bluuebunny/crossref_metadata_2025 huggingface dataset:
Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury
Authors: MacLean Mark A. , Muradov Jamil H. , Greene Ryan , Van Hameren Gerben , Clarke David B. , Dreier Jens P. , Okonkwo David O. , Friedman Alon
Published: December 2023

Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals (N= 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial.
Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway
Authors: Zhang Cheng , Yu Jiao-jiao , Yang Chen , Yuan Zhen-long , Zeng Hui , Wang Jun-jian , Shang Shuang , Lv Xiao-xi , Liu Xiao-tong , Liu Jing , Xue Qi , Cui Bing , Tan Feng-wei , Hua Fang
Published: December 2023

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1
WT
) as a potential diagnostic and prognostic biomarker for non–small cell lung cancer (NSCLC), but how IDH1
WT
modulates NSCLC progression remains elusive. Here, we report that IDH1
WT
activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1
WT
interacts with and stabilizes PHGDH and fragile X–related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports
PSAT1
mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1
WT
-PHGDH and IDH1
WT
-FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine–depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1
WT
in serine metabolism, highlighting IDH1
WT
as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.
Short-course combination treatment for experimental chronic Chagas disease
Authors: González Silvia , Wall Richard J. , Thomas John , Braillard Stephanie , Brunori Gino , Camino Díaz Isabel , Cantizani Juan , Carvalho Sandra , Castañeda Casado Pablo , Chatelain Eric , Cotillo Ignacio , Fiandor Jose M. , Francisco Amanda Fortes , Grimsditch David , Keenan Martine , Kelly John M. , Kessler Albane , Luise Chiara , Lyon Jon J. , MacLean Lorna , Marco Maria , Martin J. Julio , Martinez Martinez Maria S. , Paterson Christy , Read Kevin D. , Santos-Villarejo Angel , Zuccotto Fabio , Wyllie Susan , Miles Tim J. , De Rycker Manu
Published: December 2023

Chagas disease, caused by the protozoan parasite
Trypanosoma cruzi
, affects millions of people in the Americas and across the world, leading to considerable morbidity and mortality. Current treatment options, benznidazole (BNZ) and nifurtimox, offer limited efficacy and often lead to adverse side effects because of long treatment durations. Better treatment options are therefore urgently required. Here, we describe a pyrrolopyrimidine series, identified through phenotypic screening, that offers an opportunity to improve on current treatments. In vitro cell-based washout assays demonstrate that compounds in the series are incapable of killing all parasites; however, combining these pyrrolopyrimidines with a subefficacious dose of BNZ can clear all parasites in vitro after 5 days. These findings were replicated in a clinically predictive in vivo model of chronic Chagas disease, where 5 days of treatment with the combination was sufficient to prevent parasite relapse. Comprehensive mechanism of action studies, supported by ligand-structure modeling, show that compounds from this pyrrolopyrimidine series inhibit the Q
i
active site of
T. cruzi
cytochrome b, part of the cytochrome bc
1
complex of the electron transport chain. Knowledge of the molecular target enabled a cascade of assays to be assembled to evaluate selectivity over the human cytochrome b homolog. As a result, a highly selective and efficacious lead compound was identified. The combination of our lead compound with BNZ rapidly clears
T. cruzi
parasites, both in vitro and in vivo, and shows great potential to overcome key issues associated with currently available treatments.
Skin tropism during Usutu virus and West Nile virus infection: an amplifying and immunological role
Authors: Vouillon Axelle , Barthelemy Jonathan , Lebeau Lucie , Nisole Sébastien , Savini Giovanni , Lévêque Nicolas , Simonin Yannick , Garcia Magali , Bodet Charles
Published: December 2023

Usutu virus (USUV) and West Nile virus (WNV) are closely related emerging arboviruses belonging to the
Flavivirus
genus and posing global public health concerns. Although human infection by these viruses is mainly asymptomatic, both have been associated with neurological disorders such as encephalitis and meningoencephalitis. Since USUV and WNV are transmitted through the bite of an infected mosquito, the skin represents the initial site of virus inoculation and provides the first line of host defense. Although some data on the early stages of WNV skin infection are available, very little is known about USUV. Herein, USUV-skin resident cell interactions were characterized. Using primary human keratinocytes and fibroblasts, an early replication of USUV during the first 24 hours was shown in both skin cells. In human skin explants, a high viral tropism for keratinocytes was observed. USUV infection of these models induced type I and III interferon responses associated with upregulated expression of various interferon-stimulated genes as well as pro-inflammatory cytokine and chemokine genes. Among the four USUV lineages studied, the Europe 2 strain replicated more efficiently in skin cells and induced a higher innate immune response.
In vivo
, USUV and WNV disseminated quickly from the inoculation site to distal cutaneous tissues. In addition, viral replication and persistence in skin cells were associated with an antiviral response. Taken together, these results provide a better understanding of the pathophysiology of the early steps of USUV infection and suggest that the skin constitutes a major amplifying organ for USUV and WNV infection.

