bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison among possible design solutions for the Stray Field Shielding System of the DTT Neutral Beam Injector
Authors: Veronese Fabio , Agostinetti Piero , Calabrò Giuseppe , Crisanti Flavio , Fanelli Pierluigi , Lombroni Riccardo , Murari Andrea
Published: June 2023

Within the effort on the conceptual design of the Divertor Test Tokamak (DTT) Neutral Beam
Injector (NBI), the design of the Stray Field Shielding System (SFSS) for DTT NBI is under
development, to suppress the potentially harmful effects of the stray poloidal field from the
tokamak on the accelerated charged beam. Various possible design solutions to solve this problem
are presented and compared, with a particular focus on the stray field minimization procedure and
particle tracing simulations, used during the design validation phase with the objective of
maximizing beamline performances.
Estimating aboveground biomass density using hybrid statistical inference with GEDI lidar data and Paraguay’s national forest inventory
Authors: Bullock Eric L , Healey Sean P , Yang Zhiqiang , Acosta Regino , Villalba Hermelinda , Insfrán Katherin Patricia , Melo Joana B , Wilson Sylvia , Duncanson Laura , Næsset Erik , Armston John , Saarela Svetlana , Ståhl Göran , Patterson Paul L , Dubayah Ralph
Published: June 2023

Forests are widely recognized as critical to combating climate change due to their ability to sequester and store carbon in the form of biomass. In recent years, the combined use of data from ground-based forest inventories and remotely sensed data from light detection and ranging (lidar) has proven useful for large-scale assessment of forest biomass, but airborne lidar is expensive and data acquisition is infeasible for many countries. By contrast, the spaceborne Global Ecosystem Dynamics Investigation (GEDI) lidar instrument has collected freely available data for most of the world’s temperate and tropical forests since 2019. GEDI’s biomass products rely on models calibrated with a global network of field plots paired with GEDI waveforms simulated from airborne lidar to predict biomass. While this calibration strategy minimizes spatial and temporal offsets between field measurements and corresponding lidar returns, calibration data are sparse in many regions. Paraguay’s forests are known to be poorly represented in GEDI’s current calibration dataset, and here we demonstrate that local models calibrated opportunistically with on-orbit GEDI data and field surveys from Paraguay’s national forest inventory can be used with GEDI’s statistical estimators of aboveground biomass density (AGBD). We specify a protocol for opportunistically matching GEDI observations with field plots to calibrate a field-to-GEDI biomass model for use in GEDI’s hybrid statistical framework. Country-specific calibration using on-orbit data resulted in relatively accurate and unbiased predictions of footprint-level biomass, and importantly, supported the assumption underlying model-based inference that the model must ‘apply’ to the area of interest. Using a locally calibrated biomass model, we estimate that the mean AGBD in Paraguay is 65.55 Mg ha−1, which coincides well with the design-based approach employed by the national forest inventory. The GEDI estimates for individual forest strata range from 52.34 Mg ha−1 to 103.88 Mg ha−1. On average, the standard errors are 47% lower for estimates based on GEDI than the forest inventory, representing a significant gain in precision. Our research demonstrates that GEDI can be used by national forest inventories in countries that seek reliable estimates of AGBD, and that local calibration using existing field plots may be more appropriate in some applications than using GEDI global models, especially in regions where those models are sparsely calibrated.
Root number bias for newforms
Authors: Martin Kimball
Published: June 2023

Previously we observed that newforms obey a strict bias towards root number

+
1

+1

in squarefree levels: at least half of the newforms in

S
k

(

Γ
0

(
N
)
)

S_k(\Gamma _0(N))

with root number

+
1

+1

for

N
N

squarefree, and it is strictly more than half outside of a few special cases. Subsequently, other authors treated levels which are cubes of squarefree numbers. Here we treat arbitrary levels, and find that if the level is not the square of a squarefree number, this strict bias still holds for any weight. In fact the number of such exceptional levels is finite for fixed weight, and 0 if

k
>
12

k > 12

. We also investigate some variants of this question to better understand the exceptional levels.
Examining the Mediator of Emotional Exhaustion and the Moderator of Work Support in the Association Between Person–Job Fit and Mental Health: Evidence from a Nationally Representative Sample of Social Workers in China
Authors: Jiang Shan , Liu Zewei , Nayilan Haimiti , Du Ruoyu , Wang Lin
Published: June 2023

Social workers’ mental health issues in China have contextually important meanings, which result from its situation of extensive development and limited resources, and result in more developmental problems in the next stage. To fill research gaps in perspectives, participants and empirical evidence, this study used the Conservation of Resources theory framework and a nationally representative sample to examine a moderated mediation model. A sample of 5,965 Chinese social workers was obtained from the China Social Work Longitudinal Study in 2019. The results indicated that the relation between person–job fit and social workers’ depression was partially mediated by their emotional exhaustion. In addition, the indirect effect was moderated by supervisor support, coworker support and manager support in the workplace. This study provides a resource-based mechanism to understand social workers’ mental health issues in the context of the developing world. Practical implications on improving social workers’ person–job fit, emotional exhaustion and work support were also discussed.
Skeletal muscle in amyotrophic lateral sclerosis
Authors: Shefner Jeremy M , Musaro Antonio , Ngo Shyuan T , Lunetta Christian , Steyn Frederik J , Robitaille Richard , De Carvalho Mamede , Rutkove Seward , Ludolph Albert C , Dupuis Luc
Published: June 2023

Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS.

Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment.
Towards in vivo PET imaging of primary age-related tauopathy
Authors: Therriault Joseph , Grothe Michel J
Published: June 2023

This scientific commentary refers to ‘Age-related and amyloid-beta-independent tau deposition and its downstream effects’ by Wuestefeld et al. (https://doi.org/10.1093/brain/awad135).
ARHGAP25 suppresses the development of breast cancer by an ARHGAP25/Wnt/ASCL2 feedback loop
Authors: Han Sijia , Jin Xueying , Hu Tianyu , Chi Feng
Published: June 2023

Downregulation of ARHGAP25 was found in the tumor samples from breast cancer patients and five breast cancer cell lines. However, its precise role and molecular mechanisms in breast cancer remain completely unknown. Herein, we found that knockdown of ARHGAP25 in breast cancer cells promoted proliferation, migration and invasion of breast cancer cells. Mechanistically, ARHGAP25 silence facilitated the activation of the Wnt/β-catenin pathway and the upregulation of its downstream molecules (including c-Myc, Cyclin D1, PCNA, MMP2, MMP9, Snail and ASCL2) by directly regulating Rac1/PAK1 in breast cancer cells. In vivo xenograft experiments indicated ARHGAP25 silence promoted tumor growth and activated the Wnt/β-catenin pathway. In contrast, overexpression of ARHGAP25 in vitro and in vivo impeded all of the above cancer properties. Intriguingly, ASCL2, a downstream target of the Wnt/β-catenin pathway, transcriptionally repressed the expression of ARHGAP25 and therefore constituted a negative feedback loop. Moreover, bioinformatics analysis indicated that ARHGAP25 was significantly correlated with tumor immune cell infiltration and the survival of patients with different immune cell subgroups in breast cancer. Collectively, our work revealed that ARHGAP25 suppressed tumor progression of breast cancer. It provides a novel insight for the treatment of breast cancer.
Increasing social disparities in obesity among 15 000 pre-schoolers in a German district from 2009 to 2019
Authors: Michel Zora , Krayl Nele , Götz Katja , Wienke Andreas , Mikolajczyk Rafael , Führer Amand
Published: June 2023

Background

Although childhood obesity prevalence has stagnated in many high-income regions after decades of increase, it continues to be a major public health problem with adverse effects. The objective was to examine obesity trends as a function of parental social status to identify obesity disparities among children.

Methods

Data from school entry examinations from 2009 to 2019 of 14 952 pre-schoolers in one German district were used. Logistic regression models (obesity/overweight as dependent variable) and a linear regression [BMI z-score (BMIz) as dependent variable] were performed adjusted for social status and sex to investigate time trends in overweight and obesity.

Results

Overall, we found an increase of obesity over time [odds ratio (ORs): 1.03 per year, 95% CI: 1.01–1.06]. Children with low social status had an OR of 1.08 per year (95% CI: 1.03–1.13), while the trend was less expressed in children with high social status (OR: 1.03 per year, 95% CI: 0.98–1.08). The mean BMIz decreased per year (regression coefficient −0.005 per year, 95% CI: −0.01 to 0.0) when considering all children. This decrease was more pronounced in children with high social status (regression coefficient: −0.011 per year, 95% CI: −0.019 to −0.004), compared with a slight increase of 0.014 (95% CI: −0.003 to 0.03) per year among children with low social status. Also, children with low parental social status were heavier and smaller than their peers with high social status.

Conclusions

Although the mean BMIz decreased among pre-schoolers, obesity prevalence and status-related inequity in obesity prevalence increased from 2009 to 2019 in the region studied.
The cichlid pharyngeal jaw novelty enhances evolutionary integration in the feeding apparatus
Authors: Roberts-Hugghis Alexus S , Burress Edward D , Lam Brian , Wainwright Peter C
Published: June 2023

The modified pharyngeal jaw system of cichlid fishes is widely viewed as a key innovation that substantially facilitated the evolutionary exuberance of this iconic evolutionary radiation. We conduct comparative phylogenetic analyses of integration, disparity, and rate of evolution among feeding-related, skeletal structures in Neotropical cichlids and North American centrarchids, which lack the specialized pharyngeal jaw. Contrasting evolutionary patterns in these two continental radiations, we test a classic decoupling hypothesis. Specifically, we ask whether the modified pharyngeal jaw in cichlids resulted in enhanced evolutionary independence of the oral and pharyngeal jaws, leading to increased diversity of trophic structures. Contrary to this prediction, we find significantly stronger evolutionary integration between the oral and pharyngeal jaws in cichlids compared to centrarchids, although the two groups do not differ in patterns of integration within each jaw system. Further, though we find no significant differences in disparity, centrarchids show faster rates of morphological evolution. Our results suggest that the modified pharyngeal jaw resulted in less evolutionary independence and slower rates of evolution within the feeding system. Thus, we raise the possibility that the cichlid novelty enhances feeding performance, but does not prompt increased morphological diversification within the feeding apparatus, as has long been thought.
Newcomer perceptions of COVID-19 countermeasures in Canada
Authors: Koshy Liza , Burns Katie , Godinho Nascimento Maria H , Ike Nnenna Arianzu Uma , Herati Hoda , Filice Eric , Rotolo Bobbi , Betini Gustavo S , Ward Paul R , Dubé Ève , Meyer Samantha B
Published: June 2023

