bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards an automatic approach to modelling the circumgalactic medium: new tools for mock making and fitting of metal profiles in large surveys
Authors: Longobardi Alessia , Fossati Matteo , Fumagalli Michele , Agarwal Bhaskar , Lofthouse Emma , Galbiati Marta , Dutta Rajeshwari , Berg Trystyn A M , Welsh Louise A
Published: August 2023

We present two new tools for studying and modelling metal absorption lines in the circumgalactic medium. The first tool, dubbed ‘NMF Profile Maker’ (NMF–PM), uses a non-negative matrix factorization (NMF) method and provides a robust means to generate large libraries of realistic metal absorption profiles. The method is trained and tested on 650 unsaturated metal absorbers in the redshift interval z = 0.9–4.2 with column densities in the range of 11.2 ≤ log (N/cm−2) ≤ 16.3, obtained from high-resolution (R > 4000) and high-signal-to-noise ratio (S/N ≥ 10) quasar spectroscopy. To avoid spurious features, we train on infinite S/N Voigt models of the observed line profiles derived using the code ‘Monte-Carlo Absorption Line Fitter’ (MC–ALF), a novel automatic Bayesian fitting code that is the second tool we present in this work. MC–ALF is a Monte-Carlo code based on nested sampling that, without the need for any prior guess or human intervention, can decompose metal lines into individual Voigt components. Both MC–ALF and NMF–PM are made publicly available to allow the community to produce large libraries of synthetic metal profiles and to reconstruct Voigt models of absorption lines in an automatic fashion. Both tools contribute to the scientific effort of simulating and analysing metal absorbers in very large spectroscopic surveys of quasars like the ongoing Dark Energy Spectroscopic Instrument, the 4-m Multi-Object Spectroscopic Telescope, and the WHT Enhanced Area Velocity Explorer surveys.
Reducing cognitive arousal and sleep effort alleviates insomnia and depression in pregnant women with DSM-5 insomnia disorder treated with a mindfulness sleep program
Authors: Kalmbach David A , Cheng Philip , Reffi Anthony N , Ong Jason C , Swanson Leslie M , Espie Colin A , Seymour Grace M , Hirata Mika , Walch Olivia , Pitts D’Angela S , Roth Thomas , Drake Christopher L
Published: August 2023

Objectives

Combining mindfulness with behavioral sleep strategies has been found to alleviate symptoms of insomnia and depression during pregnancy, but mechanisms for this treatment approach remain unclear. The present study examined nocturnal cognitive arousal and sleep effort as potential treatment mechanisms for alleviating insomnia and depression via a mindfulness sleep program for pregnant women.

Methods

Secondary analysis from a proof-of-concept trial of 12 pregnant women with DSM-5 insomnia disorder who were treated with Perinatal Understanding of Mindful Awareness for Sleep (PUMAS), which places behavioral sleep strategies within a mindfulness framework. Data were collected across eight weekly assessments: pretreatment, six sessions, and posttreatment. Measures included the insomnia severity index (ISI), Edinburgh postnatal depression scale (EPDS), pre-sleep arousal scale’s cognitive factor (PSASC), and the Glasgow sleep effort scale (GSES). We used linear mixed modeling to test cognitive arousal and sleep effort as concurrent and prospective predictors of insomnia and depression.

Results

Most patients reported high cognitive arousal before PUMAS (75.0%), which decreased to 8.3% after treatment. All insomnia remitters reported low cognitive arousal after treatment, whereas half of nonremitters continued reporting high cognitive arousal. Both nocturnal cognitive arousal and sleep effort were associated with same-week changes in insomnia throughout treatment, and sleep effort yielded a prospective effect on insomnia. Lower levels of nocturnal cognitive arousal and sleep effort prospectively predicted reductions in depression.

Conclusions

The present study offers preliminary evidence that reducing sleep effort and nocturnal cognitive arousal may serve as key mechanisms for alleviating insomnia and depression via mindfulness-based insomnia therapy. ClinicalTrials.gov ID: NCT04443959
Pancreatic ductal adenocarcinoma chemoresistance: From metabolism reprogramming to novel treatment
Authors: Zhang Jingcheng , Wang Yutong , Wang Lejunzi , You Lei , Zhang Taiping
Published: August 2023

As pancreatic cancer (PC) is highly malignant, its patients tend to develop metastasis at an early stage and show a poor response to conventional chemotherapies. First-line chemotherapies for PC, according to current guidelines, include fluoropyrimidine- and gemcitabine-based regimens. Accumulating research on drug resistance has shown that biochemical metabolic aberrations in PC, especially those involving glycolysis and glutamine metabolism, are highly associated with chemoresistance. Additionally, lipid metabolism is a major factor in chemoresistance. However, emerging compounds that target these key metabolic pathways have the potential to overcome chemoresistance. This review summarizes how PC develops chemoresistance through aberrations in biochemical metabolism and discusses novel critical targets and pathways within cancer metabolism for new drug research.
Efficacy and safety of flurbiprofen cataplasms versus loxoprofen sodium cataplasms in knee osteoarthritis: a randomized controlled trial
Authors: Li Dong , Cheng Yinchu , Yuan Ping , Wu Ziyang , Liu Jiabang , Kan Jinfu , Zhang Kun , Wang Zhanguo , Zhang Hui , Zhang Guangwu , Xue Tao , Jia Junxiu , Zhai Suodi , Guan Zhenpeng
Published: August 2023

Background:

Clinical trial evidence is limited to identify better topical non-steroidal anti-inflammatory drugs (NSAIDs) for treating knee osteoarthritis (OA). We aimed to compare the clinical efficacy and safety of flurbiprofen cataplasms (FPC) with loxoprofen sodium cataplasms (LSC) in treating patients with knee OA.