IMPORTANCE

Usutu virus (USUV) and West Nile virus (WNV) are closely related emerging
Flaviviruses
transmitted through the bite of an infected mosquito. Since they are directly inoculated within the upper skin layers, the interactions between the virus and skin cells are critical in the pathophysiology of USUV and WNV infection. Here, during the early steps of infection, we showed that USUV can efficiently infect two human resident skin cell types at the inoculation site: the epidermal keratinocytes and the dermal fibroblasts, leading to the induction of an antiviral innate immune response. Moreover, following cutaneous inoculation, we demonstrated that both viruses can rapidly spread, replicate, and persist in all distal cutaneous tissues in mice, a phenomenon associated with a generalized skin inflammatory response. These results highlight the key amplifying and immunological role of the skin during USUV and WNV infection.
Complete genomic analysis of
Escherichia
phage Mangalyan infecting
Escherichia fergusonii
Authors: Manohar Prasanth , Young Ry
Published: December 2023

Escherichia fergusonii
is a rarely isolated opportunistic pathogen in animals and humans. Here, we present the annotated genome sequence of
Escherichia
phage Mangalyan, a T4-like bacteriophage infecting
E. fergusonii
isolated from chickens. Phage Mangalyan has a genome length of 140,513 bp and belongs to the
Vequintavirinae
family.
Symbiotic nutrient exchange enhances the long-term survival of cassiosomes, the autonomous stinging-cell structures of
Cassiopea
Authors: Toullec Gaëlle , Lyndby Niclas Heidelberg , Banc-Prandi Guilhem , Pogoreutz Claudia , Martin Olmos Cristina , Meibom Anders , Rädecker Nils
Published: December 2023

Medusae of the widely distributed upside-down jellyfish
Cassiopea
release autonomous, mobile stinging structures. These so-called cassiosomes play a role in predator defense and prey capture, and are major contributors to “contactless” stinging incidents in (sub-)tropical shallow waters. While the presence of endosymbiotic dinoflagellates in cassiosomes has previously been observed, their potential contribution to the metabolism and long-term survival of cassiosomes is unknown. Combining stable isotope labeling and correlative scanning electron microscopy and nanoscale secondary ion mass spectrometry imaging with a long-term
in vitro
experiment, our study reveals a mutualistic symbiosis based on nutritional exchanges in dinoflagellate-bearing cassiosomes. We show that organic carbon input from the dinoflagellates fuels the metabolism of the host tissue and enables anabolic nitrogen assimilation. This symbiotic nutrient exchange enhances the life span of cassiosomes for at least one month
in vitro
. Overall, our study demonstrates that cassiosomes, in analogy with
Cassiopea
medusae, are photosymbiotic holobionts. Cassiosomes, which are easily accessible under aquarium conditions, promise to be a powerful new miniaturized model system for in-depth ultrastructural and molecular investigation of cnidarian photosymbioses.

IMPORTANCE

The upside-down jellyfish
Cassiopea
releases autonomous tissue structures, which are a major cause of contactless stinging incidents in (sub-) tropical coastal waters. These so-called cassiosomes frequently harbor algal symbionts, yet their role in cassiosome functioning and survival is unknown. Our results show that cassiosomes are metabolically active and supported by algal symbionts. Algal photosynthesis enhances the cassiosomes long-term survival in the light. This functional understanding of cassiosomes thereby contributes to explaining the prevalence of contactless stinging incidents and the ecological success of some
Cassiopea
species. Finally, we show that cassiosomes are miniaturized symbiotic holobionts that can be used to study host-microbe interactions in a simplified system.
Generation of Quantum Vortices by Waves on the Surface of Superfluid Helium
Authors: Sultanova M. R. , Remizov I. A. , Mezhov-Deglin L. P. , Levchenko A. A.
Published: December 2023

The formation of quantum vortices by two mutually perpendicular waves excited on the surface of superfluid helium has been observed. The interaction of negative charges injected under the surface of He-II with the vortex flow of the liquid, which is formed by surface waves at frequencies from 20 to 49.9 Hz, in the temperature range of 1.5–2.17 K has been studied experimentally by analyzing the current distribution detected by vertically oriented segments of a receiving collector. The efficient capture of injected charges by quantum vortices has been observed at a temperature of T = 1.5 K, which leads to a significant redistribution of currents between segments of the receiving collector. Charges leave traps on quantum vortices at temperatures near T = 1.7 K. With a further increase in the temperature, injected charges are scattered on vortex flows of the normal component, which are generated by surface waves.
Research opportunities for the primordial prevention of rheumatic fever and rheumatic heart disease—streptococcal vaccine development: a national heart, lung and blood institute workshop report
Authors: Fulurija Alma , Cunningham Madeleine W , Korotkova Natalia , Masterson Mary Y. , Bansal Geetha P. , Baker Michael G. , Cannon Jeffrey W. , Carapetis Jonathan R. , Steer Andrew C.
Published: December 2023