Newcomers to Canada have been disproportionally affected by COVID-19, with higher rates of infection and severity of illness. Determinants of higher rates may relate to social and structural inequities that impact newcomers’ capacity to follow countermeasures. Our aim was to describe and document factors shaping newcomers’ acceptance of COVID-19 countermeasures. Semi-structured qualitative interviews were conducted with individuals living in Canada for <5 years. Participants were asked to discuss their pandemic experiences, and perceptions and acceptance of measures. Five themes were identified: (i) belief in the necessity and efficacy of countermeasures; (ii) negative impact of measures on health/wellbeing; (iii) existing barriers to newcomer settlement exacerbated by pandemic measures; (iv) countermeasure adherence related to immigration status and (v) past experiences shaping countermeasure acceptance. Government should continue to provide messaging regarding the importance of measures for individual and population heath and continue to demonstrate a commitment to the interests of citizens. Importantly, newcomer trust in government should not be taken for granted, as this trust is critical for the acceptance of government interventions now and moving forward. It will be important to ensure that newcomers are given support to overcome challenges to settlement that were intensified during the pandemic.
Development and validation of a new questionnaire to assess perceptions regarding DWELL: Design for WELLness
Authors: Aperman-Itzhak Tal , Prilleltensky Isaac , Rosen Laura
Published: June 2023

Designing home environments for health and wellness is a crucial strategy for disease prevention and health promotion. Yet, there is not a tool to evaluate perceptions regarding home design for health and wellness. This study aimed to develop and validate a new instrument to measure people’s perceptions regarding the concept of DWELL: Design for WELLness in the home environment. We developed a short 5-item online questionnaire to detect changes in knowledge, awareness, engagement and self-efficacy regarding DWELL. The instrument was validated in an online study. Of the 613 mothers who answered the questionnaire initially, 397 answered the questionnaire a second time. Factor analysis and Cronbach’s alpha indicated that all five DWELL questions load into one single factor (the model explained 61.84% of total variance), and measure a reliable scale of the same construct, with high levels of internal consistency (Cronbach’s α = 0.85) at both first and second administrations. Spearman correlations between DWELL first and second administrations of the questionnaire indicated moderate-to-high test–retest reliability (0.55–0.70, p < 0.001). DWELL was found to be a valid tool which fills a gap in the public health literature. This measure serves as a free and convenient online instrument to gain insights regarding the effect of modifying environments for disease prevention and health promotion. The tool may be used to assess perceptions in the conditions leading wellness promotion in the home.
Australian young people’s perceptions of the commercial determinants of the climate crisis
Authors: Arnot Grace , Thomas Samantha , Pitt Hannah , Warner Elyse
Published: June 2023

There is increasing public health focus on how corporate practices impact population health and well-being. While the commercial determinants of the climate crisis pose serious threats to human and planetary health, governments largely seek to balance climate action with economic imperatives. Global stakeholders recognize that young people have important voices in influencing climate responses. However, few studies have investigated young people’s perceptions of the commercial determinants of the climate crisis. A qualitatively led online survey of n = 500 young Australians (15–24 years) investigated their understanding of corporate responses to the climate crisis, factors that influenced these responses and strategies to respond. A reflexive approach to thematic analysis was used. Three themes were constructed from the data. First, young people perceived that corporate responses to the climate crisis focussed on soft options and lacked meaningful action. Second, they stated that these responses were largely influenced by economic imperatives rather than planetary health, with policy levers needed to implement environmentally responsible corporate practices. Third, young people perceived that systems needed change to create demand for a cleaner environment, leading to improved practices. Young people have a clear understanding of the commercial determinants of the climate crisis and associated threats to population health. They recognize that corporate practices (and consumer demand) will not change without significant policy and structural change. Public health and health promotion stakeholders should work alongside young people to influence decision-makers to address harmful corporate behaviours.
(Un)belonging at work: an overlooked ingredient of workplace health
Authors: Thissen Lotte , Biermann-Teuscher Dorit , Horstman Klasien , Meershoek Agnes
Published: June 2023