Methods:

This is an open-label, non-inferiority randomized controlled trial conducted at Peking University Shougang Hospital. Overall, 250 patients with knee OA admitted from October 2021 to April 2022 were randomly assigned to FPC and LSC treatment groups in a 1:1 ratio. Both medications were administered to patients for 28 days. The primary outcome was the change of pain measured by visual analog scale (VAS) score from baseline to day 28 (range, 0–10 points; higher score indicates worse pain; non-inferiority margin: 1 point; superiority margin: 0 point). There were four secondary outcomes, including the extent of pain relief, the change trends of VAS scores, joint function scores measured by the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and adverse events.

Results:

Among 250 randomized patients (One patient without complete baseline record in the flurbiprofen cataplasms was excluded; age, 62.8 ± 10.5 years; 61.4% [153/249] women), 234 (93.6%) finally completed the trial. In the intention-to-treat analysis, the decline of the VAS score for the 24-h most intense pain in the FPC group was non-inferior, and also superior to that in the LSC group (differences and 95% confidence interval, 0.414 (0.147–0.681); P <0.001 for non-inferiority; P = 0.001 for superiority). Similar results were observed of the VAS scores for the current pain and pain during exercise. WOMAC scores were also lower in the FPC group at week 4 (12.50 [8.00–22.50] vs. 16.00 [11.00–27.00], P = 0.010), mainly driven by the dimension of daily activity difficulty. In addition, the FPC group experienced a significantly lower incidence of adverse events (5.6% [7/124] vs. 33.6% [42/125], P <0.001), including irritation, rash and pain of the skin, and sticky hair uncovering pain.

Conclusions:

This study suggested that FPC is superior to LSC for treating patients with knee OA in pain relief, joint function improvement, and safety profile.
The Effect of Hand Reflexology Massage on Pain and Anxiety After Coronary Artery Bypass Graft Surgery
Authors: Göktuna Gizem , Dağcan Necibe , Arslan Gülşah Gürol
Published: August 2023

Background

Pain and anxiety are common postoperative problems that impair recovery and quality of life in patients undergoing coronary artery bypass graft (CABG) surgery. Reflexology is a nonpharmacologic method used to control pain and anxiety.

Objective

The aim of this study was to examine the effects of reflexology hand massage and stroking massage on pain and anxiety in patients in the immediate postoperative period after CABG.

Methods

In this double-blind, randomized, placebo-controlled study, we compared the effects of a 20-minute hand-reflexology massage to placebo stroking massage on pain and anxiety in newly extubated patients in the intensive care unit who had undergone CABG surgery. Pain was measured by visual analog scale and anxiety by the State-Trait Anxiety Inventory before and at 5, 30, and 60 minutes post intervention.

Results

A total of 48 patients were enrolled: 24 in the intervention group and 24 in the placebo. Mean pain scores were significantly reduced in the group who received reflexology compared with the placebo group (F = 36.569, P = .000). Mean anxiety scores were significantly reduced at 60 minutes for the reflexology group compared with the control group (P = .000).

Conclusions

We found that hand reflexology massage was effective in reducing pain and anxiety in patients during the immediate postoperative period after CABG.
The Changing Landscape of Intercultural Mindset in 616 Doctor of Physical Therapy Students Over the Past 7 Years and the Implications for Doctor of Physical Therapy Cultural Competence Education
Authors: VanHoose Lisa , Eigsti Heidi
Published: August 2023

Introduction.

This prospective longitudinal study will report the results of a quantitative analysis of the change in Intercultural Development Inventory (IDI) scores and the distribution of students in 5 orientations along the Intercultural Developmental Continuum (IDC) in 8 cohorts of Doctor of Physical Therapy (DPT) students during their academic preparation.

Review of Literature.

The expanding interest in developing intercultural sensitivity in an increasingly more complex and diverse health care environment calls for the dissemination of research on the effectiveness of innovative curricular models that include psychometrically strong outcome measures. Research suggests that health care providers can develop intercultural sensitivity when provided with didactic knowledge, experiential learning, self-reflection, mentoring, and a systematic individualized development plan.

Subjects.

The participants were from a sample of convenience of 616 DPT students from the graduating classes of 2015–2022.

Methods.

The study is a repeated-measure design. The IDI was selected to guide targeted intervention and assessment of intercultural sensitivity at an individual level and group level and was administered in semesters 3 and 8 as part of the DPT program course requirements.

Results.

There was significant improvement in the IDI Perceived and Developmental Orientation (DO; P < .001) scores between semesters 3 and 8. There was a significant change (P = .0001) in the distribution of students along the 5 DOs of the IDC with 10% of students regressing 1 orientation, 51.7% of students remaining the same, 33.3% of students advancing 1 orientation, and 5% of students advancing 2 orientations along the IDC. Nearly 40% of participants had a positive shift along the IDC.

Discussion and Conclusion.

