bluuebunny/crossref_metadata_2025 huggingface dataset:
Modern Plays
Authors: Berman Carol W.
Published: March 2023

This chapter considers modern plays. In modern plays, like The Cherry Orchard and The Seagull, Chekhov shows us characters denying reality and suffering as a result. August Strindberg gives us sadomasochistic behaviors in Miss Julie. In Tennessee Williams’ The Glass Menagerie, Laura, who may be schizophrenic or on the autistic spectrum, regresses as she tries to deal with the “gentleman caller.” Eugene O’Neill shows us numerous examples of complexes, unconscious impulses, and ego and superego struggles in his play Long Day’s Journey Into Night. The chapter examines how plays reveal various perspectives, prejudices, individual and group psychology, and, of course, various psychiatric principles of psychoanalysis.
Identity Issues
Authors: Berman Carol W.
Published: March 2023

How the patient sees him or herself is essential to understand when doing any kind of therapy. The identity of a character includes who the person is in terms of what values they hold, how they see themselves, their roles in society, their memories, experiences, relationships. There is identification with someone, like identification with the aggressors in Mamet’s Glengarry Glen Ross. Introjection is a way of establishing identity as well. In introjections people may have identification with a victim, as Willy Loman does in Arthur Miller’s Death of a Salesman. In the play Transnormal, there is understanding of how identity changes with gender. Through these identifications neural networks are formed that would never have considered.
What We Learn From Plays
Authors: Berman Carol W.
Published: March 2023

What better way is there to learn psychiatry and psychology than to have exciting examples of personality disorders, depression, and psychosis from playwrights? Every time a person goes to the theater, an experience of “psychiatry on the stage” can occur. If a professor returns to the clinic after such theater presentations, examples are available to present to psychiatry residents. In addition, new brain pathways are formed that will be invaluable. Greek playwrights, Shakespeare, and modern playwrights have given us invaluable gifts with their plays. Great playwrights like Tom Stoppard stimulate our brains with their brilliant works. I look forward to viewing many more plays to maintain my brain functions.
Central nervous system tumours
Authors: Ajithkumar Thankamma
Published: March 2023

Central nervous system tumours, which can arise from any structures within the cranial vault and spinal canal, are heterogeneous with different histological subtypes. The clinical behaviour of these tumours depends on the site of disease and histologically. While most tumours are locally invasive, some have a predilection for leptomeningeal spread. The current WHO classification of tumours is based on histology, immunohistochemistry, and cytogenetics. This chapter discusses the clinical and imaging features of common types of central nervous system tumours, the role of radiotherapy, integration of systemic treatment with radiotherapy, and practical details on radiotherapy planning. It also summarizes the evidence underpinning current clinical practice.
Thoracic cancers
Authors: Ajithkumar Thankamma
Published: March 2023

Lung cancer is the commonest cause of cancer death in the industrialised world. For therapeutic purposes, lung cancers are divided in small cell lung cancer and non-small cell lung cancer. Radiotherapy has a well-established role in the curative and palliative management of lung cancer. Radiotherapy has also been used in the management of malignant mesothelioma and thymoma. This chapter discusses the clinical and imaging features of lung cancers, malignant mesothelioma, and thymoma, the role of radiotherapy in these tumours, and practical details on radiotherapy planning. The role of prophylactic cranial irradiation in small cell lung cancer is also discussed. It also summarizes the evidence underpinning current clinical practice.
Haematological malignancies
Authors: Ajithkumar Thankamma
Published: March 2023

Over the last couple of decades, the role of radiotherapy for haematological malignancies has progressively diminished. Nevertheless, radiotherapy still plays a curative role in the management of early-stage lymphomas. Radiotherapy is an essential component of the treatment of early-stage classical Hodgkin lymphoma and high-grade lymphomas. Definitive radiotherapy is the treatment of choice for early-stage nodal and extranodal indolent lymphomas. Definitive radiotherapy is curative in approximately 50% of solitary plasmacytomas. Consolidation radiotherapy is considered in advanced-stage lymphomas after definitive chemo-immunotherapy if there are inadequate response at sites of initial bulky disease or has residual active disease. Radiotherapy is also used for conditioning for transplantation, bridging strategy during CAR-T and for palliation in incurable disease.
What to do in the first few days
Authors: Harwood Rowan H. , Huwez Farhad Umer , Guyler Paul , Alam Sajid , Gaynor Catherine
Published: March 2023

This chapter tackles what to do in the first few days after a stroke. It starts with the need to focus immediately on assessment for, and delivery of, re-perfusion therapies. The role of Hyperacute Stroke Units (HASU) is described, and the medical functions they deliver. Specific acute medical management of cerebral infarcts and bleeds is described, along with the management of coma, acute nursing care, and monitoring requirements.
Rehabilitation
Authors: Harwood Rowan H. , Huwez Farhad Umer , Guyler Paul , Alam Sajid , Gaynor Catherine
Published: March 2023

