides informed by these survey findings, we then carried out qualitative focus groups with patients and clinicians. Themes were identified using reflexive thematic analysis.

Results

Of 67 patients and 27 clinicians completing the scoping surveys, 67% (43 of 64 patients) and 78% (21 of 27 clinicians) supported the use of ‘as needed’ biologic therapy, respectively. Respondents highlighted advantages such as a reduction in healthcare burden and greater ownership of care. Challenges included logistics of ‘as needed’ drug provision and potential risks of disease flare and drug immunogenicity. Focus groups comprised 15 patients with psoriasis [9 female patients (60%), average disease duration 32 years (range 9–64)] and 9 dermatology clinicians [8 female clinicians (89%), average dermatology experience 20 years (range 8–33)]. Both patients and clinicians felt that an ‘as needed’ treatment approach will deliver a reduction in treatment burden and present an opportunity for patient-led ownership of care. Both groups highlighted the importance of ensuring ongoing access to medication and discussing the potential impact of psoriasis recurrence. Patient preferences were influenced by their lived experiences, particularly previous difficulties with medication delivery logistics and establishing disease control. Clinician perspectives were informed by personal experience of their patients adapting their own dosing schedules. Clinicians highlighted the importance of targeted patient selection for an ‘as needed’ approach, ongoing disease monitoring, and prompt reaccess to medications upon psoriasis recurrence.

Conclusions

These data indicate that ‘as needed’ biologic therapy in psoriasis is acceptable for both patients and clinicians. Formal assessment of clinical effectiveness and cost-effectiveness is warranted to enable the real-world potential of this approach to be realized.
Clinical efficacy of motion-insensitive imaging technique with deep learning reconstruction to improve image quality in cervical spine MR imaging
Authors: Song You Seon , Lee In Sook , Hwang Moonjung , Jang Kyoungeun , Wang Xinzeng , Fung Maggie
Published: February 2024

Objective

To demonstrate that a T2 periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) technique using deep learning reconstruction (DLR) will provide better image quality and decrease image noise.

Methods

From December 2020 to March 2021, 35 patients examined cervical spine MRI were included in this study. Four sets of images including fast spin echo (FSE), original PROPELLER, PROPELLER DLR50%, and DLR75% were quantitatively and qualitatively reviewed. We calculated the signal-to-noise ratio (SNR) of the spinal cord and sternocleidomastoid (SCM) muscle and the contrast-to-noise ratio (CNR) of the spinal cord by applying region-of-interest at the spinal cord, SCM muscle, and background air. We evaluated image noise with regard to the spinal cord, SCM, and back muscles at each level from C2-3 to C6-7 in the 4 sets.

Results

At all disc levels, the mean SNR values for the spinal cord and SCM muscles were significantly higher in PROPELLER DLR50% and DLR75% compared to FSE and original PROPELLER images (P < .0083). The mean CNR values of the spinal cord were significantly higher in PROPELLER DLR50% and DLR75% compared to FSE at the C3-4 and 4-5 levels and PROPELLER DLR75% compared to FSE at the C6-7 level (P < .0083). Qualitative analysis of image noise on the spinal cord, SCM, and back muscles showed that PROPELLER DLR50% and PROPELLER DLR75% images showed a significant denoising effect compared to the FSE and original PROPELLER images.

Conclusion

The combination of PROPELLER and DLR improved image quality with a high SNR and CNR and reduced noise.

Advances in knowledge

Motion-insensitive imaging technique (PROPELLER) increased the image quality compared to conventional FSE images. PROPELLER technique with a DLR reduced image noise and improved image quality.
Differentiation of acute coronary syndrome with radiomics of pericoronary adipose tissue
Authors: Jing Mengyuan , Xi Huaze , Sun Jianqing , Zhu Hao , Deng Liangna , Han Tao , Zhang Bin , Zhang Yuting , Zhou Junlin
Published: February 2024

Objective

To assess the potential values of radiomics signatures of pericoronary adipose tissue (PCAT) in identifying patients with acute coronary syndrome (ACS).

Methods

In total, 149, 227, and 244 patients were clinically diagnosed with ACS, chronic coronary syndrome (CCS), and without coronary artery disease (CAD), respectively, and were retrospectively analysed and randomly divided into training and testing cohorts at a 2:1 ratio. From the PCATs of the proximal left anterior descending branch, left circumflex branch, and right coronary artery (RCA), the pericoronary fat attenuation index (FAI) value and radiomics signatures were calculated, among which features closely related to ACS were screened out. The ACS differentiation models AC1, AC2, AC3, AN1, AN2, and AN3 were constructed based on the FAI value of RCA and the final screened out first-order and texture features, respectively.