Organizations offer activities and programmes to improve their employees’ health. These workplace health promotion (WHP) activities usually have an individualized and top-down focus, a low uptake among employees, and are perceived to be out of line with employees’ experiences and definitions of health. This paper follows up on studies that have broadened the focus of WHP by including social relations and delves deeper into how daily practices and experiences of (un)belonging at work relate to workplace health. Based on ethnographic research in two companies in the Netherlands, this paper analyses how (un)belonging is expressed and experienced by employees. The paper shows that employees define health at work as a social practice. It also demonstrates how dynamics at work shape different dimensions of (un)belonging that, in turn, affect employees’ perceived health at work. These findings indicate the importance of including (un)belonging in the workplace as an ingredient of WHP.
Attenuated Expression of SLCO2A1 Caused by DNA Methylation in Pediatric Inflammatory Bowel Disease
Authors: Ito Natsuki , Kudo Takahiro , Eguchi Hidetaka , Jimbo Keisuke , Furuhata Atsushi , Okuno Toshiaki , Takeuchi Ichiro , Arai Katsuhiro , Ishige Takashi , Okazaki Yasushi , Shimizu Toshiaki
Published: June 2023

Background

SLCO2A1 encodes a prostaglandin (PG) transporter, and autosomal recessive pathogenic variants of this gene cause chronic enteropathy associated with SLCO2A1. It is unclear whether a heterozygous pathogenic variant of SLCO2A1 has a role in the pathogenesis of other types of inflammatory bowel disease (IBD). In this study, we investigated the possible involvement of a local epigenetic alteration in SLCO2A1 in patients with a heterozygous pathogenic variant.

Methods

We conducted whole-exome sequencing of samples from 2 sisters with suspected monogenic IBD. In addition, we performed bisulfite sequencing using DNA extracted from their small and large intestine samples to explore epigenetic alterations.

Results

A heterozygous splicing site variant, SLCO2A1:c.940 + 1G > A, was detected in both patients. To explore the possible involvement of epigenetic alterations, we analyzed protein and messenger RNA expression of SLCO2A1, and observed attenuated SLCO2A1 expression in the inflamed lesions of these patients compared with that in the control individuals. Furthermore, bisulfite sequencing indicated dense methylation in the promoter region of SLCO2A1 only in the inflamed lesions of both patients. The urinary PG metabolite levels in these patients were comparable to those in patients with chronic enteropathy associated with SLCO2A1 and higher than those in the control individuals. We found considerably higher levels of the metabolites in patient 1, who showed more severe symptoms than patient 2.

Conclusions

Local DNA methylation attenuated SLCO2A1 expression, which may evoke local inflammation of the mucosa by the unincorporated PG. These findings may improve our understanding of the epigenetic mechanisms underlying IBD development.
The Blow-Up Analysis on B2(1) Affine Toda System: Local Mass and Affine Weyl Group
Authors: Cui Leilei , Wei Jun-cheng , Yang Wen , Zhang Lei
Published: June 2023

It has been established that the local mass of blow-up solutions to Toda systems associated with the simple Lie algebras $\textbf{A}_{n}$, $\textbf{B}_{n}$, $\textbf{C}_{n}$, and $\textbf{G}_{2}$ can be represented by a finite Weyl group. In particular, at each blow-up point, after a sequence of bubbling steps (via scaling) is performed, the transformation of the local mass at each step corresponds to the action of an element in the Weyl group. In this article, we present the results in the same spirit for the affine $\textbf{B}_{2}^{(1)}$ Toda system with singularities. Compared with the Toda system with simple Lie algebras, the computation of local masses is more challenging due to the infinite number of elements of the affine Weyl group of type $\textbf{B}_{2}^{(1)}$. In order to give an explicit expression for the local mass formula, we introduce two free integers and write down all the possibilities into $8$ types. This shows a striking difference to previous results on Toda systems with simple Lie algebras. The main result of this article seems to provide the first major advance in understanding the relation between the blow-up analysis of affine Toda system and the affine Weyl group of the associated Lie algebras.
Improvement of the stability and catalytic efficiency of heparan sulfate N-sulfotransferase for preparing N-sulfated heparosan
Authors: Xi Xintong , Hu Litao , Huang Hao , Wang Yang , Xu Ruirui , Du Guocheng , Chen Jian , Kang Zhen
Published: June 2023

The chemo-enzymatic and enzymatic synthesis of heparan sulfate and heparin are considered as an attractive alternative to the extraction of heparin from animal tissues. Sulfation of the hydroxyl group at position 2 of the deacetylated glucosamine is a prerequisite for subsequent enzymatic modifications. In this study, multiple strategies, including truncation mutagenesis based on B-factor values, site-directed mutagenesis guided by multiple sequence alignment, and structural analysis were performed to improve the stability and activity of human N-sulfotransferase. Eventually, a combined variant Mut02 (MBP–hNST-NΔ599-602/S637P/S741P/E839P/L842P/K779N/R782V) was successfully constructed, whose half-life at 37°C and catalytic activity were increased by 105-fold and 1.35-fold, respectively. After efficient overexpression using the Escherichia coli expression system, the variant Mut02 was applied to N-sulfation of the chemically deacetylated heparosan. The N-sulfation content reached around 82.87% which was nearly 1.88-fold higher than that of the wild-type. The variant Mut02 with high stability and catalytic efficiency has great potential for heparin biomanufacturing.
A case of attenuated familial adenomatous polyposis in which genetic testing revealed that the children were asymptomatic gene carriers
Authors: Sonoda Hiromichi , Yamada Takeshi , Yamaguchi Tatsuro , Eguchi Hidetaka , Okazaki Yasushi , Yoshida Hiroshi , Ishida Hideyuki
Published: June 2023