Rehabilitation, is more of a way of thinking than a treatment in itself. Rehabilitation comprises elements of re-ablement, resettlement, and readjustment. Rehabilitation aims to maximize functional ability and increase the options patients have over their eventual discharge. Progress is the best assessed by monitoring disability, which has three key dimensions: mobility, continence, and behaviour, amongst many other functional activities that may be affected. The chapter emphasises the importance of multi-professional working including rehabilitation nursing. It describes different trajectories of recovery. It also considers the various issues patients encounter while recovering from a stroke, such as depression, urinary continence, and shoulder pain. Family involvement is a key feature of successful stroke recoveries.
Preventing strokes and other vascular events
Authors: Harwood Rowan H. , Huwez Farhad Umer , Guyler Paul , Alam Sajid , Gaynor Catherine
Published: March 2023

This chapter describes how to prevent strokes and other vascular events. It explains how preventive measures should be tailored to the patient. Stroke survivors are at high risk of another stroke or other vascular events such as heart attacks. Important risk factors include blood pressure, cholesterol, smoking, blood sugar, atrial fibrillation and carotid stenosis. The chapter explores ways to reduce risk through lifestyle, general vascular prevention and stroke-specific interventions.
The SAMI–Fornax Dwarfs Survey – III. Evolution of [α/Fe] in dwarfs, from Galaxy Clusters to the Local Group
Authors: Romero-Gómez J , Peletier Reynier F , Aguerri J A L , Mieske Steffen , Scott Nicholas , Bland-Hawthorn Joss , Bryant Julia J , Croom Scott M , Eftekhari F Sara , Falcón-Barroso Jesús , Hilker Michael , van de Ven Glenn , Venhola Aku
Published: March 2023

Using very deep, high spectral resolution data from the SAMI Integral Field Spectrograph, we study the stellar population properties of a sample of dwarf galaxies in the Fornax Cluster, down to a stellar mass of 107 M⊙, which has never been done outside the Local Group. We use full spectral fitting to obtain stellar population parameters. Adding massive galaxies from the ATLAS3D project, which we re-analysed, and the satellite galaxies of the Milky Way, we obtained a galaxy sample that covers the stellar mass range 104–1012 M⊙. Using this large range, we find that the mass–metallicity relation is not linear. We also find that the [α/Fe]-stellar mass relation of the full sample shows a U-shape, with a minimum in [α/Fe] for masses between 109 and 1010 M⊙. The relation between [α/Fe] and stellar mass can be understood in the following way: when the faintest galaxies enter the cluster environment, a rapid burst of star formation is induced, after which the gas content is blown away by various quenching mechanisms. This fast star formation causes high [α/Fe] values, like in the Galactic halo. More massive galaxies will manage to keep their gas longer and form several bursts of star formation, with lower [α/Fe] as a result. For massive galaxies, stellar populations are regulated by internal processes, leading to [α/Fe] increasing with mass. We confirm this model by showing that [α/Fe] correlates with clustercentric distance in three nearby clusters and also in the halo of the Milky Way.
Management of diabetic kidney disease: where do we stand?: A narrative review
Authors: Sindhu Devada , Sharma Gaurav Shekhar , Kumbala Damodar
Published: March 2023

Diabetic kidney disease is the leading cause of chronic kidney disease and end-stage renal disease. The pathogenesis and risk factors for the development of diabetic kidney disease are complex and multifaceted, resulting in glomerular hypertrophy, tubulointerstitial inflammation, and fibrosis. The clinical staging progresses over 5 stages from early hyperfiltration to overt nephropathy. Primary prevention like glycaemic control, control of blood pressure, treatment of dyslipidemia and lifestyle modifications have shown promising benefits. Despite widespread research, very few drugs are available to retard disease progression. More literature and research are needed to fill these lacunae. We carried out a literature search focusing on newer updates in diabetic kidney disease pathophysiology, diagnosis and management using a PubMed search through the National library of medicine using keywords “Diabetic kidney disease,” and “Diabetic nephropathy” till the year 2022. We have summarized the relevant information from those articles.
Membranihabitans maritimus sp. nov., a marine bacterium isolated from deep seawater
Authors: Guo Li-Li , Yi Li-Dong , Wang Ming-Lei , Qian Yu-Rong , Xu Xue-Wei , Fu Ge-Yi
Published: March 2023

A Gram-stain-negative, non-motile, rod-shaped bacterial strain, designated C281T, was isolated from seawater sampled at the Marshallese seamount chain. Results of 16S rRNA gene analysis revealed that strain C281T was most closely related to Membranihabitans marinus CZ-AZ5T with 92.7 % sequence similarity. Phylogenetic analysis indicated that the new isolate represented a novel species by forming a distinctive lineage within the family

Saprospiraceae

. The DNA G+C content of strain C281T was 38.4 mol%. The genome sizes of strain C281T and the reference strain

M. marinus

CZ-AZ5T were 5 962 917 and 5 395 999 bp, respectively. The average nucleotide identity and in silico DNA–DNA hybridization values between strains C281T and