The results of this study suggest that intercultural sensitivity or mindset, as measured by the IDI, can be developed in DPT students who participate in a targeted intercultural development curriculum based on the Process Model of Cultural Competence by Deardorff and the Developmental Model of Intercultural Sensitivity by Bennett.
An Autopsy Analysis of a Patient With Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency Caused by Compound Heterozygous HADHA Gene Mutations
Authors: Zhang Qinjian , Yao Nan , Liu Zunzhong , Xu Changmiao , Ding Zijiao
Published: August 2023

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a rare mitochondrial disease characterized by lipid oxidation disorder. It is an autosomal recessive disease induced by a mutation in the HADHA gene, which encodes the LCHAD deficiency. The clinical manifestations of this disease are diverse, primarily affecting the heart, liver, and skeletal muscles. Common symptoms include cardiomyopathy, peripheral neuropathy, retinopathy, and even lead to death in severe cases.

Herein, we report a patient who was hospitalized due to flatulence, crying, irritability, and died of acute cardiopulmonary failure after 8 days in hospital. An autopsy was performed to determine the cause of death. Clinical examination revealed abnormal liver and kidney function, and the genetic metabolic disease profile indicated significantly elevated levels of long-chain acyl-carnitine and long-chain 3-OH-acyl-carnitine. Histopathological examination revealed diffuse hepatic steatosis, and the genetic sequencing results detected compound heterozygous mutations in the HADHA gene (c.1528G>C [p.E510Q] and c.703_704dupCG [p.T236Gfs*3]). Of note, the mother had a history of acute fatty liver during pregnancy. Collectively, our study may contribute to understanding the HADHA gene mutation profile and the clinical phenotype of LCHAD deficiency, emphasizing the importance of genetic testing in forensic pathology.
Acute 1,2-Dichloropropane Poisoning due to Ingestion of Rubber Cement
Authors: Pang Qiuyu , Zheng Lexin , Huang Ruoyu , Xu Heng , Pan Chong , Wang Zhiyong , Wang Tao
Published: August 2023

1,2-Dichloropropane (1,2-DCP) is a common industrial solvent and chemical intermediate that can cause acute poisoning to humans through exposure during its production and industrial use. The target organs of 1,2-DCP include the eyes, respiratory system, liver, kidney, central nervous system, and skin. Forensic identification of 1,2-DCP poisoning is difficult because of the lack of characteristic pathological changes. This article reports an autopsy case of acute 1,2-DCP poisoning caused by self-ingestion of rubber cement. A woman developed seizures and coagulation dysfunction after ingesting approximately 10 mL of rubber cement and died 43 hours later. Autopsy revealed generalized subcutaneous hemorrhage, cardiopulmonary multifocal hemorrhage, bronchopneumonia, severe cerebral edema, focal hepatic necrosis, granular deposition in the glomerular capsule and renal tubules, and delipidation of the adrenal cortex. These findings indicate that 1,2-DCP poisoning can induce central nervous system dysfunction, respiratory system damage, liver and kidney function damage, hemolytic anemia, disseminated intravascular coagulation, and adrenal damage. This case may provide useful perspectives for forensic identification of 1,2-DCP poisoning in the future.
Pathological neurons generate ripples at the UP-DOWN transition disrupting information transfer
Authors: Weiss Shennan Aibel , Fried Itzhak , Engel Jerome , Bragin Anatol , Wang Shuang , Sperling Michael R , Wong Robert , Nir Yuval , Staba Richard J
Published: August 2023

Objective: To confirm and investigate why pathological HFOs (pHFOs) are generated during the UP-DOWN transition of the slow wave and if pHFOs interfere with information transmission. Methods: We isolated 217 total units from 175.95 iEEG contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (0.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the seizure onset zone (SOZ), HFOs and associated action potentials (APs) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross correlograms. Results: At the group level in the SOZ, HFO and HFO associated action potential probability was highest during the UP-DOWN transition of slow wave excitability (p<<0.001). In the non-SOZ, HFO and HFO associated action probability was highest during the DOWN-UP transition (p<<0.001). In the SOZ, at the unit level, 15.6% and 20% of units exhibited more robust firing during ripples (Cohens d=0.11-0.83) and fast ripples (d=0.36-0.90) at the UP-DOWN transition (p<0.05 f.d.r corrected), respectively. By comparison, also in the SOZ, significantly less firing at the UP-DOWN transition were observed in only 6.6% (d=0.14-0.30) and 8.5% (d=0.33-0.41) of units during ripples and fast ripples, respectively. Ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by ~50-80% in the SOZ compared to the non-SOZ (N=3). Significance: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs, and these pHFOs disrupt ripple temporal correlations that may be important in memory consolidation.
Prognosis and personalizedin-silicoprediction of treatment efficacy in cardiovascular and chronic kidney disease: a proof-of-concept study
Authors: Jaimes Campos Mayra Alejandra , Andújar Iván , Keller Felix , Mayer Gert , Rossing Peter , Staessen Jan A , Delles Christian , Beige Joachim , Glorieux Griet , Clark Andrew L , Mullen William , Schanstra Joost P , Vlahou Antonia , Rossing Kasper , Peter Karlheinz , Ortiz Alberto , Campbell Archie , Persson Frederik , Latosinska Agnieszka , Mischak Harald , Siwy Justyna , Jankowski Joachim
Published: August 2023

(1)

Background

kidney and cardiovascular diseases are responsible for a large fraction of population morbidity and mortality. Early, targeted, personalized intervention represents the ideal approach to cope with this challenge. Proteomic/peptidomic changes are largely responsible for onset and progression of these diseases and should hold information about optimal means for treatment and prevention.

(2)

Methods

we investigated prediction of renal or cardiovascular events using previously defined urinary peptidomic classifiers CKD273, HF2 and CAD160 in a cohort of 5585 subjects in a retrospective study.