Streptococcus pyogenes,also known as group A streptococcus (StrepA), is a bacterium that causes a range of human diseases, including pharyngitis, impetigo, invasive infections, and post-infection immune sequelae such as rheumatic fever and rheumatic heart disease. StrepA infections cause some of the highest burden of disease and death in mostly young populations in low-resource settings. Despite decades of effort, there is still no licensed StrepA vaccine, which if developed, could be a cost-effective way to reduce the incidence of disease. Several challenges, including technical and regulatory hurdles, safety concerns and a lack of investment have hindered StrepA vaccine development. Barriers to developing a StrepA vaccine must be overcome in the future by prioritising key areas of research including greater understanding of StrepA immunobiology and autoimmunity risk, better animal models that mimic human disease, expanding the StrepA vaccine pipeline and supporting vaccine clinical trials. The development of a StrepA vaccine is a complex and challenging process that requires significant resources and investment. Given the global burden of StrepA infections and the potential for a vaccine to save lives and livelihoods, StrepA vaccine development is an area of research that deserves considerable support. This report summarises the findings of the Primordial Prevention Working Group-VAX, which was convened in November 2021 by the National Heart, Lung, and Blood Institute. The focus of this report is to identify research gaps within the current StrepA vaccine landscape and find opportunities and develop priorities to promote the rapid and successful advancement of StrepA vaccines.
Opportunities to improve asthma and COPD prevention and care: insights from the patient journey obtained through focus groups
Authors: Collins-Fairclough Aneisha , Rideout Karen , Joshi Phalgun , Philips Jeremiah , Lanier Tony , Chow Santa , Smith Dan , Hoens Alison , FitzGerald J Mark , Rauscher Chris , Strydom Nardia , Carlsten Christopher
Published: December 2023

Background

The healthcare experiences of patients hold valuable insights for improving the quality of services related to their well-being. We therefore invited and explored the perspectives of patients living with asthma and chronic obstructive pulmonary disease (COPD) on their interaction with the systems supporting health, in order to identify opportunities to improve services to prevent, treat and manage these conditions.

Methods

Two virtual focus groups were held in August 2021, one for adult asthma and one for COPD, to learn of patients’ experiences receiving care for these conditions in the Vancouver Coastal Health (VCH) region of British Columbia. Participants were recruited through online postings or their clinician. We discussed the care pathway for each condition and invited participants to share their experiences of the past 5 years, specifically their reflections on the process, including feelings, points of praise and frustration, and opportunities for improvement in this context. Composite patient journey maps were developed for each condition to reflect the experiences shared. Audio recordings of the focus groups were transcribed and used in qualitative data analysis.

Results

Thematic analysis revealed the following as possible areas for improvement: low public awareness of asthma and COPD and associated risk factors, non-standardised diagnosis pathways that delay diagnosis, and inconsistency in delivering valued aspects of care such as supports for self-management, trust-inspiring acute care, empowering patient communication and timely access to care.

Conclusion

We successfully used focus groups to generate composite journey maps of the experiences of patients living with asthma (n=8) and COPD (n=9) to identify features that these patients consider important for improving the healthcare system for asthma and COPD in VCH. Health professionals, decision makers and patient advocates in VCH and beyond can consider these insights when evaluating, and planning changes to, current practices and policies in service delivery.
Sex differences in the effectiveness of first-line tumour necrosis factor inhibitors in axial spondyloarthritis: results from the EuroSpA Research Collaboration Network
Authors: Hellamand Pasoon , van de Sande Marleen , Ørnbjerg Lykke MIdtbøll , Klausch Thomas , Nurmohamed Michael T , van Vollenhoven Ronald F , Nordström Dan , Hokkanen Anna Mari , Santos Maria Jose , Vieira-Sousa Elsa , Loft Anne G , Glintborg Bente , Hetland Merete Lund , Lindström Ulf , Wallman Johan K , Michelsen Brigitte , Klami Kristianslund Eirik , Ciurea Adrian , Nissen Michael S , Codreanu Catalin , Mogosan Corina , Macfarlane Gary J , Rotariu Ovidiu , Rotar Ziga , Tomšič Matija , Castrejon Isabel , Otero-Varela Lucia , Gudbjornsson Bjorn , Geirsson Arni Jon , Vencovský Jiří , Pavelka Karel , Gulle Semih , Zengin Berrin , Iannone Florenzo , Foti Rosario , Ostergaard Mikkel , van der Horst-Bruinsma Irene
Published: December 2023

Objective

Evidence indicates reduced treatment effectiveness of TNFi in women with axial spondyloarthritis (axSpA) compared with men. We aimed to investigate sex differences in treatment response and retention rates over 24 months of follow-up in axSpA patients initiating their first TNFi.

Methods

Data from axSpA patients initiating a TNFi in 1 of 15 registries within EuroSpA collaboration were pooled. We investigated the association of sex with treatment response using logistic regression. The primary outcome was clinically important improvement (CII) at 6 months according to Ankylosing Spondylitis Disease Activity Score with C-reactive protein (CRP) (≥1.1 decrease). We adjusted for age, country and TNFi start year. A secondary outcome was retention rates over 24 months of follow-up assessed by Kaplan-Meier estimator.