M. marinus

CZ-AZ5T were found to be low (69.3 and 17.6 %, respectively). Different functional genes were found in the genome of strain C281T, such as CZC CBA, polysaccharide utilization loci and linear azol(in)e-containing peptide cluster coding genes. The NaCl range for growth was 0.5–15.0 %. Positive results were obtained for hydrolysis of Tween 60 and urease. MK-7 was the sole respiratory quinone. The major fatty acids were C16 : 1
 ω6c and/or C16 : 1
 ω7c, iso-C15 : 0 and iso-C15 : 1 F. The major polar lipids of strain C281T were phosphatidylethanolamine, phosphatidylglycerol, two unidentified lipids and five unidentified glycolipids. On the basis of its taxonomic characteristics, the isolate represents a novel species of the genus Membranihabitans, for which the name Membranihabitans maritimus sp. nov. (type strain C281T=KCTC 92171T=MCCC M27001T) is proposed.
Genetic and environmental contributions to ancestry differences in gene expression in the human brain
Authors: Benjamin Kynon J.M. , Chen Qiang , Eagles Nicholas J. , Huuki-Myers Louise A. , Collado-Torres Leonardo , Stolz Joshua M. , Pertea Geo , Shin Joo Heon , Paquola Apuã C.M. , Hyde Thomas M. , Kleinman Joel E. , Jaffe Andrew E. , Han Shizhong , Weinberger Daniel R.
Published: March 2023

Ancestral differences in genomic variation are determining factors in gene regulation; however, most gene expression studies have been limited to European ancestry samples or adjusted for ancestry to identify ancestry-independent associations. We instead examined the impact of genetic ancestry on gene expression and DNA methylation (DNAm) in admixed African/Black American neurotypical individuals to untangle effects of genetic and environmental factors. Ancestry-associated differentially expressed genes (DEGs), transcripts, and gene networks, while notably not implicating neurons, are enriched for genes related to immune response and vascular tissue and explain up to 26% of heritability for ischemic stroke, 27% of heritability for Parkinson’s disease, and 30% of heritability for Alzhemier’s disease. Ancestry-associated DEGs also show general enrichment for heritability of diverse immune-related traits but depletion for psychiatric-related traits. The cell-type enrichments and direction of effects vary by brain region. These DEGs are less evolutionarily constrained and are largely explained by genetic variations; roughly 15% are predicted by DNAm variation implicating environmental exposures. We also compared Black and White Americans, confirming most of these ancestry-associated DEGs. Our results highlight how environment and genetic background affect genetic ancestry differences in gene expression in the human brain and affect risk for brain illness.

We examine the impact of genetic ancestry on gene expression and DNA methylation of admixed African/Black Americans, highlighting how genetic and environmental background affect risk for brain illness.
Percutaneous Coronary Intervention vs Coronary Artery Bypass Graft In- hospital Outcomes in Diabetes
Authors: Luo Qianyun , Li Renxi
Published: March 2023

Background

Despite extensive research on coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) outcome differences, current literature lacks representation of short-term in-hospital outcomes in patients with existing medical conditions. This study aimed to compare perioperative outcomes of these two revascularization procedures in diabetes mellitus (DM) patients.

Methods

The National Inpatient Sample (NIS) was used to extract patients who received CABG or PCI surgery between the last quarter of 2015 to 2020 based on ICD10-PCS. Patients of age<40 were excluded for congenital heart defects. Preoperative differences were noted and adjusted using multivariable logistic regression. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were estimated between PCI and CAGB groups.

Results

A total number of 90,662 CABG and 173,725 PCI cases of patients with DM were identified in NIS. Compared to CABG, patients who underwent PCI had increased mortality (2.75% vs 2.00%, aOR 1.266, p<0.0001), myocardial infarction (1.5% vs 1.17%, aOR 1.223, p<0.0001), and were less likely to experience respiratory events (0.38% vs 6.33%, aOR 0.055, p<0.0001), stroke (0.03% vs 0.06%, aOR 0.385, p<0.0001), acute kidney injury (20.37% vs 25.37%, aOR 0.727, p<0.0001), sepsis (0.01% vs 0.05%, aOR 0.172, p<0.0001), shock (0.11% vs 0.74%, aOR 0.139, p<0.0001).

Conclusions

The NIS database collects enormous records from nationwide providers, offering great statistical power. PCI was associated with a markedly higher in-hospital mortality rate but a lower morbidity rate in patients with DM as compared to CABG. Therefore, physicians should weigh both mortality and morbidity when considering surgical treatment to DM patients.
IL-21/23 axis modulates inflammatory cytokines and RANKL expression in RA CD4+T cells via p-Akt signaling
Authors: Bhattacharya Gargee , Sengupta Soumya , Jha Rohila , Shaw Shubham K , Jogdand Gajendra M , Barik Prakash K , Padhan Prasanta , Parida Jyoti R , Devadas Satish
Published: March 2023

The role of CD4+T cells specifically, Th17 has been well documented in RA pathogenesis. Here we focus on the critical role of cytokines IL-21 and IL-23 in facilitating the aberrant status of RA Th17-like cells and report their significant contribution(s) in modulating the expression of inflammatory cytokines and RANKL. Neutralizing IL-21 or IL- 23 (p19 and p40) or both, resulted in downregulation of the cytokines, TNF-α, IFN-γ and IL- 17 and RANKL expression in RA CD4+T cells. Ourex vivohuman Th17 studies also validated the above findings and we hypothesize a common pathway responsible for regulation of inflammatory cytokines and RANKL expression. Subsequent dissection of the signalling pathway found p-Akt1 as the key phosphoprotein downstream of both IL-21 and IL-23, capable of augmenting inflammatory cytokines and RANKL production. Altogether, these findings identify IL-21/23 axis in RA CD4+T cells as a key regulator dictating two critical processes i.e. exaggerated inflammation and higher osteoclastogenesis and provide critical targets in their downstream signalling for therapeutic approaches.
Splicing accuracy varies across human introns, tissues and age
Authors: García-Ruiz S , Zhang D , Gustavsson E K , Rocamora-Perez G , Grant-Peters M , Fairbrother-Browne A , Reynolds R H , Brenton J W , Gil-Martínez A L , Chen Z , Rio D C , Botia J A , Guelfi S , Collado-Torres L , Ryten M
Published: March 2023

Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigated mis-splicing using RNA-sequencing data from ~14K control samples and 42 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that mis-splicing occurs at different rates across introns and tissues and that these splicing inaccuracies are primarily affected by the abundance of core components of the spliceosome assembly and its regulators. Using publicly available data on short-hairpin RNA-knockdowns of numerous spliceosomal components and related regulators, we found support for the importance of RNA-binding proteins in mis-splicing. We also demonstrated that age is positively correlated with mis-splicing, and it affects genes implicated in neurodegenerative diseases. This in-depth characterisation of mis-splicing can have important implications for our understanding of the role of splicing inaccuracies in human disease and the interpretation of long-read RNA-sequencing data.
TNF-NFkB-p53 axis restrictsin vivosurvival of hPSC-derived dopamine neuron
Authors: Kim Tae Wan , Koo So Yeon , Riessland Markus , Cho Hyunwoo , Chaudhry Fayzan , Kolisnyk Benjamin , Russo Marco Vincenzo , Saurat Nathalie , Mehta Sanjoy , Garippa Ralph , Betel Doron , Studer Lorenz
Published: March 2023

Ongoing, first-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson’s disease (PD). However, a major unresolved challenge in the field is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neuronsin vivo. We identified p53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. As a translationally applicable strategy to purify postmitotic dopamine neurons, we performed a cell surface marker screen that enabled purification without the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved and widely used TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic human PSC-derived dopamine neurons in PD.

Highlights

In vivoCRISPR-Cas9 screen identifies p53 limiting survival of grafted human dopamine neurons.

TNFα-NFκB pathway mediates p53-dependent human dopamine neuron death

Cell surface marker screen to enrich human dopamine neurons for translational use.

FDA approved TNF-alpha inhibitor rescuesin vivodopamine neuron survival within vivofunction.
Prevalence of Slam-dependent hemophores in Gram-negative bacteria
Authors: Shin Hyejin Esther , Pan Chuxi , Curran David M. , Bateman Thomas J. , Chong Derrick HY , Ng Dixon , Shah Megha , Moraes Trevor F.
Published: March 2023

Iron acquisition systems are crucial for pathogen growth and survival in iron-limiting host environments. To overcome nutritional immunity, bacterial pathogens evolved to use diverse mechanisms to acquire iron. Here, we examined a heme acquisition system driven by hemophores called HphAs from several Gram-negative bacteria. Structural determination of HphAs revealed a N-terminal clamp-like domain that binds heme and a C-terminal eight-stranded β-barrel domain that shares the same architecture as the Slam-dependent Neisserial surface lipoproteins. The structure of these HphAs is strikingly similar to a novel hemophore discovered by Latham et al. (2019), named hemophilin1. The genetic organization of HphAs consist of genes encoding a Slam homolog and a TonB-dependent receptor (TBDR). We investigated the Slam-HphA system in the native organism or the reconstituted system inE. colicells and found that the efficient secretion of HphA is dependent on Slam. The TBDR also played an important role for heme uptake and conferred specificity for its cognate HphA. Furthermore, bioinformatic analysis of HphA homologs revealed that HphAs are conserved in the alpha, beta, and gammaproteobacteria Together, these results show that HphA presents a new class of hemophores in Gram-negative bacteria and further expands the role of Slams in transporting soluble proteins supporting it role as a type 11 secretion system.
Novel insight into the etiology of ischemic stroke gained by integrative transcriptome-wide association study
Authors: Jung Junghyun , Lu Zeyun , de Smith Adam , Mancuso Nicholas
Published: March 2023

Stroke, characterized by sudden neurological deficits, is the second leading cause of death worldwide. Although genome-wide association studies (GWAS) have successfully identified many genomic regions associated with ischemic stroke (IS), the genes underlying risk and their regulatory mechanisms remain elusive. Here, we integrate a large-scale GWAS (N=1,296,908) for IS together with mRNA, splicing, enhancer RNA (eRNA) and protein expression data (N=11,588) from 50 tissues. We identify 136 genes/eRNA/proteins associated with IS risk across 54 independent genomic regions and find IS risk is most enriched for eQTLs in arterial and brain-related tissues. Focusing on IS-relevant tissues, we prioritize 9 genes/proteins using probabilistic fine-mapping TWAS analyses. In addition, we discover that blood cell traits, particularly reticulocyte cells, have shared genetic contributions with IS using TWAS-based pheWAS and genetic correlation analysis. Lastly, we integrate our findings with a large-scale pharmacological database and identify a secondary bile acid, deoxycholic acid, as a potential therapeutic component. Our work highlights IS risk genes/splicing-sites/enhancer activity/proteins with their phenotypic consequences using relevant tissues as well as identify potential therapeutic candidates for IS.
Impact of Case and Control Selection on Training AI Screening of Cardiac Amyloidosis
Authors: Vrudhula Amey , Stern Lily , Cheng Paul C , Ricchiuto Piero , Daluwatte Chathuri , Witteles Ronald , Patel Jignesh , Ouyang David
Published: March 2023

Background

Recent studies suggest that cardiac amyloidosis (CA) is significantly underdiagnosed. For rare diseases like CA, the optimal selection of cases and controls for artificial intelligence (AI) model training is unknown and can significantly impact model performance.

