bluuebunny/crossref_metadata_2025 huggingface dataset:
Mucosal vaccination in a murine gnotobiotic model of
Giardia lamblia
infection
Authors: Ihara Sozaburo , Nguyen Brian V. , Miyamoto Yukiko , Eckmann Lars
Published: May 2024

Giardia lamblia
is an important protozoan cause of diarrheal disease worldwide, delayed development and cognitive impairment in children in low- and middle-income countries, and protracted post-infectious syndromes in developed regions.
G. lamblia
resides in the lumen and at the epithelial surface of the proximal small intestine but is not mucosa invasive. The protozoan parasite is genetically diverse with significant genome differences across strains and assemblages. Animal models, particularly murine models, have been instrumental in defining mechanisms of host defense against
G. lamblia
, but mice cannot be readily infected with most human pathogenic strains. Antibiotic pretreatment can increase susceptibility, suggesting that the normal microbiota plays a role in controlling
G. lamblia
infection in mice, but the broader implications on susceptibility to diverse strains are not known. Here, we have used gnotobiotic mice to demonstrate that robust intestinal infection can be achieved for a broad set of human-pathogenic strains of the genetic assemblages A and B. Furthermore, gnotobiotic mice were able to eradicate infection with a similar kinetics to conventional mice after trophozoite challenge. Germ-free mice could also be effectively immunized by the mucosal route with a protective antigen, α1-giardin, in a manner dependent on CD4 T cells. These results indicate that the gnotobiotic mouse model is powerful for investigating acquired host defenses in giardiasis, as the mice are broadly susceptible to diverse
G. lamblia
strains yet display no apparent defects in mucosal immunity needed for controlling and eradicating this lumen-dwelling pathogen.
Comparison of CcrM-dependent methylation in
Caulobacter crescentus
and
Brucella abortus
by nanopore sequencing
Authors: Campbell Maxwell , Barton Ian Scott , Roop R. Martin , Chien Peter
Published: May 2024

Bacteria rely on DNA methylation for restriction-modification systems and epigenetic control of gene expression. Here, we use direct detection of methylated bases by nanopore sequencing to monitor global DNA methylation in Alphaproteobacteria, where use of this technique has not yet been reported. One representative of this order,
Caulobacter crescentus
, relies on DNA methylation to control cell cycle progression, but it is unclear whether other members of this order, such as
Brucella abortus
, depend on the same systems. We addressed these questions by first measuring CcrM-dependent DNA methylation in
Caulobacter
and showing excellent correlation between nanopore-based detection and previously published results. We then directly measure the impact of Lon-mediated CcrM degradation on the epigenome, verifying that loss of Lon results in pervasive methylation. We also show that the AlkB demethylase has no global impact on DNA methylation during normal growth. Next, we report on the global DNA methylation in
B. abortus
for the first time and find that CcrM-dependent methylation is reliant on Lon but impacts the two chromosomes differently. Finally, we explore the impact of the MucR transcription factor, known to compete with CcrM methylation, on the
Brucella
methylome and share the results with a publicly available visualization package. Our work demonstrates the utility of nanopore-based sequencing for epigenome measurements in Alphaproteobacteria and reveals new features of CcrM-dependent methylation in a zoonotic pathogen.

IMPORTANCE

DNA methylation plays an important role in bacteria, maintaining genome integrity and regulating gene expression. We used nanopore sequencing to directly measure methylated bases in
Caulobacter crescentus
and
Brucella abortus
. In
Caulobacter
, we showed that stabilization of the CcrM methyltransferase upon loss of the Lon protease results in prolific methylation and discovered that the putative methylase AlkB is unlikely to have a global physiological effect. We measured genome-wide methylation in
Brucella
for the first time, revealing a similar role for CcrM in cell-cycle methylation but a more complex regulation by the Lon protease than in Caulobacter. Finally, we show how the virulence factor MucR impacts DNA methylation patterns in
Brucella
.
A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels and activates the DNA damage response
Authors: Prabhakar Apurva T. , James Claire D. , Youssef Aya H. , Hossain Reafa A. , Hill Ronald D. , Bristol Molly L. , Wang Xu , Dubey Aanchal , Karimi Elmira , Morgan Iain M.
Published: May 2024