Results

In total, 6451 axSpA patients with data on CII were assessed for treatment response; 2538 (39%) were women and 3913 (61%) were men. Women presented at baseline with lower CRP levels but had higher scores on patient-reported outcome measures. At 6 months, 53% of the women and 66% of the men had CII. Women had a lower relative risk of CII compared with men (0.81; 95% CI 0.77 to 0.84). This sex difference was similar in adjusted analysis (0.85; 95% CI 0.82 to 0.88). Retention rates were evaluated in 27 702 patients. The TNFi 6/12/24 months retention rates were significantly lower among women (79%/66%/53%) than men (88%/79%/69%).

Conclusion

Treatment response and retention rates are lower among women with axSpA initiating their first TNFi. Sex differences in treatment effectiveness were present regardless of the outcome measure used for treatment response, and differences in retention rates transpired early and increased as time progressed.
Diagnostic utility of serum IgG4 level in IgG4-related diseases: a comprehensive systematic review and meta-analysis
Authors: Chang Che-Tzu , Chan Tien-Ming , Yu Han-Hua , Yu Kuang-Hui
Published: December 2023

Background

Despite many studies suggesting an association between serum IgG4 and IgG4-related diseases (IgG4-RD), the evidence of the utility of serum IgG4 titres in differentiating between IgG4-RD and non-IgG4-RD remains uncertain.

Methods

The primary analysis was based on published studies. Data were pooled by means of a random-effect model, and sensitivity, specificity, positive likelihood ratios (LR+), negative likelihood ratios (LR–), diagnostic ORs (DOR) and summary receiver operating characteristic curve (SROC) were calculated. Subgroup analyses were performed based on the racial/ethnic distribution of these studies.

Results

A total of 27 studies with 1691 (8.6%) IgG4-RD cases and 17 944 non-IgG4-RD subjects were included. Moreover, 1462 (86.5%) of the 1691 IgG4-RD patients had elevated serum IgG4 levels whereas 10.5% (1,882 of 17,944) of the non-IgG4-RD subjects had elevated serum IgG4 levels. The pooled sensitivity of serum IgG4 was 86% (85%–88%), specificity was 90% (89%–90%), LR+ was 9.19 (7.16–11.78), LR– was 0.17 (0.12–0.24), and the DOR was 60.8 (40.9–90.4), respectively. The area under the SROC curve for the differential diagnosis between IgG4-RD and non-IgG4-RD was 0.95 (0.94–0.97). Ethnic subgroup analyses revealed different findings with respect to DOR for Asian (103.8; 95% CI 63.3 to 170.2), and Caucasian (25.7; 95% CI 17.6 to 37.5) populations.

Conclusions

Overall, elevated serum IgG4 levels were associated with IgG4-RD. The results revealed a moderate-to-high sensitivity (86%, 85%–88%) and high specificity (90%, 89%–90%). Subgroup analyses in serum IgG4 diagnostic performance revealed differences among Asian and Caucasian populations.
No Little Feet: Managing Pseudocyesis in a Homeless, Acutely Manic Patient with Schizoaffective Disorder, Bipolar Type
Authors: West Talitha , Ajibade Omotola , Fontanetta Anthony , Munir Samreen
Published: December 2023

Pseudocyesis is a complex psychiatric manifestation of the physical symptoms of pregnancy. Although not pregnant, the pseudocyetic patient displays signs and symptoms consistent with pregnancy, such as abdominal distention, cramping, and/or sensations of fetal movement. Pseudocyesis is more common in developing countries than in the developed world, possibly due to the importance that traditional societies attach to childbearing and the low social status that these societies assign to women who are unable to produce children. Socioeconomically disadvantaged women in developed countries may also be at increased risk. Although the etiology, pathogenesis, diagnosis, and management of pseudocyesis are poorly understood, it manifests with real symptoms, which may complicate both the patient’s perspective about her condition and the medical and psychiatric teams’ approach to the patient. This case report is one of only a few in the literature to present an example of pseudocyesis developing in the context of acute mania. After describing the patient’s clinical course, from her initial symptoms of pseudocyesis to their eventual resolution, this report will provide recommendations for the sensitive care of patients with this rare but significant condition.
Detection of Human Stress Using Optimized Feature Selection and Classification in ECG Signals
Authors: G Narmadha , S Deivasigamani , Vellaisamy Muthukumar , Freitas Lídio Inácio , R Badlishah Ahmad , B Sakthivel
Published: December 2023