Results

The FAI values were all higher in patients with ACS than in those with CCS and no CAD (all P < .05). For the identification of ACS and CCS, the area-under-the-curve (AUC) values of AC1, AC2, and AC3 were 0.92, 0.94, and 0.91 and 0.91, 0.86, and 0.88 in the training and testing cohorts, respectively. For the identification of ACS and no CAD, the AUC values of AN1, AN2, and AN3 were 0.95, 0.94, and 0.94 and 0.93, 0.87, and 0.89 in the training and testing cohorts, respectively.

Conclusions

Identification models constructed based on the radiomics signatures of PCAT are expected to be an effective tool for identifying patients with ACS.

Advances in knowledge

The radiomics signatures of PCAT and FAI values are expected to differentiate between patients with ACS, CCS and those without CAD on imaging.
Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study
Authors: Millar Vernetti Patricio , Norcliffe-Kaufmann Lucy , Palma Jose-Alberto , Biaggioni Italo , Shibao Cyndya A , Peltier Amanda , Freeman Roy , Gibbons Christopher , Goldstein David S , Low Phillip A , Singer Wolfgang , Coon Elizabeth A , Miglis Mitchell G , Wenning Gregor K , Fanciulli Alessandra , Vernino Steven , Betensky Rebecca A , Kaufmann Horacio
Published: February 2024

We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain.

Patients diagnosed with PAF were evaluated at eight centres (seven US-based and one European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features.

A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3–10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB and 23% to MSA). Faster phenoconversion from study enrolment to any diagnosis was associated with urinary and sexual dysfunction [hazard ratio (HR) 5.9, 95% confidence interval (CI): 1.6–22 and HR: 3.6, 95% CI: 1.1–12] followed by subtle motor signs (HR: 2.7, 95% CI: 1.2–6), trouble swallowing (HR 2.5, 95% CI: 1.4–4.5) and changes in speech (HR:2.4, 95% CI:1.1–4.8) at enrolment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95% CI: 1.1–5.9) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95% CI: 1.2–38). Patients with a younger age of PAF onset (HR: 11, 95% CI: 2.6–46), preserved olfaction (HR: 8.7, 95% CI: 1.7–45), anhidrosis (HR: 1.8, 95% CI: 1–3.1, P = 0.042) and severe urinary problems (HR 1.6, 95% CI: 1–2.5, P = 0.033) were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95% CI: 1.4–26).

Patients with PAF have an estimated 12% (95% CI: 9–15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.
Anatomo-functional basis of emotional and motor resonance elicited by facial expressions
Authors: Del Vecchio Maria , Avanzini Pietro , Gerbella Marzio , Costa Sara , Zauli Flavia Maria , d’Orio Piergiorgio , Focacci Elena , Sartori Ivana , Caruana Fausto
Published: February 2024

Simulation theories predict that the observation of other’s expressions modulates neural activity in the same centres controlling their production. This hypothesis has been developed by two models, postulating that the visual input is directly projected either to the motor system for action recognition (motor resonance) or to emotional/interoceptive regions for emotional contagion and social synchronization (emotional resonance). Here we investigated the role of frontal/insular regions in the processing of observed emotional expressions by combining intracranial recording, electrical stimulation and effective connectivity.

First, we intracranially recorded from prefrontal, premotor or anterior insular regions of 44 patients during the passive observation of emotional expressions, finding widespread modulations in prefrontal/insular regions (anterior cingulate cortex, anterior insula, orbitofrontal cortex and inferior frontal gyrus) and motor territories (Rolandic operculum and inferior frontal junction). Subsequently, we electrically stimulated the activated sites, finding that (i) in the anterior cingulate cortex and anterior insula, the stimulation elicited emotional/interoceptive responses, as predicted by the ‘emotional resonance model’; (ii) in the Rolandic operculum it evoked face/mouth sensorimotor responses, in line with the ‘motor resonance’ model; and (iii) all other regions were unresponsive or revealed functions unrelated to the processing of facial expressions. Finally, we traced the effective connectivity to sketch a network-level description of these regions, finding that the anterior cingulate cortex and the anterior insula are reciprocally interconnected while the Rolandic operculum is part of the parieto-frontal circuits and poorly connected with the former.