Attenuated familial adenomatous polyposis, which accounts for ~10% of familial adenomatous polyposis, is difficult to diagnose because of its milder course and later onset. In both familial adenomatous polyposis and attenuated familial adenomatous polyposis, duodenal cancer is usually recognized 10–20 years after the diagnosis of colonic polyposis. We present herein a 66-year-old man who received pancreaticoduodenectomy due to ampullary carcinoma 17 years before onset of colonic polyposis. He then received extended right hemicolectoy for ascending colon cancer and ⁓100 polyps located from ceacum to splenic flexure of colon 2 years ago. The patient received Adenomatous polyposis coli (APC) genetic testing and detected a germline pathogenic frameshift variant in the APC gene (NM_000038.6:c.4875delA, ClinVar variant ID (127299)). The variant is classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. APC genetic testing was subsequently performed on his younger children (30 and 26 year old) and they found a same frameshift variant as his father. They were not detected any colonic polyposis by colonoscopy. This is a rare case report of attenuated familial adenomatous polyposis that diagnosed with gastric and colon polyposis >10 years after the diagnosis of ampullary carcinoma and the first report of genetic diagnosis of an attenuated familial adenomatous polyposis variant in young relatives before the onset of the disease.
Clinical complete response maintained for more than 5 years after aggressive chemoradiotherapy for advanced rectal cancer with necrotizing fasciitis: a case report
Authors: Yoshikawa Yusuke , Suzuki Keiichi , Hashimoto Takeo , Omagari Kenshi , Sasaki Taketo , Tomita Yusuke , Tamura Akihiko
Published: June 2023

We report the case of a 65-year-old male diagnosed with advanced rectal cancer associated with necrotizing fasciitis (NF). Since radical surgery, total pelvic exenteration with sacrectomy, was rejected because of detrimental effects on quality of life, chemoradiotherapy (CRT) was chosen as anti-cancer treatment after urgent debridement. Although CRT was paused unintentionally just after delivering the total dose of radiation owing to the relapse of NF, the patient has maintained clinical complete response (cCR) without any distant metastasis for >5 years. Advanced rectal cancer is recognized as an NF risk factor. No definitive treatment strategies have been reported for NF-inducing rectal cancer; however, some reports have demonstrated curative extended surgery. Thus, CRT may be a less-invasive treatment option for NF-inducing rectal cancer, whereas severe adverse effects including re-infection after debridement should be closely monitored.
OK432 sclerotherapy for refractory chylous leakage after neck dissection
Authors: Hashimoto Yuiko , Teshima Masanori , Yui Mitsuko , Tatehara Shun , Iritani Keisuke , Furukawa Tatsuya , Shinomiya Hirotaka , Nibu Ken-ichi
Published: June 2023

Chylous leakage is a rare but serious postoperative complication of neck dissection (ND). Most chylous leakages are successfully treated either by drainage or ligation of the thoracic duct, but the resolution is occasionally prolonged. OK432 sclerotherapy is used to treat various refractory cystic diseases of the head and neck. Three patients were treated with OK432 sclerotherapy for refractory chylous leakage following ND. Case 1 involved a 77-year-old man with chylous leakage after a total laryngectomy and bilateral ND. Case 2 involved a 71-year-old woman who underwent total thyroidectomy and left ND for thyroid cancer. Case 3 involved a 61-year-old woman who underwent right ND for oropharyngeal cancer. In all patients, chylous leakage rapidly improved after OK432 injection without any complications. Our results suggest the efficacy of OK432 sclerotherapy in patients with refractory chylous leakage after ND.
Reduction in PLANT DEFENSIN 1 expression in Arabidopsis thaliana results in increased resistance to pathogens and zinc toxicity
Authors: Nguyen Ngoc Nga , Lamotte Olivier , Alsulaiman Mohanad , Ruffel Sandrine , Krouk Gabriel , Berger Nathalie , Demolombe Vincent , Nespoulous Claude , Dang Thi Minh Nguyet , Aimé Sébastien , Berthomieu Pierre , Dubos Christian , Wendehenne David , Vile Denis , Gosti Françoise
Published: June 2023

Ectopic expression of defensins in plants correlates with their increased capacity to withstand abiotic and biotic stresses. This applies to Arabidopsis thaliana, where some of the seven members of the PLANT DEFENSIN 1 family (AtPDF1) are recognised to improve plant responses to necrotrophic pathogens and increase seedling tolerance to excess zinc (Zn). However, few studies have explored the effects of decreased endogenous defensin expression on these stress responses. Here, we carried out an extensive physiological and biochemical comparative characterization of (i) novel artificial microRNA (amiRNA) lines silenced for the five most similar AtPDF1s, and (ii) a double null mutant for the two most distant AtPDF1s. Silencing of five AtPDF1 genes was specifically associated with increased aboveground dry mass production in mature plants under excess Zn conditions, and with increased plant tolerance to different pathogens — a fungus, an oomycete and a bacterium, while the double mutant behaved similarly to the wild type. These unexpected results challenge the current paradigm describing the role of PDFs in plant stress responses. Additional roles of endogenous plant defensins are discussed, opening new perspectives for their functions.
Ubiquitin negatively regulates ABA responses by inhibiting SnRK2.2 and SnRK2.3 kinase activity in Arabidopsis
Authors: Shao Zhengyu , Yang Shuhua , Gu Yinghui , Guo Yan , Zhou Huapeng , Yang Yongqing
Published: June 2023