Objectives

This study evaluates the performance of ECG waveform-based AI models for CA screening and assesses impact of different criteria for defining cases and controls.

Methods

Models were trained using different criteria for defining cases and controls including amyloidosis by ICD 9/10 code, cardiac amyloidosis, patients seen in CA clinic). The models were then tested on test cohorts with identical selection criteria as well as population-prevalence cohorts.

Results

In matched held out test datasets, different model AUCs ranged from 0.660 to 0.898. However, these same algorithms exhibited variable generalizability when tested on a population cohort, with AUCs dropping to 0.467 to 0.880. More stringent case definitions during training result in higher AUCs on the similarly constructed test cohort; however representative population controls matched for age and sex resulted in the best population screening performance.

Conclusions

AUC in isolation is insufficient to evaluate the performance of a deep learning algorithm, and the evaluation in the most clinically meaningful population is key. Models designed for disease screening are best with matched population controls and performed similarly irrespective of case definitions.
Mapping RUNX2 transcriptional dynamics during multi-lineage differentiation of human mesenchymal stem cells
Authors: Govindaraj Kannan , Kannan Sakshi , Karperien Marcel , Post Janine N.
Published: March 2023

The multi-lineage differentiation capacity of human mesenchymal stem cells (hMSCs) enables its potential for tissue engineering and regenerative medicine. Master transcription factors play a key role during development, differentiation, homeostasis and disease pathology. RUNX2 is the master transcription factor for bone development, and it regulates several important signaling pathways during chondrogenic and osteogenic differentiation of hMSCs. However, modulation of RUNX2 activity during hMSC differentiation into various lineages is not yet fully described. We differentiated hMSCs into chondro-, osteo-, and adipogenic lineages and studied RUNX2 protein dynamics using Transcription Factor - Fluorescence Recovery After Photobleaching (TF-FRAP) at different time points. The TF-FRAP method can capture the dynamic changes of RUNX2 protein mobility at the single cell level resolution, and cluster analysis shows how RUNX2 dynamics change at subpopulation level in proliferating and differentiating hMSCs. Our data show that although whole hMSC population is exposed to differentiation stimuli, some subpopulations in hMSCs do not respond to environmental cues.
InCampylobacter jejunia new type of chaperone receives hemebfrom ferrochelatase
Authors: Beas Jordi Zamarreño , Videira Marco A.M. , Karavaeva Val , Lourenço Frederico S. , Almeida Mafalda R. , Sousa Filipa , Saraiva Lígia M.
Published: March 2023

Intracellular heme formation and trafficking are fundamental processes in living organisms. Three biogenesis pathways are used by bacteria and archaea to produce iron protoporphyrin IX (hemeb) that diverge after the formation of the common intermediate uroporphyrinogen III (uro’gen III). In this work, we identify and provide a detailed characterization of the enzymes involved in the transformation of uro’gen III into heme. We show that in this organism operates the protoporphyrin-dependent pathway (PPD pathway), in which the last reaction is the incorporation of ferrous iron into the porphyrin ring by the ferrochelatase enzyme. In general, following this final reaction, little is known about how the formed hemebreaches the target proteins. In particular, the chaperons that are thought to be required to traffic heme for incorporation into hemeproteins to avoid the cytotoxicity associated to free heme, remain largely unidentified. We identified inC. jejunia chaperon-like protein, named CgdH2, that binds heme with a dissociation constant of 4.9 ± 1.0 µM, a binding that is impaired upon mutation of residues histidine 45 and 133. We show thatC. jejuniCgdH2 establishes protein-protein interactions with ferrochelatase, which should enable for the observed transfer of heme from ferrochelatase to CgdH2. Phylogenetic analysis revealed thatC. jejuniCgdH2 is evolutionarily distinct from the currently known chaperones. Therefore, CgdH2 is a novel chaperone and the first protein identified as an acceptor of the intracellularly formed heme, thus enlarging our understanding of bacterial heme homeostasis.
Integrated spatiotemporal transcriptomic resolution of embryonic palate osteogenesis
Authors: Piña Jeremie Oliver , Raju Resmi , Roth Daniela M. , Chattaraj Parna , Kidwai Fahad , Faucz Fabio R. , Iben James , Mitra Apratim , Campbell Kiersten , Fridell Gus , Esnault Caroline , Dale Ryan K. , D’Souza Rena N.
Published: March 2023