(3)

Results

we demonstrate highly significant prediction of events with HR of 2.59, 1.71, and 4.12 for HF, CAD and CKD respectively. We applied in silico treatment, implementing on each patient urinary profile, changes onto the classifiers corresponding to exactly defined peptide abundance changes following commonly used interventions (MRA, SGLT2i, DPP4i, ARB, GLP1RA, olive oil and exercise), as defined in previous studies. Applying the proteomic classifiers after in silico treatment indicated individual benefits of specific interventions on a personalized level.

(4)

Conclusions

thein-silicoevaluation may provide information on the future impact of specific drugs and intervention on endpoints, opening the door to a precision medicine approach. Investigation of the extent of the benefit of this approach in a prospective clinical trial is warranted.
Deciphering the Genetic Code of Neuronal Type Connectivity Through Bilinear Modeling
Authors: Qiao Mu
Published: August 2023

Understanding how different neuronal types connect and communicate is critical to interpreting brain function and behavior. However, it has remained a formidable challenge to decipher the genetic underpinnings that dictate the specific connections formed between neuronal types. To address this, we propose a novel bilinear modeling approach that leverages the architecture similar to that of recommendation systems. Our model transforms the gene expressions of presynaptic and postsynaptic neuronal types, obtained from single-cell transcriptomics, into a covariance matrix. The objective is to construct this covariance matrix that closely mirrors a connectivity matrix, derived from connectomic data, reflecting the known anatomical connections between these neuronal types. When tested on a dataset ofCaenorhabditis elegans, our model achieved a performance comparable to, if slightly better than, the previously proposed spatial connectome model (SCM) in reconstructing electrical synaptic connectivity based on gene expressions. Through a comparative analysis, our model not only captured all genetic interactions identified by the SCM but also inferred additional ones. Applied to a mouse retinal neuronal dataset, the bilinear model successfully recapitulated recognized connectivity motifs between bipolar cells and retinal ganglion cells, and provided interpretable insights into genetic interactions shaping the connectivity. Specifically, it identified unique genetic signatures associated with different connectivity motifs, including genes important to cell-cell adhesion and synapse formation, highlighting their role in orchestrating specific synaptic connections between these neurons. Our work establishes an innovative computational strategy for decoding the genetic programming of neuronal type connectivity. It not only sets a new benchmark for single-cell transcriptomic analysis of synaptic connections but also paves the way for mechanistic studies of neural circuit assembly and genetic manipulation of circuit wiring.
TRAFfic signals: High-throughput CAR discovery in NK cells reveals novel TRAF-binding endodomains that drive enhanced persistence and cytotoxicity
Authors: Williams Maddie D. , Chen Aye T. , Stone Matthew R. , Guo Lan , Belmont Brian J. , Turk Rebekah , Bogard Nick , Kearns Nora , Young Mary , Daines Bryce , Darnell Max
Published: August 2023

Natural killer (NK) cells are a promising alternative therapeutic platform to CAR T cells given their favorable safety profile and potent killing ability. However, CAR NK cells suffer from limited persistencein vivo, which is, in part, thought to be the consequence of limited cytokine signaling. To address this challenge, we developed an innovative high-throughput screening strategy to identify CAR endodomains that could drive enhanced persistence while maintaining potent cytotoxicity. We uncovered a family of TRAF-binding endodomains that outperform benchmarks in primary NK cells along dimensions of persistence and cytotoxicity, even in low IL-2 conditions. This work highlights the importance of cell-type-specific cell therapy engineering and unlocks a wide range of high-throughput molecular engineering avenues in NK cells.
Cellular Senescence Affects ECM Regulation in COPD Lung Tissue
Authors: Woldhuis R.R. , Bekker N.J. , van Nijnatten J.L.L. , Meuleman R.A. , Kooistra W. , Wolters J.C. , Horvatovich P.L. , Guryev V. , van den Berge M. , Timens W. , Brandsma CA.
Published: August 2023

Rationale

Higher levels of senescence have been demonstrated in COPD patients, including severe early onset (SEO)-COPD. Recently we demonstrated a link between senescence and extracellular matrix (ECM) changes in lung fibroblasts. Whether thisin vitroobservation also translatesin vivohas not been demonstrated.

Objectives

To determine whether senescence can contribute to COPD-associated ECM-related changes in lung tissue.

Methods

Transcriptomics and proteomics analyses were performed on lung tissue from 60 COPD patients (including 18 SEO-COPD patients) and 32 controls. Transcript and protein levels of 471 ECM-related proteins were compared between (SEO-)COPD and control. Differentially expressed genes and proteins were correlated with six major senescence markers. Significant correlations were validated at single cell level andin vitro.

Results

We identified 15 COPD- and 61 SEO-COPD-associated changes in ECM-related proteins, of which 12 and 57 at transcript and 4 and 9 at protein level, respectively. More than half (36 out of 68) of the (SEO-)COPD-associated ECM-related proteins were significantly correlated with one or more senescence markers at transcript level, with the most and strongest correlations with p21. The correlation of 6 ECM-related genes, including THBS1, ADAMTS1, and ADAMTS4, with p21 was validated at single cell level and ADAMTS1 in senescent lung fibroblastsin vitro.

Conclusions

Many of the (SEO-)COPD-associated ECM-related changes in lung tissue were correlated with the senescence marker p21. As many of these ECM-related proteins are involved in ECM organization and include proteases, these results indicate a role for cellular senescence in disturbed ECM organization and protease-antiprotease imbalance in COPD.