Abscisic acid (ABA) is an essential phytohormone for plant responses to complex and variable environmental conditions. The molecular basis of the ABA signaling pathway has been well elucidated. SnRK2.2 and SnRK2.3 are key protein kinases participating in ABA responses, and the regulation of their activity plays an important role in signaling. Previous mass spectroscopy analysis of SnRK2.3 suggested that ubiquitin and homologous proteins may bind directly to the kinase. Ubiquitin typically recruits E3 ubiquitin ligase complexes to target proteins, marking them for degradation by the 26S proteasome. Here, we show that SnRK2.2 and SnRK2.3 interact with ubiquitin but are not covalently attached to the protein, resulting in the suppression of their kinase activity. The binding between SnRK2.2, SnRK2.3, and ubiquitin is weakened under prolonged ABA treatment. Overexpression of ubiquitin positively regulated the growth of seedlings exposed to ABA. Our results thus demonstrate a novel function for ubiquitin, which negatively regulates ABA responses by directly inhibiting SnRK2.2 and SnRK2.3 kinase activity.
Clinical characteristics of central nervous system phaeohyphomycosis: A brief report of 20 years’ experience
Authors: Chesdachai Supavit , Yetmar Zachary A , Tabaja Hussam , Wengenack Nancy L , Abu Saleh Omar M
Published: June 2023

Central nervous system (CNS) phaeohyphomycosis is a rare and often fatal fungal infection. Our study reported a case series of eight CNS phaeohyphomycosis cases at our institution over the past 20 years. We did not observe the common pattern of risk factors, abscess location, or number of abscesses among them. Most patients were immunocompetent without classic risk factors for fungal infection. Early diagnosis and aggressive management with surgical intervention and prolonged antifungal therapy can lead to a favorable outcome. The study highlights the need for further research to better understand the pathogenesis and optimal management of this challenging rare infection.
Rapid population synthesis of black hole high-mass X-ray binaries: implications for binary stellar evolution
Authors: Romero-Shaw Isobel , Hirai Ryosuke , Bahramian Arash , Willcox Reinhold , Mandel Ilya
Published: June 2023

We conduct binary population synthesis to investigate the formation of wind-fed high-mass X-ray binaries containing black holes (BH-HMXBs). We evolve multiple populations of high-mass binary stars and consider BH-HMXB formation rates, masses, spins, and separations. We find that systems similar to Cygnus X-1 likely form after stable Case A mass transfer (MT) from the main-sequence progenitors of BHs, provided such MT is characterized by low accretion efficiency, β ≲ 0.1, with modest orbital angular momentum losses from the non-accreted material. Additionally, efficient BH-HMXB formation relies on a new simple treatment for Case A MT that allows donors to retain larger core masses compared to traditional rapid population-synthesis assumptions. At solar metallicity, our Preferred model yields $\mathcal {O}(1)$ observable BH-HMXBs in the Galaxy today, consistent with observations. In this simulation, 8  per cent of BH-HMXBs go on to merge as binary black holes or neutron star-black hole binaries within a Hubble time; however, none of the merging binaries have BH-HMXB progenitors with properties similar to Cygnus X-1. With our preferred settings for core mass growth, mass transfer efficiency, and angular momentum loss, accounting for an evolving metallicity, and integrating over the metallicity-specific star formation history of the Universe, we find that BH-HMXBs may have contributed ≈2–5 BBH merger signals to detections reported in the third gravitational-wave transient catalogue of the LIGO–Virgo–KAGRA Collaboration. We also suggest MT efficiency should be higher during stable Case B MT than during Case A MT.
Searching for signatures of H α spicule-like features in the solar transition region
Authors: Vilangot Nhalil Nived , Shetye Juie , Doyle J Gerry
Published: June 2023

New instruments and telescopes covering the optical and ultraviolet spectral regions have revealed a range of small-scale dynamic features, many which may be related. For example, the range of spicule-like features hints towards a spectrum of features and not just two types; however, direct observational evidence in terms of tracking spicules across multiple wavelengths is needed in order to provide further insight into the dynamics of the Sun’s outer atmosphere. This paper uses H α data obtained with the CRisp Imaging SpectroPolarimeter instrument on the Swedish 1-m Solar Telescope, and in the transition region using the Interface Region Imaging Spectrograph with the SJI 1400 Å channel plus spectral data via the Si iv 1394 Å line to track spicules termed rapid blueshifted excursions (RBEs). The RBEs as seen in the H α blue wing images presented here can be subdivided into two categories: a single or multithreaded feature. Based on the H α spectra, the features can be divided into events showing broadening and line core absorption, events showing broadening and line core emission, events with a pure blueshifted H α profile without any absorption in the red wing, and broadened line profile with the absorption in the blue stronger compared to the red wing. From the RBE-like events that have a Si iv 1394 Å line profile, 78  per cent of them show a Si iv line flux increase. Most of these features show a second broadened Si iv component that is slightly blueshifted.
Relativistic binary systems in scale-independent energy–momentum squared gravity
Authors: Akarsu Özgür , Nazari Elham , Roshan Mahmood
Published: June 2023