The differentiation of osteoblasts and the subsequent formation of bone marks an important terminal phase in palate formation that leads to the separation of the oral and nasal cavities. While the developmental events that precede palatal osteogenesis are well explored, major gaps remain in our understanding of the molecular mechanisms that lead to the bony union of fusing palatal shelves. Herein, the timeline of osteogenic transcriptional programming is unveiled in the embryonic palate by way of integrated bulk, single-cell, and spatially resolved RNA-seq analyses. We define spatially restricted expression patterns of key marker genes, both regulatory and structural, that are differentially expressed during palatal fusion, including the identification of several novel genes (Deup1, Dynlrb2, Lrrc23) spatially restricted in expression to the palate, providing a relevant framework for future studies that identify new candidate genes for cleft palate anomalies in humans as well as the timing of mammalian embryonic palatal osteogenesis.
Induction of mitophagy reverts age-associated decline of the hematopoietic and immune systems
Authors: Girotra Mukul , Chiang Yi-Hsuan , Charmoy Melanie , Ginefra Pierpaolo , Schyrr Frederica , Franco Fabien , Ho Ping-Chih , Naveiras Olaia , Auwerx Johan , Held Werner , Vannini Nicola
Published: March 2023

Aging compromises hematopoietic and immune system functions, making elderly individuals especially susceptible to hematopoietic failure, infections and tumor development and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward myeloid lineage (myeloid-bias). These processes are accompanied by an aberrant accumulation of mitochondria in HSCs. The administration of the mitophagy-inducer Urolithin-A re-establishes the correct mitochondrial homeostasis in HSCs and completely restores the blood reconstitution capability of “old” HSCs. Moreover, Urolithin-A supplemented food restores lymphoid compartments, boosts HSCs function and improves the immune response to viral infection in old mice. Altogether our results demonstrate that targeting mitophagy reverts aging phenotype in the hematopoietic and immune system.
Blood biomarkers-defined subgroups show heterogeneity in post-acute COVID-19 syndrome: a rationale for precision medicine
Authors: Charvet Benjamin , Lucas Alexandre , Pierquin Justine , Brunel Joanna , Fried Steven , Bernis Corinne , Orban Zachary S. , Jimenez Millenia , Hanson Barbara A. , Visvabharathy Lavanya , Koralnik Igor J. , Perron Hervé
Published: March 2023

Acute COVID-19 can cause a post-infectious syndrome in a significant percentage of patients, with multifacted and long lasting symptoms. We hypothesized that this Post-Acute COVID syndrome (PASC) could result from various underlying causes, which may compromise the demonstration of efficacy for treatments evaluated on cohorts of heterogeneous patients.

To assess the feasibility of stratifying or characterizing subgroups of post-COVID-19 patients consistent with different indications in a precision medicine perspective, we tested serum biomarkers in a pilot cross-sectional study of patients with neuro-cognitive symptoms from the Northwestern University post-COVID-19 clinic (Chicago,USA). Patient health status was evaluated with the use of standardized PROMIS questionnaires and underwent validated cognitive tests with the NIH Toolbox. Serum biomarkers were chosen as proteins known to be involved in the pathogenic features of a neuro-inflammatory disease, i.e., multiple sclerosis, with a final selection of the most discriminant ones. A multi-isotypes serology against SARS-CoV-2 spike and nucleocapsid antigens was performed to allow detailed analyses of the humoral immune status.

Despite the limited numbers of this feasibility study, results showed that clinical data could not differentiate PASC patients with persisting neuro-cognitive impairment, while three major PASC subgroups were identified with serum biomarkers according to the presence or absence of the HERV-W ENV soluble protein combined with neurofilaments light chains and, to a lesser extent, with elevated levels of IL-6. SARS-CoV-2 serological results in PASC compared to healthy controls also revealed a significant increase of anti-Spike and/or Nucleocapsid IgM, IgA and, unexpectedly, IgE. For IgG, a significant difference was observed with Nucleocapsid only since anti-Spike IgG titers were normally elevated in vaccinated controls. This multi-Ig isotypes serology may provide additional information on the infectious and immunological status of individual patients and should be considered in face of a potential viral persistence in some individuals.

Altogether the results show the feasibility of using serum biomarkers to discriminate relevant subgroups or individual patients for precision medicine indications in post-COVID syndromes. This pilot study paves the way to further exploring biological assays for the definition of subtypes of PASC, also called long COVID, useful for the choice of relevant therapeutic strategies.
Subgrouping multimorbid patients with ischemic heart disease by means of unsupervised clustering: A cohort study of 72,249 patients defined comprehensively by diagnoses prior to presentation
Authors: Haue Amalie D. , Holm Peter C. , Banasik Karina , Lundgaard Agnete T. , Muse Victorine P. , Röder Timo , Westergaard David , Chmura Piotr J. , Christensen Alex H. , Weeke Peter E. , Sørensen Erik , Pedersen Ole B. V. , Ostrowski Sisse R. , Iversen Kasper K. , Køber Lars V. , Ullum Henrik , Bundgaard Henning , Brunak Søren
Published: March 2023

Background

There are no methods for classifying patients with ischemic heart disease (IHD) based on the entire spectrum of pre-existing diseases. Such methods might be clinically useful due to the marked differences in presentation and course of disease.