These results support the hypothesis that the pathways hypothesized by the ‘emotional resonance’ and the ‘motor resonance’ models work in parallel, differing in terms of spatio-temporal fingerprints, reactivity to electrical stimulation and connectivity patterns.
HSV-1 reactivation results in post-herpetic neuralgia by upregulating Prmt6 and inhibiting cGAS-STING
Authors: Kong Erliang , Hua Tong , Li Jian , Li Yongchang , Yang Mei , Ding Ruifeng , Wang Haowei , Wei Huawei , Feng Xudong , Han Chaofeng , Yuan Hongbin
Published: February 2024

Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of post-herpetic neuralgia (PHN). The immune escape mechanism of VZV remains elusive. As to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well established PHN mice model.

Transcriptional expression analysis identified that the protein arginine methyltransferases 6 (Prmt6) was upregulated upon HSV-1 infection, which was further confirmed by immunofluorescence staining in spinal dorsal horn. Prmt6 deficiency decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load in vivo and in vitro. Overexpression of Prmt6 in microglia dampened antiviral innate immunity and increased HSV-1 load. Mechanistically, Prmt6 methylated and inactivated STING, resulting in reduced phosphorylation of TANK binding kinase-1 (TBK1) and interferon regulatory factor 3 (IRF3), diminished production of type I interferon (IFN-I) and antiviral innate immunity. Furthermore, intrathecal or intraperitoneal administration of the Prmt6 inhibitor EPZ020411 decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load.

Our findings revealed that HSV-1 escapes antiviral innate immunity and results in PHN by upregulating Prmt6 expression and inhibiting the cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN.
Dementia risk and thalamic nuclei volumetry in healthy midlife adults: the PREVENT Dementia study
Authors: Shah Sita N , Dounavi Maria-Eleni , Malhotra Paresh A , Lawlor Brian , Naci Lorina , Koychev Ivan , Ritchie Craig W , Ritchie Karen , O’Brien John T
Published: February 2024

A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer’s disease, mild cognitive impairment and asymptomatic individuals with risk factors for early-onset Alzheimer’s disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition. Seven hundred participants aged 40–59 years were recruited into the PREVENT Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3 T MRI scans using FreeSurfer 7.1.0. Thalamic nuclei were grouped into six regions: (i) anterior, (ii) lateral, (iii) ventral, (iv) intralaminar, (v) medial and (vi) posterior. Cognitive performance was evaluated using the computerized assessment of the information-processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate correction for multiple comparisons. We did not find significant volumetric differences in the thalamus or its subregions, which survived false discovery rate correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without a dementia family history. A larger volume of the mediodorsal medial nucleus (Pfalse discovery rate = 0.019) was associated with a faster processing speed in those without a dementia family history. Larger volumes of the thalamus (P = 0.016) and posterior thalamus (Pfalse discovery rate = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein ε4 allele carriers. We did not find significant volumetric differences in thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without a dementia family history but have little effect on those with a dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein ε4 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis.
Brain dynamics predictive of response to psilocybin for treatment-resistant depression
Authors: Vohryzek Jakub , Cabral Joana , Lord Louis-David , Fernandes Henrique M , Roseman Leor , Nutt David J , Carhart-Harris Robin L , Deco Gustavo , Kringelbach Morten L
Published: February 2024

Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression—to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a healthy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-hydroxytryptamine 2a and 5-hydroxytryptamine 1a, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression, and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.
Development of a β-lactamase activity assay for detecting ligand–protein interactions using an engineered split intein and β-lactamase
Authors: Hagiwara Hiroaki , Fujii Eriho , Iwabuchi Taisei , Takahashi Tsuyoshi
Published: February 2024