What is already known on this topic

Accelerated ageing, including cellular senescence, has been recognized as a feature of COPD, while the functional implications of higher levels of senescence on lung tissue are largely unclear. Previously, we demonstrated a link between senescence and extracellular matrix (ECM) dysregulation in primary lung fibroblasts, but whether this translatesin vivohas not been demonstrated yet.

What this study adds

Here, we demonstrate that cellular senescence is linked to ECM dysregulationin vivoin COPD lung tissue mainly by impacting the regulators of ECM organization and contributing to the protease-antiprotease imbalance in COPD.

How this study might affect research, practice or policy

Our study points towards an important functional consequence of increased senescence on disease pathology in COPD patients, including the protease-antiprotease imbalance and dysregulated elastogenesis. Our findings support the development of new therapeutic strategies of targeting senescence to restore ECM regulation in COPD.
Compound models and Pearson residuals for single-cell RNA-seq data without UMIs
Authors: Lause Jan , Ziegenhain Christoph , Hartmanis Leonard , Berens Philipp , Kobak Dmitry
Published: August 2023

Recent work employed Pearson residuals from Poisson or negative binomial models to normalize UMI data. To extend this approach to non-UMI data, we model the additional amplification step with a compound distribution: we assume that sequenced RNA molecules follow a negative binomial distribution, and are then replicated following an amplification distribution. We show how this model leads to compound Pearson residuals, which yield meaningful gene selection and embeddings of Smart-seq2 datasets. Further, we suggest that amplification distributions across several sequencing protocols can be described by a broken power law. The resulting compound model captures previously unexplained overdispersion and zero-inflation patterns in non-UMI data.
Determinants of COVID-19 vaccine uptake in the Netherlands: a nationwide registry-based study
Authors: Pijpers Joyce , van Roon Annika , van Roekel Caren , Labuschagne Lisanne , Smagge Bente , Ferreira José A. , de Melker Hester , Hahné Susan
Published: August 2023

By September 2022, uptake of at least one dose of COVID-19 vaccine in the Dutch adult population was 84%. Ecological studies have indicated lower uptake in certain population groups. We aimed to investigate determinants of COVID-19 vaccine uptake in the Netherlands at individual level to evaluate and optimize implementation of the vaccination program and generate hypotheses for research on drivers of and barriers to vaccination. A retrospective database study was performed including the entire Dutch population ≥18. Vaccination data (5 January 2021 – 18 November 2021) were at individual level linked to sociodemographic data. Random forest analyses ranked sociodemographic determinants of COVID-19 vaccine uptake. The most important determinant was age; uptake increased until the age of 80 (67% in 18-35 years, 92% in 67-79 years and 88% in those >80). Personal income and socioeconomic position ranked second and third, followed by migration status. Uptake was lower among individuals in the lowest income group (69%), receiving social benefits (56%), and individuals with two parents born abroad (59%). Our finding that age is the most important determinant for uptake likely reflects the prioritisation of elderly in the programme and the general understanding of their increased vulnerability. However, our findings also reveal important other disparities in vaccine uptake. How to best address this inequity in future vaccination campaigns requires further research.
Comprehensive genome editing confers ‘off-the-shelf’ CAR-T cells superior efficacy against solid tumors
Authors: Murray Ryan , Navarrete Nuria Roxana Romero , Desai Kashvi , Chowdhury Md Raihan , Chilakapati Shanmuga Reddy , Chong Brian , Messana Angelica , Sobon Hanna , Rocha Joe , Musenge Faith , Camblin Adam , Ciaramella Giuseppe , Sitkovsky Michail , Maldini Colby , Hatfield Stephen
Published: August 2023

Biochemical and immunological negative regulators converge to inhibit tumor-reactive Chimeric Antigen Receptor T (CAR-T) cells, which may explain clinical failures of CAR-T cell therapies against solid tumors. Here, we developed a multifaceted approach to genetically engineer allogeneic (‘off -the-shelf’) CAR-T cells resistant to both biochemical (adenosine) and immunological (PD-L1 and TGF-β) inhibitory signaling. We multiplexed an adenine base editor with a CRISPR-Cas12b nuclease to manufacture a CAR-T cell product comprising six gene edits to evade allorejection (B2M, CIITA), prevent graft-versus-host disease (CD3E) and resist major biochemical (ADORA2A) and immunological (PDCD1,TGFBR2) immunosuppressive barriers in solid tumors. Combinatorial genetic disruption in CAR-T cells enabled superior anti-tumor efficacy leading to improved tumor elimination and survival in humanized mouse models that recapitulated the suppressive features of a human tumor microenvironment (TME). This novel engineering strategy conferred CAR-T cells resistance to a diverse TME, which may unlock the therapeutic potential of CAR-T cells against solid tumors.

One Sentence Summary

Multiplex genome engineered CAR-T cells resistant to allorejection and the convergence of biochemical and immunological negative regulators within the tumor microenvironment exhibit superior efficacy against solid tumors.
Super-resolution optical imaging reveals accumulation of small mitochondria in the nucleoli of mouse embryos and stem cells
Authors: Qin Kezhou , Wu Xinyi
Published: August 2023

The nuclear mitochondrial DNA (NUMT) is found in cancer cells, but the mitochondrial DNAs entering the nuclei in normal cells have not been captured. Here, we utilized super-resolution optical imaging to capture the phenomenon by the probe PicoGreen and found mitochondrial DNAs and mitochondria accumulated in the nucleoli by four probes and overexpressing the MRPL58-DsRed. Our results provide an new explanation for mtDNA carryover and lay the foundation for the involvement of nuclear export of nucleoli in de novo mitochondrial biogenesis in another of our unpublished articles.
Determinants of COVID-19 booster uptake in the Netherlands, autumn 2022: how well were those at risk for severe disease reached?
Authors: van Roekel Caren , Labuschagne Lisanne , Pijpers Joyce , van Roon Annika , Smagge Bente , Ferreira José A. , Hahné Susan , de Melker Hester
Published: August 2023

Background

A booster with bivalent COVID-19 vaccine was offered in the Netherlands in autumn, 2022. We aimed to investigate vaccine uptake during the autumn 2022 booster round among the population subgroups at risk for severe COVID-19 that were specifically targeted by this campaign: the medical risk group aged 18-59 years and individuals ≥60 years. We calculated booster uptake in both populations and analyzed determinants of booster uptake among those who had received at least one prior COVID-19 vaccination.