In this paper, we study the gravitational-wave (GW) radiation and radiative behaviour of relativistic compact binary systems in the scale-independent energy–momentum squared gravity (EMSG). The field equations of this theory are solved approximately. The gravitational potential of a gravitational source is then obtained by considering two matter Lagrangian densities that both describe a perfect fluid in general relativity (GR). We derive the GW signals emitted from a compact binary system. The results are different from those obtained in GR. It is shown that the relevant non-GR corrections modify the wave amplitude and leave the GW polarizations unchanged. Interestingly, this modification depends on the choice of the matter Lagrangian density. This means that for different Lagrangian densities, this theory presents different predictions for the GW radiation. In this case, the system loses energy to modified GWs. This leads to a change in the secular variation of the Keplerian parameters of the binary system. In this work, we investigate the non-GR effects on the radiative parameter, that is, the first time derivative of the orbital period. Next, applying these results together with GW observations from the relativistic binary systems, we constrain/test the scale-independent EMSG theory in the strong-field regime. After assuming that GR is the valid gravity theory, as a priori expectation, we find that the free parameter of the theory is of the order 10−5 from the direct GW observation, the GW events GW190425 and GW170817, as well as the indirect GW observation, the double pulsar PSR J0737−3039A/B experiment.
Phylogenetic Comparative Approach Reveals Evolutionary Conservatism, Ancestral Composition, and Integration of Vertebrate Gut Microbiota
Authors: Perez-Lamarque Benoît , Sommeria-Klein Guilhem , Duret Loréna , Morlon Hélène
Published: June 2023

How host-associated microbial communities evolve as their hosts diversify remains equivocal: how conserved is their composition? What was the composition of ancestral microbiota? Do microbial taxa covary in abundance over millions of years? Multivariate phylogenetic models of trait evolution are key to answering similar questions for complex host phenotypes, yet they are not directly applicable to relative abundances, which usually characterize microbiota. Here, we extend these models in this context, thereby providing a powerful approach for estimating phylosymbiosis (the extent to which closely related host species harbor similar microbiota), ancestral microbiota composition, and integration (evolutionary covariations in bacterial abundances). We apply our model to the gut microbiota of mammals and birds. We find significant phylosymbiosis that is not entirely explained by diet and geographic location, indicating that other evolutionary-conserved traits shape microbiota composition. We identify main shifts in microbiota composition during the evolution of the two groups and infer an ancestral mammalian microbiota consistent with an insectivorous diet. We also find remarkably consistent evolutionary covariations among bacterial orders in mammals and birds. Surprisingly, despite the substantial variability of present-day gut microbiota, some aspects of their composition are conserved over millions of years of host evolutionary history.
Mono- and binuclear complexes of copper(II) with dimethylaminomethyl derivatives of 2-naphthol and 6-quinolinol: synthesis and in vitro study of antitumor properties
Authors: Akhmetova Vnira R , Galimova El'miraM , Mescheryakova Ekaterina S , Dzhemileva Lilya U , Dzhemilev Usein M , D'yakonov Vladimir A
Published: June 2023

1-(Dimethylamino)methyl-6-quinolinol scaffold, a structural moiety of the molecule of anticancer drug topotecan, was modified into copper-containing products to study cytotoxic properties. New mononuclear and binuclear Cu(II) complexes with 1-(N,N-dimethylamino)methyl-6-quinolinol were synthesized for the first time. The same way Cu(II) complexes with 1-(dimethylamino)methyl-2-naphtol ligand were synthesized. The structures of mono- and binuclear Cu(II) complexes with 1-aminomethyl-2-naphtol were confirmed by X-ray diffraction. The obtained compounds were examined for in vitro cytotoxic activity against Jurkat, K562, U937, MDA-MB-231, MCF7, T47D, and HEK293 cells. The induction of apoptosis and the effect of novel Cu complexes on the cell cycle were investigated. The cells showed a higher sensitivity to mononuclear Cu(II) complex with 1-(N,N-dimethylamino)methyl-6-quinolinolligand. All synthesized Cu(II) complexes had higher antitumor activity than the drugs topotecan, camptothecin, and platinum containing cisplatin.
Genotoxicity of cytokines at chemotherapy-induced ‘storm’ concentrations in a model of the human bone marrow
Authors: Asurappulige Harshini S H , Thomas Adam D , Morse H Ruth
Published: June 2023