Several synthetic compounds bind to proteins of interest and inhibit protein–protein interactions. To develop a detection method for the interactions between the synthetic compounds and the target proteins, we used an engineered split intein derived from Nostoc punctiforme PCC73102 (Npu) DnaE and TEM-1 β-lactamase as reporter proteins. We constructed synthetic ligands bearing a 6-residue C-terminal peptide from Npu DnaE and Cys-Trp as the C-extein, and target proteins bearing the N-terminal region of the engineered Npu DnaE and residues 24–284 of β-lactamase. Specific ligand–protein interactions such as phosphopeptide–Src homology domain 2 (SH2) of c-Src and imatinib–quinone reductase 2 (NQO2) increased the protein trans-splicing (PTS) reaction rates and yields. The PTS product showed the enhanced β-lactamase activity compared with the starting materials. The PTS-based β-lactamase activity assay was used for the quantitative analysis of the ligand–protein interactions. The signal sequence and 9-residue N-terminal sequence of Escherichia coli (E. coli) lipoprotein (Lpp) and residues 46–159 of outer membrane protein A (OmpA) (LppOmpA) were conjugated with the target proteins bearing split intein and β-lactamase to display them on live E. coli cell surfaces. PTS on live E. coli surfaces provided enhanced resistance to carbenicillin.
State Silence as Acceptance: A Presumption and an Exception
Authors: Azaria Danae
Published: February 2024

This study considers State silence which may entail acquiescence and can thus contribute inter alia to the formation of historic rights, the identification of customary international law, and the interpretation of treaties over time. Relying on the historical understanding of acquiescence in British and francophone literature, it argues that there are probability and normative justifications for establishing acquiescence as a ‘presumption of acceptance’ in international law, and that these considerations have influenced the modern international law understanding of acquiescence as an exceptional occurrence subject to stringent qualifications.
tRF-29-79 regulates lung adenocarcinoma progression through mediating glutamine transporter SLC1A5
Authors: Shi Yuanjian , Pan Zehao , Feng Yipeng , Zhou Qinyao , Wang Qinglin , Wang Hui , Dong Gaochao , Xia Wenjie , Jiang Feng
Published: February 2024

In recent decades, considerable evidence has emerged indicating the involvement of tRNA-derived fragments (tRFs) in cancer progression through various mechanisms. However, the biological effects and mechanisms of tRFs in lung adenocarcinoma (LUAD) remain unclear. In this study, we screen out tRF-29-79, a 5ʹ-tRF derived from tRNAGlyGCC, through profiling the tRF expressions in three pairs of LUAD tissues. We show that tRF-29-79 is downregulated in LUAD and downregulation of tRF-29-79 is associated with poorer prognosis. In vivo and in vitro assay reveal that tRF-29-79 inhibits proliferation, migration and invasion of LUAD cells. Mechanistically, we discovered that tRF-29-79 interacts with the RNA-binding protein PTBP1 and facilitates the transportation of PTBP1 from nucleus to cytoplasm, which regulates alternative splicing in the 3ʹ untranslated region (UTR) of SLC1A5 pre-mRNA. Given that SLC1A5 is a core transporter of glutamine, we proved that tRF-29-79 mediate glutamine metabolism of LUAD through affecting the stability of SLC1A5 mRNA, thus exerts its anticancer function. In summary, our findings uncover the novel mechanism that tRF-29-79 participates in glutamine metabolism through interacting with PTBP1 and regulating alternative splicing in the 3ʹ UTR of SLC1A5 pre-mRNA.
LMO3 is a suppressor of the basal-like/squamous subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism
Authors: Ohara Yuuki , Craig Amanda J , Liu Huaitian , Yang Shouhui , Moreno Paloma , Dorsey Tiffany H , Cawley Helen , Azizian Azadeh , Gaedcke Jochen , Ghadimi Michael , Hanna Nader , Ambs Stefan , Hussain S Perwez
Published: February 2024

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.
Surgical stress induced tumor immune suppressive environment
Authors: Yang Fan , Hua Qing , Zhu Xiaoyan , Xu Pingbo
Published: February 2024

Despite significant advances in cancer treatment over the decades, surgical resection remains a prominent management approach for solid neoplasms. Unfortunately, accumulating evidence suggests that surgical stress caused by tumor resection may potentially trigger postoperative metastatic niche formation. Surgical stress not only activates the sympathetic-adrenomedullary axis and hypothalamic–pituitary–adrenocortical axis but also induces hypoxia and hypercoagulable state. These adverse factors can negatively impact the immune system by downregulating immune effector cells and upregulating immune suppressor cells, which contribute to the colonization and progression of postoperative tumor metastatic niche. This review summarizes the effects of surgical stress on four types of immune effector cells (neutrophils, macrophages, natural killer cells and cytotoxic T lymphocytes) and two types of immunosuppressive cells (regulatory T cells and myeloid-derived suppressor cells), and discusses the immune mechanisms of postoperative tumor relapse and progression. Additionally, relevant therapeutic strategies to minimize the pro-tumorigenic effects of surgical stress are elucidated.