Methods

Having had an autumn 2022 booster dose was defined as having received a COVID-19 vaccination between 19 September 2022 and 7 March 2023. The study population included individuals who received at least one previous COVID-19 vaccination. National registries of sociodemographic determinants and COVID-19 vaccination were linked by a unique person identifier. Voting proportions for political parties were included at neighborhood level. Determinants of COVID-19 vaccine autumn booster uptake were ranked by importance by random forest analyses.

Results

Booster uptake was 68% among those aged ≥60 and 30% among those aged 18-59 years with a medical risk factor for severe disease. For both target groups the most important determinant for booster uptake was age (15% in 18-29 years to 72% in 80+ years). Voting proportions for progressive liberal political parties ranked second in the random forest analysis in both groups, with an increasing proportion of votes associated with higher uptake. In the 60+ group, household type ranked third, with highest vaccine uptake among married couples without children (72%) and the lowest uptake among unmarried couples with children (47%). In the medical risk group, migration status ranked third. Migrants with two parents born abroad had the lowest uptake (18%), whereas migrants with both parents born in the Netherlands had the highest uptake (35%).

Conclusion

Among individuals who had received at least one prior COVID-19 vaccination, the autumn 2022 COVID-19 booster uptake was 68% in people ≥60 years and 30% in in the medical risk group aged 18-59 years. The most important determinant of booster uptake was age, followed by political preference and household type (60+ group) or migration status (medical risk group). Uptake varied considerably among subgroups in both target groups. Further research should be aimed at understanding the drivers and barriers of vaccine uptake among the subgroups with notably low uptake.
Shared and distinct molecular effects of regulatory genetic variants provide insight into mechanisms of distal enhancer-promoter communication
Authors: Ray-Jones Helen , Song Zeji , Chan Lai Ting , Haglund Alexander , Artemov Pavel , Rosa Monica Della , Ruje Luminita , Burden Frances , Kreuzhuber Roman , Litovskikh Anna , Weyenbergh Eline , Brusselaers Zoï , Tan Vanessa Xue Hui , Frontini Mattia , Wallace Chris , Malysheva Valeriya , Bottolo Leonardo , Vigorito Elena , Spivakov Mikhail
Published: August 2023

Gene enhancers often form long-range contacts with promoters, but it remains unclear if enhancer activity and their chromosomal contacts are mediated by the same DNA sequences and recruited factors. We studied the effects of expression quantitative trait loci (eQTLs) on enhancer activity and promoter contacts in primary monocytes isolated from 34 individuals. Using eQTL-Capture Hi-C and a Bayesian approach considering both intra- and inter-individual variation, we initially detected 19 eQTLs associated with enhancer-eGene promoter contacts, most of which also associated with enhancer accessibility and activity. Capitalising on these shared effects, we devised a multi-modality Bayesian strategy, which identified 629 “trimodal QTLs” jointly associated with enhancer accessibility, eGene promoter contact, and gene expression. Causal mediation analysis and CRISPR interference revealed causal relationships between these three modalities. Many detected QTLs overlapped disease susceptibility loci and influenced the predicted binding of myeloid transcription factors, including SPI1, GABPB and STAT3. Additionally, a variant associated withPCK2promoter contact directly disrupted a CTCF binding motif and impacted promoter insulation from downstream enhancers. Jointly, our findings suggest an inherent genetic link between the activity and connectivity of enhancers with relevance for human disease, and highlight the role of genetically-determined chromatin boundaries in gene control.
Differential substrate affinity and catabolite repression enable preferential use of urea by ammonia-oxidizing bacteria
Authors: Qin Wei , Wei Stephany P. , Zheng Yue , Choi Eunkyung , Li Xiangpeng , Johnston Juliet , Wan Xianhui , Abrahamson Britt , Flinkstrom Zachary , Wang Baozhan , Li Hanyan , Hou Lei , Tao Qing , Chlouber Wyatt W. , Sun Xin , Wells Michael , Ngo Long , Hunt Kristopher A. , Urakawa Hidetoshi , Tao Xuanyu , Wang Dongyu , Yan Xiaoyuan , Wang Dazhi , Pan Chongle , Weber Peter K. , Jiang Jiandong , Zhou Jizhong , Zhang Yao , Stahl David A. , Ward Bess B. , Mayali Xavier , Martens-Habbena Willm , Winkler Mari-Karoliina H.
Published: August 2023