Donor cell leukaemia (DCL) is a complication of haematopoietic stem cell transplantation where donated cells become malignant within the patient’s bone marrow. As DCL predominates as acute myeloid leukaemia, we hypothesized that the cytokine storm following chemotherapy played a role in promoting and supporting leukaemogenesis. Cytokines have also been implicated in genotoxicity; thus, we explored a cell line model of the human bone marrow (BM) to secrete myeloid cytokines following drug treatment and their potential to induce micronuclei. HS-5 human stromal cells were exposed to mitoxantrone (MTX) and chlorambucil (CHL) and, for the first time, were profiled for 80 cytokines using an array. Fifty-four cytokines were detected in untreated cells, of which 24 were upregulated and 10 were downregulated by both drugs. FGF-7 was the lowest cytokine to be detected in both untreated and treated cells. Eleven cytokines not detected at baseline were detected following drug exposure. TNFα, IL6, GM-CSF, G-CSF, and TGFβ1 were selected for micronuclei induction. TK6 cells were exposed to these cytokines in isolation and in paired combinations. Only TNFα and TGFβ1 induced micronuclei at healthy concentrations, but all five cytokines induced micronuclei at storm levels, which was further increased when combined in pairs. Of particular concern was that some combinations induced micronuclei at levels above the mitomycin C positive control; however, most combinations were less than the sum of micronuclei induced following exposure to each cytokine in isolation. These data infer a possible role for cytokines through chemotherapy-induced cytokine storm, in the instigation and support of leukaemogenesis in the BM, and implicate the need to evaluate individuals for variability in cytokine secretion as a potential risk factor for complications such as DCL.
CREEPY: CRISPR-mediated editing of synthetic episomes in yeast
Authors: Zhao Yu , Coelho Camila , Lauer Stephanie , Majewski Miłosz , Laurent Jon M , Brosh Ran , Boeke Jef D
Published: June 2023

Use of synthetic genomics to design and build ‘big’ DNA has revolutionized our ability to answer fundamental biological questions by employing a bottom-up approach. Saccharomyces cerevisiae, or budding yeast, has become the major platform to assemble large synthetic constructs thanks to its powerful homologous recombination machinery and the availability of well-established molecular biology techniques. However, introducing designer variations to episomal assemblies with high efficiency and fidelity remains challenging. Here we describe CRISPR Engineering of EPisomes in Yeast, or CREEPY, a method for rapid engineering of large synthetic episomal DNA constructs. We demonstrate that CRISPR editing of circular episomes presents unique challenges compared to modifying native yeast chromosomes. We optimize CREEPY for efficient and precise multiplex editing of >100 kb yeast episomes, providing an expanded toolkit for synthetic genomics.
Structural insights into CodY activation and DNA recognition
Authors: Hainzl Tobias , Bonde Mari , Almqvist Fredrik , Johansson Jörgen , Sauer-Eriksson A Elisabeth
Published: June 2023

Virulence factors enable pathogenic bacteria to infect host cells, establish infection, and contribute to disease progressions. In Gram-positive pathogens such as Staphylococcus aureus (Sa) and Enterococcus faecalis (Ef), the pleiotropic transcription factor CodY plays a key role in integrating metabolism and virulence factor expression. However, to date, the structural mechanisms of CodY activation and DNA recognition are not understood. Here, we report the crystal structures of CodY from Sa and Ef in their ligand-free form and their ligand-bound form complexed with DNA. Binding of the ligands—branched chain amino acids and GTP—induces conformational changes in the form of helical shifts that propagate to the homodimer interface and reorient the linker helices and DNA binding domains. DNA binding is mediated by a non-canonical recognition mechanism dictated by DNA shape readout. Furthermore, two CodY dimers bind to two overlapping binding sites in a highly cooperative manner facilitated by cross-dimer interactions and minor groove deformation. Our structural and biochemical data explain how CodY can bind a wide range of substrates, a hallmark of many pleiotropic transcription factors. These data contribute to a better understanding of the mechanisms underlying virulence activation in important human pathogens.
Chromatin opening ability of pioneer factor Pax7 depends on unique isoform and C-terminal domain
Authors: Bascunana Virginie , Pelletier Audrey , Gouhier Arthur , Bemmo Amandine , Balsalobre Aurelio , Drouin Jacques
Published: June 2023

Pioneer factors are transcription factors (TFs) that have the unique ability to recognise their target DNA sequences within closed chromatin. Whereas their interactions with cognate DNA is similar to other TFs, their ability to interact with chromatin remains poorly understood. Having previously defined the modalities of DNA interactions for the pioneer factor Pax7, we have now used natural isoforms of this pioneer as well as deletion and replacement mutants to investigate the Pax7 structural requirements for chromatin interaction and opening. We show that the GL+ natural isoform of Pax7 that has two extra amino acids within the DNA binding paired domain is unable to activate the melanotrope transcriptome and to fully activate a large subset of melanotrope-specific enhancers targeted for Pax7 pioneer action. This enhancer subset remains in the primed state rather than being fully activated, despite the GL+ isoform having similar intrinsic transcriptional activity as the GL– isoform. C-terminal deletions of Pax7 lead to the same loss of pioneer ability, with similar reduced recruitments of the cooperating TF Tpit and of the co-regulators Ash2 and BRG1. This suggests complex interrelations between the DNA binding and C-terminal domains of Pax7 that are crucial for its chromatin opening pioneer ability.