An autonomic nervous system (ANS) of humans is majorly affected by psychological stress. The changes in ANS may cause several chronic diseases in humans. The electrocardiogram (ECG) signal is used to observe the variation in ANS. Numerous techniques are presented for an ECG stress signal handling feature extraction and classification. This work managed a heart rate variability feature acquired from smaller peak waveforms such as P, Q, S, and T waves. Also, the R peak is detected, which is a significant part of the ECG waveform. In this work, the proposed stress classification work has been categorized into two main processes: feature selection (FS) and classification. The main aim of the proposed work is to propose an optimized FS and classifier model for the detection of stress in ECG signals. The Metaheuristics model of the African vulture optimization (AVO) technique is presented to perform an FS. This selection is made to choose the required features and minimize the data for classification. The AVO‐based modified Elman recurrent neural network (MERNN) technique is proposed to perform an efficient classification. The AVO is used for fine‐tuning the weight of the MERNN technique. The experimental result of this technique is evaluated in terms of Recall (91.56%), Accuracy (92.43%), Precision (92.78%), and F1 score (95.86%). Thus, the proposed performance achieved a superior result than the conventional techniques.
Circulating Inhibitor against Factor X: A Rare Cause of Hemorrhagic Diathesis
Authors: Rossignon P. , Grandjean F. , Claessens A. , Weynants N.
Published: December 2023

Acquired coagulopathies resulting from factor X deficiency are rare and typically associated with amyloidosis or plasma cell dyscrasia. Factor X plays a pivotal role in the coagulation cascade, converting prothrombin into thrombin and facilitating the formation of fibrinogen and thrombus. While its occurrence following common infections is extremely rare, isolated cases have been documented. We present a rare case of bleeding diathesis in a patient with community-acquired pneumonia, where prolonged activated partial thromboplastin time (aPTT) and prothrombin time (PT) led to the diagnosis of an infectious-triggered acquired circulating inhibitor targeting factor X. Prompt treatment with methylprednisolone effectively controlled the inhibitor without recurrence. This case report provides insights into the diagnostic strategies, differential algorithm, and therapeutic approaches for managing this rare coagulopathy.
Material Removal Mechanism and Evolution of Subsurface Defects during Nanocutting of Monocrystalline Cu
Authors: Liu Bing , Wang Yurong , Yang Haijie
Published: December 2023

Multigroup large-scalenanocutting models of monocrystalline Cu were established by molecular dynamics simulations to investigate the influence of cutting parameters on the material removal mechanism. The formation and distribution of subsurface defect structures were revealed, and the evolution behavior of the complete prismatic dislocation loop was analyzed in depth. It was demonstrated that the chips and machined surface of monocrystalline Cu were mainly formed under the coupling effect of shearing and extrusion forces. A diamond tool with a larger edge radius or a negative rake angle could produce a noticeable suppression on the chip formation. The corresponding relationship between the location of defect atoms and the distribution of von Mises stress was studied, which indicated that the shear stress would become larger at the subgrain boundaries, dislocation lines, and the amorphous atoms than that in their nearby regions. The complete prismatic dislocation loop was formed by cross-slip between two sets of stacking faults; meanwhile, the generated multiple Lomer–Cottrell locks hindered its movement and promoted the work-hardening phenomenon. These research results are of great theoretical value to enrich the nanocutting mechanism and technology of plastic materials.
IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation
Authors: Landberg Niklas , Köhnke Thomas , Feng Yang , Nakauchi Yusuke , Fan Amy C. , Linde Miles H. , Karigane Daiki , Lim Kelly , Sinha Rahul , Malcovati Luca , Thomas Daniel , Majeti Ravindra
Published: December 2023

Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia.

Significance:

A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition.

See related commentary by Steensma, p. 83.

This article is featured in Selected Articles from This Issue, p. 80
Well-Differentiated Adenocarcinoma Spreading Widely in the Gastric Submucosa
Authors: Kataoka Naoki , Oura Shoji , Nishino Eisei
Published: December 2023

A 56-year-old woman was referred to our hospital due to dry mouth. Diagnostic upper gastrointestinal endoscopy showed slightly elevated lesions both on the anterior wall and lesser curvature in the upper part of the stomach. Biopsy-proven tuble-forming atypical cells in the two lesions led us to treat the presumed early gastric cancers with endoscopic submucosal dissection (ESD). Pathological examination of the ESD specimen showed well-differentiated malignant cells spreading widely in the submucosa with positive lateral and deep margins. On retrospective image re-evaluation after ESD, we noticed the correlation between the presumed early gastric cancers and the multiple submucosal cyst-like lesions in the gastric wall on computed tomography. Under the tentative diagnosis of gastric cancers originating not from orthotopic gastric mucosa but from submucosal ectopic gastric gland, the patient underwent laparoscopic total gastrectomy and regional lymph node dissection, revealing the tumor infiltration to the serosa and regional lymph node swelling. Postoperative pathological evaluation showed lymph node metastases, multiple submucosal cyst-like lesions lined with a single layer of presumably benign epithelium, papillary adenocarcinoma cells in the submucosa, and tubular adenocarcinoma cells both in the mucosal and subserosal regions. The patient was discharged on the postoperative 7th day without any events and completed adjuvant chemotherapy on an outpatient basis. General surgeons should note that cyst-like lesion(s) in the gastric wall might be a predictor of extensive submucosal cancer cell spreading even in a case of well-differentiated gastric adenocarcinoma.
Phenotypic and Genetic Alterations in Adult-Onset Cone and Cone-Rod Dystrophy
Authors: Kim Dong Ju , Woo Se Joon , Joo Kwangsic
Published: December 2023