Four distinct lineages of ammonia-oxidizing microorganisms (AOM) collectively contribute to one of the largest nitrogen fluxes in the global nitrogen budget. AOM possess widely different specific affinities for ammonia, thought to determine their niche differentiation. Nevertheless, ammonia-oxidizing archaea and bacteria (AOA, AOB), and complete ammonia oxidizers (comammox) co-occur in soils, freshwater sediments, and aquifers, suggesting that other factors must drive their coexistence. Here, we show that representatives of four AOM lineages employ distinct regulatory strategies for ammonia or urea utilization, thereby minimizing direct competition for either substrate. The tested AOA and comammox species preferentially used ammonia over urea, while beta-proteobacterial AOB favored urea utilization, repressed ammonia transport in the presence of urea, and showed higher affinity for urea than ammonia, whereas gamma-proteobacterial AOB co-utilized both substrates. Stable isotope tracing, kinetics, and transcriptomics experiments revealed that both assimilation and oxidation of ammonia are transport-dependent. These results reveal novel mechanisms of nitrogen metabolism regulation and transporter-based affinity underlying the contrasting niche adaptation and coexistence patterns among the major AOM lineages.
Prediction of A. thaliana’s MCTP4 Structure using Deep Learning-Based tools and Exploration of Transmembrane domain Dynamics using Coarse-Grained Molecular Dynamics Simulations
Authors: Sritharan Sujith , Versini Raphaelle , Petit Jules , Bayer Emmanuelle , Taly Antoine
Published: August 2023

Multiple C2 Domains and Transmembrane region Proteins (MCTPs) in plants have been identified as important functional and structural components of plasmodesmata cytoplasmic bridges, which are vital for cell-cell communication. MCTPs are endoplasmic reticulum (ER)-associated proteins which contain three to four C2 domains and two transmembrane regions. In this study, we created structural models ofArabidopsisMCTP4 ER-anchor transmembrane region (TMR) domain using several prediction methods based on deep learning (DL). This region, critical for driving ER association, presents a complex domain organization and remains largely unknown. Our study demonstrates that using a single deep-learning method to predict the structure of membrane proteins can be challenging. Our deep learning models presented three different conformations for the MCTP4 structure, provided by different deep learning methods, indicating the potential complexity of the protein’s conformational landscape. For the first time, we used simulations to explore the behaviour of the TMR of MCTPs within the lipid bilayer. We found that the TMR of MCTP4 is not rigid, but can adopt various conformations including some not identified by deep learning tools. These findings underscore the complexity of predicting protein structures. We learned that combining different methods, such as deep learning and simulations, enhances our understanding of complex proteins.
Discovery of an APP-Selective BACE1 Inhibitor for Alzheimer’s Disease
Authors: Campagna Jesus , Jagodzinska Barbara , Wi Dongwook , Zhu Chunni , Lee Jessica , Cohn Whitaker , Jun Michael , Elias Chris , Descamps Olivier , Zhang Qiang , Gorostiza Olivia , Poksay Karen , Spilman Patricia , Bredesen Dale , John Varghese
Published: August 2023

Inhibition of amyloid precursor protein (APP) beta-site cleaving enzyme 1 (BACE1; BACE) has been a target for Alzheimer’s disease (AD) therapeutic development, but has been impaired by off-target effects of clinically evaluated inhibitors, including inhibition of cleavage of non-APP substrates. Here, we report our identification of a BACE inhibitors series that are not only selective for the APP substrate, but also for BACE1 as the targeted enzyme. These APP-selective fluoro aminohydantoin (FAH) inhibitor compounds were identified by screening a compound library for inhibition of BACE cleavage of a maltose binding protein (MBP)-conjugated-APPC125 substrate followed by IC50 determination using the P5-P5’ substrate assay. In multiple substrate and enzyme cell-free assays, the lead compound FAH65 displayed substrate selectivity for inhibition of APP cleavage, with little activity against BACE substrates neuregulin 1 (NRG1) or p-selectin glycoprotein ligand -1 (PSGL1). We also demonstrate FAH65 shows little inhibitory activity against the enzyme cathepsin D (Cat D) or BACE2. FAH65 inhibits production of BACE cleavage products soluble APPβ (sAPPβ) and the β C-terminal fragment (βCTF), as well as amyloid-β (Aβ)1-40 and 1-42,in vitroin cells andin vivoin an animal model of AD. In a murine model of AD, FAH65 improved the discrimination score in the Novel Object Recognition (NOR) memory testing paradigm. The active enantiomer of FAH65, FAH65E(-), was obtained and tested in in vivo pharmacokinetic and pharmacodynamic (PK/PD) analysis, wherein it displayed good brain-penetrance and target engagement. Given its demonstrated selectivity for both enzyme and substrate, along with evidence it can improve cognitive performance in an animal model, FAH65 and its E(-) enantiomer merit continued pre-clinical development towards clinical testing as an APP-selective BACE1 inhibitor. Such a candidate would reduce Aβ levels and overcome the deleterious effects of the non-selective BACE1 inhibitors that have failed in the clinic and potentially could be used as a maintenance therapy along with or following clearance of Aβ from the brain with the approved antibody therapy for AD.
Altered primary somatosensory neuron development in aPtenheterozygous model for autism spectrum disorder
Authors: Fernandez Alejandra , Sarn Nick , Eng Charis , Wright Kevin M.
Published: August 2023