Methods

A population-based cohort study from a Danish secondary care setting of patients with IHD (2004-2016) and subjected to a coronary angiography (CAG) or coronary computed tomography angiography (CCTA). Data sources were The Danish National Patient Registry, in-hospital laboratory data, and genetic data from Copenhagen Hospital Biobank. Comorbidities included diagnoses assigned prior to presentation of IHD. Patients were clustered by means of the Markov Clustering Algorithm using the entire spectrum of registered multimorbidity. The two prespecified outcomes were: New ischemic events (including death from IHD causes) and death from non-IHD causes. Patients were followed from date of CAG/CCTA until one of the two outcomes occurred or end of follow-up, whichever came first. Biological and clinical appropriateness of clusters was assessed by comparing risks (estimated from Cox proportional hazard models) in clusters and by phenotypic and genetic enrichment analyses, respectively.

Findings

In a cohort of 72,249 patients with IHD (mean age 63.9 years, 63.1% males), 31 distinct clusters (C1-31, 67,136 patients) were identified. Comparing each cluster to the 30 others, seven clusters (9,590 patients) had statistically significantly higher or lower risk of new ischemic events (five and two clusters, respectively). 18 clusters (35,982 patients) had a higher or lower risk of death from non-IHD causes (12 and six clusters, respectively). All clusters at increased risk of new ischemic events, associated with risk of death from non-IHD causes as well. Cardiovascular or inflammatory diseases were commonly enriched in clusters (13), and distributions for 24 laboratory test results differed significantly across clusters. Clusters enriched for cerebrovascular diseases were generally not at increased risk of the two outcomes. Polygenic risk scores were increased in a total of 15 clusters (48.4%).

Conclusions

Clustering of patients with IHD based on pre-existing comorbidities identified subgroups of patients with significantly different clinical outcomes and presented a tool to rank pre-existing comorbidities based on their association with clinical outcomes. This novel method may support better classification of patients and thereby differentiation of treatment intensity depending on expected outcomes in subgroups.
Volatility transmission dynamics between energy and financial indices of emerging markets: a comparison between the subprime crisis and the COVID-19 pandemic
Authors: Molina-Muñoz Jesús , Mora–Valencia Andrés , Perote Javier , Rodríguez-Raga Santiago
Published: March 2023

Purpose

This paper aims to analyze the volatility transmission between an energy stock index and a financial stock index in emerging markets during recent high instability periods. The study considers the impact of both the period under analysis and the data frequency on the direction and intensity of the contagion, as well as the effect of the potential spillovers on the risk measures. These questions still lack definitive answers and have become more relevant in a context of financially unsettling events such as COVID-19 crises.

Design/methodology/approach

This study employs an extension of the dynamic conditional correlation (DCC) model that allows for the time-varying dependence relationship between the variables. This dependence is analyzed at daily, weekly and monthly basis using data from the Bloomberg platform on energy and stock market indices for emerging markets between 2001 and 2021.

Findings

The results for a sample spanning from 2001 to mid-2021 show bidirectional volatility transmission on a daily basis, whereas only evidence of volatility transmission from the financial to the energy exists for weekly and monthly frequencies. However, considering different subsamples of daily data, the authors only find volatility transmission from financial (energy) index to the energy (financial) during the Great Recession (COVID-19) as a consequence of the different source of the shock and transmission channels.

Originality/value

This study reveals that volatility transmission between energy and stocks in emerging markets has changed and presents a unidirectional pattern from energy to financial markets during the COVID-19 period in contrast to calm and the sub-prime crisis intervals. These results differ from previous studies, focused on global markets, that show bidirectional spillovers during this period.
Desire and craving measured using behavioral ratings and brain network topology differ significantly among moderate to heavy alcohol consumers
Authors: Peterson‐Sockwell Hope , Veach Laura J. , Simpson Sean L. , Fanning Jason , Laurienti Paul J. , Gauvin Lise
Published: March 2023

Background

"Craving" is a central concept in alcohol research, but the semantic interpretation of craving as a concept varies. Multiple studies that have investigated differences in operational definitions of craving have demonstrated a lack of agreement among them. This study investigated whether moderate to heavy drinkers would rate craving and “desire” for alcohol similarly and explored potential neurobiological differences underpinning feelings of craving and desire.

Methods

Thirty‐nine individuals who consumed an average of at least 7 drinks/week for females and 14 drinks/week for males were studied across 3‐day periods of their typical alcohol consumption and imposed abstinence. Ratings of desire and craving for alcohol were collected approximately every three hours during waking periods across the two experimental periods (n = 35, 17 males). At the end of each period, participants underwent functional MRI scanning during neutral and alcohol image viewing (n = 39, 17 males) followed by ratings of desire and craving for alcohol (n = 32, 16 males). Survey responses were analyzed using 2‐level nested hierarchical modeling, image ratings were compared using a hierarchical mixed‐effects regression, and brain networks constructed from fMRI data were assessed with a two‐part mixed‐effect regression (α = 0.05 in all analyses).

Results

Ratings of desire and craving differed significantly from one another in the survey data and in the ratings collected during image viewing. The strength of the desire experience was higher overall than craving, but the fluctuations over time were similar. Results for desire and craving differed on brain network attributes associated with distributed processing and those regional specific within the default mode network. Significant associations were found between ratings of desire and connection strength and between ratings of craving and connection probability.