Introduction: The objective of this study was to investigate the clinical characteristics and genetic spectrum of adult-onset cone/cone-rod dystrophy (AOCD/AOCRD) in Korean individuals. Methods: This is a single-center, retrospective cross-sectional study. We analyzed 22 individuals with genetically confirmed cone dystrophy, with symptoms beginning after 30 years of age. All patients underwent comprehensive ophthalmic and electrophysiological examinations. Exome sequencing of 296 genes associated with inherited retinal disease was performed. The clinical features of patients with AOCD/AOCRD and the causative genes and variants detected by exome sequencing were analyzed. Results: The median age at the first visit was 52 years (range, 31–76 years), and the most common initial symptom was reduced visual acuity. In most cases, fundus photography showed a bull’s eye pattern with foveal sparing, consistent with perifoveal photoreceptor loss on optical coherence tomography. We identified disease-causing variants in six genes: RP1, CRX, CDHR1, PROM1, CRB1, and GUCY2D. Pathogenic variants in RP1, CRX, and CDHR1 were identified in 77% of the AOCD/AOCRD cases, including p.Cys1399LeufsTer5, p.Arg1933Ter, and p.Ile2061SerfsTer12 in RP1; p.Ter300GlnextTer118 in CRX; and p.Glu201Lys in CDHR1. No characteristic imaging differences were observed for any of the causative genes. Most of the RP1-related AOCD/AOCRD cases showed a decreased amplitude only in the photopic electroretinogram (ERG), whereas CRX-related AOCD/AOCRD cases showed a slightly decreased amplitude in both the scotopic and photopic ERGs. Conclusion: In case of visual impairment with bull’s eye pattern of RPE atrophy recognized after the middle age, a comprehensive ophthalmic examination and genetic test should be considered, with the possibility of AOCD/AOCRD in East Asians.
Ethnic Differences in Carotid Intima-Media Thickness and Plaque Presence: The HELIUS Study
Authors: Vriend Esther M.C. , Bouwmeester Thomas A. , Artola Arita Vicente , Bots Michiel L. , Meijer Rudy , Galenkamp Henrike , Stronks Karien , Collard Didier , Moll van Charante Eric P. , van den Born Bert-Jan H. , Franco Oscar H.
Published: December 2023

Introduction: In the Netherlands, the prevalence of cardiovascular diseases (CVDs) is higher among South-Asian Surinamese and lower among Moroccans compared to the Dutch. Traditional risk factors for atherosclerotic CVD do not fully explain these disparities. We aimed to assess ethnic differences in plaque presence and carotid intima-media thickness (cIMT) and explore to what extent these differences are explained by traditional risk factors. Methods: We used cross-sectional data from a subgroup of participants enrolled in the multi-ethnic population-based Healthy Life in an Urban Setting (HELIUS) study who underwent carotid ultrasonography. Logistic and linear regression models were built to assess ethnic differences in plaque presence and cIMT with the Dutch population as reference. Additional models were created to adjust for socioeconomic status, body height, and cardiovascular risk factors. Results: Of the 3,022 participants, 1,183, 1,051, and 790 individuals were of Dutch, South-Asian Surinamese, and Moroccan descent, respectively. Mean age was 60.9 years (SD: 8.0), and 52.8% were female. Compared to the Dutch, we found lower odds for plaque presence in Moroccans (0.77, 95% CI: 0.62; 0.95) and no significant differences between the South-Asian Surinamese and Dutch population (0.91, 95% CI: 0.76; 1.10). After adjustment for CVD risk factors, we found a lower plaque presence in South-Asian Surinamese (0.63, 95% CI: 0.48; 0.82). In both Moroccan and South-Asian Surinamese individuals, adjustment for socioeconomic status did not materially change the results. cIMT was lower in South-Asian Surinamese compared to the Dutch (−17.9 μm, 95% CI: −27.9; −7.9) and partly explained by ethnic differences in the body height as South-Asian Surinamese individuals were, on average, shorter than the Dutch population. No differences in cIMT between Moroccans and Dutch were found. Conclusions: cIMT and plaque prevalence differ between ethnic groups independent of CVD risk. Lower plaque prevalence in Moroccans was partly attributable to a lower prevalence of traditional CVD risk factors, while body height was an important contributor to differences in cIMT in South Asians. This study emphasizes the need for ethnic-specific cut-off values for plaque presence and cIMT.
Findings from the Use of Spinal Anesthesia in the Laparoscopic Treatment of Extrauterine Pregnancy: Could It Represent an Alternative to General Anesthesia?
Authors: Della Corte Luigi , Guarino Maria Chiara , Dell'Aquila Michela , Ascione Mario , Guerra Serena , De Rosa Rossella , Del Piano Annaclaudia , Bruzzese Dario , Bifulco Giuseppe , Giampaolino Pierluigi
Published: December 2023