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social interactions, repetitive behaviors, and hyper- or hyposensitivity to sensory stimuli. The mechanisms underlying the emergence of sensory features in ASD are not fully understood, but recent studies in rodent models highlight that these may result from differences in primary sensory neurons themselves. We examined sensory behaviors in aPtenhaploinsufficient mouse model (PtenHet) for syndromic ASD and identified elevated responses to mechanical stimuli and a higher threshold to thermal responses. Transcriptomic andin vivoanatomical analysis identified alterations in subtype-specific markers of primary somatosensory neurons inPtenHetdorsal root ganglia (DRG). These defects emerge early during DRG development and involve dysregulation of multiple signaling pathways downstream ofPten. Finally, we show that mice harboring an ASD-associated mutation (PtenY69H) also show altered expression of somatosensory neuron subtype-specific markers. Together, these results show that precise levels ofPtenare required for proper somatosensory development and provide insight into the molecular and cellular basis of sensory abnormalities in a model for syndromic ASD.
Decoding auditory working memory content from intracranial high frequency activity in humans
Authors: Uluç Işıl , Peled Noam , Paulk Angelique C. , Bush Alan , Gumenyuk Valentina , Kotlarz Parker , Lankinen Kaisu , Mamashli Fahimeh , Matsuda Nao , Richardson Mark R. , Stufflebeam Steven M. , Cash Sydney S. , Ahveninen Jyrki
Published: August 2023

How the human brain maintains information in working memory (WM), a process critical for all our goal-directed function, has been debated for decades. Classic neurophysiological models, which argue that WM is maintained via persistent content-specific “delay activity,” have been challenged by alternative ideas suggesting a combination of dynamic activity patterns and activity-silent mechanisms. Here, utilizing human intracranial stereo-EEG (sEEG) recordings and machine learning techniques, we tested understudied auditory WM in multiple cortical and subcortical brain areas. Neuronal activity was quantified as broadband high frequency activity (HFA, 70-190 Hz) which has been shown to be highly correlated with multiunit activity of neuron populations. Our multivariate pattern analysis (MVPA) results, validated via robust non-parametric permutation testing, show that information can be decoded from multiple brain regions, including prefrontal regions, superior temporal auditory cortices, and the hippocampus. However, the recording sites with high WM decoding accuracies were not accompanied by statistically significant increases in HFA power. In contrast, HFA power was reduced relative to the period preceding WM encoding in many frontal, superior temporal, and hippocampal sEEG recording sites. These results are in line with the hypothesis that WM maintenance can be supported by highly dynamic, “activity silent” processes rather than via persistent activity only.
Mucilage Produced by Sorghum (Sorghum bicolor) Aerial Roots Hosts Diazotrophs that Provide Significant Amounts of Nitrogen to the Plant
Authors: Venado Rafael E. , Wilker Jennifer , Pankievicz Vania , Infante Valentina , MacIntyre April , Wolf Emily S. A. , Vela Saddie , Robbins Fletcher , Fernandes-Júnior Paulo Ivan , Vermerris Wilfred , Ané Jean-Michel
Published: August 2023

Sorghum (Sorghum bicolor) is a significant crop globally, serving as an important source of food, feed, and fodder, and is increasingly recognized as an energy crop due to its high potential for biomass production. Certain sorghum accessions exhibit prolific aerial root development and produce abundant carbohydrate-rich mucilage after precipitation. This aerial root mucilage bears resemblance to that found in landraces of maize (Zea mays) from southern Mexico, which have previously been found to harbor diazotrophs. In this study, we examined the aerial root development of specific sorghum accessions and investigated the influence of humidity on this trait. Our microbiome analysis of the aerial root mucilage of maize and sorghum revealed the presence of numerous diazotrophs in sorghum mucilage, withPseudomonadota,Bacillota, andBacteriodotabeing the predominant phyla observed. However, the community composition varied significantly depending on the host plant and location. Through acetylene reduction,15N2gas feeding, and15N isotope dilution assays, we determined that these sorghum accessions can acquire approximately 40% of their nitrogen from the atmosphere through these symbiotic associations on aerial roots. The nitrogen fixation occurring in sorghum aerial root mucilage presents a promising opportunity to reduce reliance on synthetic fertilizers and advance sustainable agricultural practices for food, feed, fodder, and bioenergy production.
Mitochondrial DNA released by senescent cells triggers immunosuppression in cancer
Authors: Lai Ping , Liu Lei , Bancaro Nicolò , Troiani Martina , Calì Bianca , Chen Jingjing , Singh Prafull Kumar , Arzola Rydell Alvarez , Attanasio Giuseppe , Pernigoni Nicolò , Pasquini Emiliano , Mosole Simone , Rinaldi Andrea , Sgrignani Jacopo , Li Yuxin , Qiu Shi , Song Pan , Li Yingrui , Desbats Maria Andrea , Ángel Azucena Rendón , Mestre Ricardo Pereira , Barile Lucio , Cavalli Andrea , de Bono Johann , Alimonti Andrea
Published: August 2023

DNA is a potent damage-associated molecular pattern signaling that, once in the extracellular space, triggers the activation of the innate immune system. Here we find that senescent cells release mtDNA to both the cytosol and the extracellular space. In cells undergoing cellular senescence, the release of mtDNA precedes that of nuclear DNA resulting in the activation of the cGAS/STING pathway and establishment of cellular senescence. Intriguingly, by exploiting co-culture and in vivo cross-species experiments, we show that extracellular mtDNA released by senescent tumors cells is specifically captured by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment (TME). Mechanistically we find that PMN-MDSCs uptake mtDNA to enhance their immunosuppressive ability. Pharmacological inhibition of mtDNA released from senescent tumor cells blocks the PMN-MDSCs immunosuppressive activity, improving the efficacy of therapy-induced senescence (TIS) in cancer. These results reveal the crucial role of mtDNA in initiating cellular senescence and immunosuppression independently of the SASP. Thus, targeting mtDNA release-mediated pathway may hold promise to reprogram the immune suppressive microenvironment in patients treated with chemotherapy.