Conclusions

These results demonstrate that the difference between ratings of craving for alcohol and desire for alcohol is not trivial. The different ratings and their association with alcohol consumption or abstinence experiences may have significant biological and clinical implications.
Window‐dressing policy: Thailand's misuse of soft power as cursory practice
Authors: Charoenvattananukul Peera
Published: March 2023

Joseph Nye's soft power has become popular among academics and practitioners in Thailand for decades. Despite its pervasiveness in Thai society, the soft power concept, which is predicated on the outcome‐based definition of power, has been misconstrued by Thai policymakers as synonymous with the resource‐based definition of power. This policy review examines key strategic blueprints of the relevant Thai state agencies and argues that they misunderstand soft power in its entirety. Mistaking soft power as cultural resources gravely affects how the Thai state agencies outline policy evaluation criteria, which neither conform to Nye's expectations nor achieve the Thai government's objectives. This policy review, however, discovers that “Thailand Foundation,” which is the affiliated organization of Thailand's Ministry of Foreign Affairs, appropriately designs soft power indicators that can be emulated by the other Thai state agencies to make soft power strategies work for Thailand.
The need to belong: Girls' trajectory perspectives on friendship forming in the school setting
Authors: Forsberg Camilla
Published: March 2023

This article is based on pair and group interviews with 40 girls in lower secondary school in Sweden and examines their perspectives on friendship forming. Constructivist grounded theory was used throughout the study. The findings address girls' trajectory perspectives on friendship forming and how the school setting, gender norms and social exclusion anxiety influence their friendships over time. In particular, they highlight a fear of being excluded as associated with the school setting. This fear shows how friendship forming and bullying connect to each other by highlighting how the need to socially belong is the most important thing in school.
The landscapes of lives I: An action landscape approach to practices and the interface of individual and society
Authors: Worthman Carol M. , Cummings Constance A. , Lende Daniel
Published: March 2023

Practices occupy the intersection of human behavior with its personal and societal dimensions, operating in social theory as bridges between high‐order cultural features and on‐the‐ground dynamics that reciprocally shape the conditions of everyday life and animate human experience. Yet precisely how this bridging occurs remains underspecified. We address that gap in this and a companion article (Worthman, Cummings, and Lende 2023). This article situates practices in dynamic action space, while the second details how those dynamics work and applies them to questions of inequity, resilience, and contemplative practice. We trace a spectrum of practices from mundane activities to formal rituals and self‐transformational pursuits. We then situate them within a socioecological framework, drawing on the visual metaphor of Charles Waddington's epigenetic landscape to represent fields of possible practices or action landscapes that are contingent, situated, and dynamically configured to constitute the middle ground bridging social actors and lived experience with sociocultural worlds.
Climate drivers alter nitrogen availability in surface peat and decouple N2 fixation from CH4 oxidation in the Sphagnum moss microbiome
Authors: Petro Caitlin , Carrell Alyssa A. , Wilson Rachel M. , Duchesneau Katherine , Noble‐Kuchera Sekou , Song Tianze , Iversen Colleen M. , Childs Joanne , Schwaner Geoff , Chanton Jeffrey P. , Norby Richard J. , Hanson Paul J. , Glass Jennifer B. , Weston David J. , Kostka Joel E.
Published: March 2023

Peat mosses (Sphagnum spp.) are keystone species in boreal peatlands, where they dominate net primary productivity and facilitate the accumulation of carbon in thick peat deposits. Sphagnum mosses harbor a diverse assemblage of microbial partners, including N2‐fixing (diazotrophic) and CH4‐oxidizing (methanotrophic) taxa that support ecosystem function by regulating transformations of carbon and nitrogen. Here, we investigate the response of the Sphagnum phytobiome (plant + constituent microbiome + environment) to a gradient of experimental warming (+0°C to +9°C) and elevated CO2 (+500 ppm) in an ombrotrophic peatland in northern Minnesota (USA). By tracking changes in carbon (CH4, CO2) and nitrogen (NH4‐N) cycling from the belowground environment up to Sphagnum and its associated microbiome, we identified a series of cascading impacts to the Sphagnum phytobiome triggered by warming and elevated CO2. Under ambient CO2, warming increased plant‐available NH4‐N in surface peat, excess N accumulated in Sphagnum tissue, and N2 fixation activity decreased. Elevated CO2 offset the effects of warming, disrupting the accumulation of N in peat and Sphagnum tissue. Methane concentrations in porewater increased with warming irrespective of CO2 treatment, resulting in a ~10× rise in methanotrophic activity within Sphagnum from the +9°C enclosures. Warming's divergent impacts on diazotrophy and methanotrophy caused these processes to become decoupled at warmer temperatures, as evidenced by declining rates of methane‐induced N2 fixation and significant losses of keystone microbial taxa. In addition to changes in the Sphagnum microbiome, we observed ~94% mortality of Sphagnum between the +0°C and +9°C treatments, possibly due to the interactive effects of warming on N‐availability and competition from vascular plant species. Collectively, these results highlight the vulnerability of the Sphagnum phytobiome to rising temperatures and atmospheric CO2 concentrations, with significant implications for carbon and nitrogen cycling in boreal peatlands.