Introduction: Minimally invasive procedures performed in laparoscopy, such as salpingectomy for ectopic pregnancy, can be combined with a minimally invasive anesthesia. The aim of this study was to assess the feasibility and the intraoperative and postoperative outcomes of laparoscopic surgery for ectopic pregnancy under spinal anesthesia (SA) compared to general anesthesia (GA) from the point of view of the surgeon, anesthesiologist, and patient. Methods: A retrospective cohort study was performed at DAI Materno Infantile of AOU Federico II of Naples, analyzing all medical records of women who met the inclusion criteria between April 2020 and April 2023. Eighty-two women (35 under SA in group A and 47 under GA in group B) undergone elective or emergency laparoscopic salpingectomy for ectopic tubal or ovarian pregnancy were included. Results: Patients in group A reported less pain at 0 h (adjusted mean difference: −1.5; 95% CI: −2.3 to −0.7; p < 0.001) and after 6 h (adjusted mean difference: −1.1; 95% CI: −2.0 to −0.3; p = 0.01) while no statistically significant differences between the two groups at 12 and 24 h after surgery. No differences were observed among the type of analgesic and during the postoperative observation time, except for paracetamol at 0 h in group B. A faster resumption of bowel motility, patient’s mobilization, and a shorter hospital stay were observed in group A compared to group B. Also greater odds of returning faster to daily activities emerged in group A (adjusted OR: 5.39; 95% CI: 1.77–16.37). A greater number of patients in group A were satisfied with the entire procedure compared to those of group B (33 [94.3%] vs. 37 [78.7%]). The general surgeon satisfaction was always very good or excellent in group A. Finally, all surgical steps were well tolerated in group A. Conclusion: In specific settings, SA is a feasible and safe procedure for the laparoscopic treatment of ectopic pregnancy.
Novel Variants of HPS6 Cause Suspected Ocular Albinism: A Report of 2 Cases and the Profile of HPS6 Variants
Authors: Zhou Biting , Yang Juhua , Bai Yue , Li Yufei , Chen Shuyang , Chen Xiaole , Zhang Nanwen , Cao Zongfu , Zhu Yihua , Xu Yingying
Published: December 2023

Introduction: Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disease characterized by ocular albinism (OA) or oculocutaneous albinism (OCA), platelet dysfunction, and other symptoms. This study aimed to analyze the molecular defect in two Chinese families with suspected OA, as well as to investigate the profile of HPS6 variants and their genotype-phenotype correlations. Methods: Seven members from two families were recruited and underwent clinical ophthalmologic examinations. The genomic DNA was extracted from peripheral blood leukocytes. Whole-exome sequencing was performed on the proband of family JX. The single coding exon of HPS6 was directly Sanger sequenced based on PCR amplification in all available family members. An additional 46 probands from families or sporadic cases with the pathogenic variants of HPS6 reported in the literature were reviewed. Results: We identified two different compound heterozygous truncating variants of HPS6 in probands with suspected OA from two independent families. The proband of family JX had c.1674dup and c.503-504del variants, and the other proband from family CZ had a nonsense variant of c.1114C>T and a frameshift variant of c.1556del. Among them, c.1674dup and c.1556del variants in HPS6 have not been reported previously. Therefore, our patients were diagnosed as HPS6 disease by molecular diagnostics. In the retrospective cohort of HPS6 patients, we delineated the profile of HPS6 variants and revealed a significant overlap between CpG islands and the variants of HPS6, suggesting a potential link between DNA methylation and HPS6 variants. We also observed a spatial aggregation of the variants in 3D structure of HPS6 protein, implying the possible functional significance of these structural regions. In addition, we did not find any significant genotype-phenotype correlation of HPS6, and neither did we observe a correlation between the truncation length of the HPS6 protein and the phenotype of HPS6 disease. Conclusion: Our research expands the spectrum of HPS6 variants, providing a comprehensive delineation of their profile and systematically investigating genotype-phenotype correlations in HPS6. These findings could offer potentially valuable clues for investigating the molecular mechanism underlying HPS6 pathogenesis, as well as aiding the clinical diagnosis of HPS6 patients and improving disease prognosis.
As práticas informacionais na construção da identidade transgênero
Authors: Pinto Elton Martires , Leite Fernando César Lima
Published: December 2023

Pessoas transgênero têm necessidades, comportamentos e práticas informacionais específicas. Este artigo apresenta a relação entre as práticas informacionais de mulheres transgênero e suas percepções sobre suas identidades de gênero. Metodologicamente, baseia-se em um modelo conceitual, utiliza abordagem qualitativa e propósito descritivo. A amostra, por sua vez, foi composta por mulheres que se consideram em processo de transição de gênero e a técnica utilizada foi a bola de neve. Os dados foram coletados a partir de entrevistas semiestruturadas e, em seguida, analisados por meio de codificação temática. Destacam-se como resultados principais que: as necessidades de informação e as práticas empregadas durante os processos de busca, acesso e uso estão associadas e são influenciadas por questões de saúde, construção cognitiva e física, bem como pela disseminação de conhecimentos para outras pessoas que estão passando pelo mesmo processo. Dessa relação com a informação, as mulheres passam a visualizar a construção de suas personalidades, corpos e, por fim, identidades.
Da iconoclastia ao iconoclash, de Bruno Latour
Authors: Imparato Marcella
Published: December 2023

Em texto introdutório ao catálogo da exposição Iconoclash: Beyond the Image Wars in Science, Religion, and Art, curada por Bruno Latour e Peter Weibel, realizada no Centro de Arte e Mídia Karlsruhe (ZKM), Alemanha, em 2002, Latour cunha o termo iconoclash para pensar a ambiguidade de gestos iconoclastas, que não só produziriam um efeito imediato de destruição, mas também de produção de novas imagens, no campo da religião, da ciência e das artes. À luz dessa nova interpretação, o artigo retoma algumas das análises no campo das artes produzidas por autores que colaboraram para o catálogo da exposição, nas quais se evidencia a ambiguidade das estratégias iconoclastas. A potência produtiva de tal gesto é especialmente destacada em relação à arte moderna e contemporânea, em que inúmeras intervenções e transformações, seja no plano material das obras, seja no plano conceitual ou simbólico, são observadas, colocando em questão sua capacidade de representação e mediação do real e apontando para o esgotamento de certas narrativas históricas.
Developing Offshore Wind Farms – A Comparison and Analysis of the Legal and Governance Frameworks of the North Sea Coastal States
Authors: Nieuwenhout Ceciel
Published: December 2023

With high offshore wind ambitions, the North Sea coastal states have each followed a different path in the development of the legal framework for offshore wind development. This article compares the legal frameworks of the coastal states on three main issues: the location choice, including selection of developers; the permitting procedures, and the connection of the owf s. The analysis shows legislative and governance convergence across the North Sea, but also a few instances where different choices are made. The consequences of the choices are discussed and analysed, with recommendations for other coastal states wishing to develop an offshore wind regulatory framework.
Croton carajasensis, a new species from Serra dos Carajás, Pará, Brazilian Amazon
Authors: SODRÉ RODOLFO CARNEIRO , SECCO RICARDO DE S.
Published: December 2023

During a floristic survey of Euphorbiaceae in cangas (areas of iron-rich soils) of the Serra dos Carajás (Pará State, Brazil), a new species of Euphorbiaceae was found. Croton carajasensis is only known from cangas vegetation and it is herein described and illustrated. The relationships of the new taxon with the most morphologically similar species (C. abaitensis, C. adamantinus, C. harleyi and C. ramosissimus) and its infrageneric position are discussed. We also include a distribution map, comments on habitat, flowering, fruiting, and a preliminary assessment of the species’ conservation status.
Four Forms That Fit Most Organizations
Authors: Mintzberg Henry
Published: December 2023

Organizations dominate our lives, yet how well do we really understand them, and their differences? To get past the one-size-fits-all notion of organization design, this article presents four forms of organizations—the personal enterprise, the programmed machine, the professional assembly, and the project pioneer—each with its own way of managing and crafting strategy. Many organizations come remarkably close to one of these forms, while others can be understood as hybrids of them. Nevertheless, since organizations are made up of people, every one of us different, every single organization structure must be customized through a process of design doing.
Relational Marginalisation: Comparing Scheduled Tribe Gaddi in Himachal Pradesh and Bhils in Maharashtra, India
Authors: Axelby Richard , Thakur Vikramaditya
Published: December 2023

The socio-economic condition of Scheduled Tribe (ST) groups of India has been a key academic concern since the administrative category was established by Constitutional Order in 1950. This article explores the integration of ST groups into the present-day Indian capitalist economy along with the social and political forces that have shaped this process of inclusion from the colonial period onwards. Specifically, it compares experiences of residual poverty and relational inequality among two groups administratively classified as ST—Gaddi in Himachal Pradesh and Bhils in Maharashtra. Recognising that Gaddi and Bhils remain rooted at the bottom of socio-economic hierarchies we ask why this remains the case despite affirmative action programmes aimed at ensuring ST inclusion in educational institutions, government jobs and elected bodies along with many welfare schemes. Against the backdrop of booming India, the article documents how Bhils and Gaddis struggle to negotiate the obstacles which block paths to economic and social mobility.
Acute right atrial thrombus formation after extracorporeal life support removal during LVAD-implantation
Authors: Woehrle Anne , Sachs Alexander , Doss Mirko , Popov Aron Frederik
Published: December 2023

A 58-year-old male underwent LVAD-Implantation after ECLS explantation. After removal of ECLS (A) transesophageal echocardiography revealed thrombus in the inferior vena cava (B) and right atrium (C). The thrombus was removed with a second pump run including RVAD-Implantation. (D) The diameter of thrombus formations was 6 × 1 cm and 5 × 1.5 cm.