An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 and BRD4 is required for E2 plasmid segregation function. The E2-TopBP1 interaction promotes increased mitotic E2 protein levels in U2OS and N/Tert-1 cells, as well as in human foreskin keratinocytes immortalized by HPV16 (HFK + HPV16). SIRT1 deacetylation reduces E2 protein stability and here we demonstrate that increased E2 acetylation occurs during mitosis in a TopBP1 interacting-dependent manner, promoting E2 mitotic stabilization. p300 mediates E2 acetylation and acetylation is increased due to E2 switching off SIRT1 function during mitosis in a TopBP1 interacting-dependent manner, confirmed by increased p53 stability and acetylation on lysine 382, a known target for SIRT1 deacetylation. SIRT1 can complex with E2 in growing cells but is unable to do so during mitosis due to the E2-TopBP1 interaction; SIRT1 is also unable to complex with p53 in mitotic E2 wild-type cells but can complex with p53 outside of mitosis. E2 lysines 111 and 112 are highly conserved residues across all E2 proteins and we demonstrate that K111 hyper-acetylation occurs during mitosis, promoting E2 interaction with Topoisomerase 1 (Top1). We demonstrate that K112 ubiquitination promotes E2 proteasomal degradation during mitosis. E2-TopBP1 interaction promotes mitotic acetylation of CHK2, promoting phosphorylation and activation of the DNA damage response (DDR). The results present a new model in which the E2-TopBP1 complex inactivates SIRT1 during mitosis, and activates the DDR. This is a novel mechanism of HPV16 activation of the DDR, a requirement for the viral life cycle.

IMPORTANCE

Human papillomaviruses (HPVs) are causative agents in around 5% of all human cancers. While there are prophylactic vaccines that will significantly alleviate HPV disease burden on future generations, there are currently no anti-viral strategies available for the treatment of HPV cancers. To generate such reagents, we must understand more about the HPV life cycle, and in particular about viral-host interactions. Here, we describe a novel mitotic complex generated by the HPV16 E2 protein interacting with the host protein TopBP1 that controls the function of the deacetylase SIRT1. The E2-TopBP1 interaction disrupts SIRT1 function during mitosis in order to enhance acetylation and stability of viral and host proteins. We also demonstrate that the E2-TopBP1 interaction activates the DDR. This novel complex is essential for the HPV16 life cycle and represents a novel anti-viral therapeutic target.
The unusual mode of action of the polyketide glycoside antibiotic cervimycin C
Authors: Hoffmann Alina , Steffens Ursula , Maček Boris , Franz-Wachtel Mirita , Nieselt Kay , Harbig Theresa Anisja , Scherlach Kirstin , Hertweck Christian , Sahl Hans-Georg , Bierbaum Gabriele
Published: May 2024

Cervimycins A–D are bis-glycosylated polyketide antibiotics produced by
Streptomyces tendae
HKI 0179 with bactericidal activity against Gram-positive bacteria. In this study, cervimycin C (CmC) treatment caused a spaghetti-like phenotype in
Bacillus subtilis
168, with elongated curved cells, which stayed joined after cell division, and exhibited a chromosome segregation defect, resulting in ghost cells without DNA. Electron microscopy of CmC-treated
Staphylococcus aureus
(3 × MIC) revealed swollen cells, misshapen septa, cell wall thickening, and a rough cell wall surface. Incorporation tests in
B. subtilis
indicated an effect on DNA biosynthesis at high cervimycin concentrations. Indeed, artificial downregulation of the DNA gyrase subunit B gene (
gyrB
) increased the activity of cervimycin in agar diffusion tests, and, in high concentrations (starting at 62.5 × MIC), the antibiotic inhibited
S. aureus
DNA gyrase supercoiling activity
in vitro
. To obtain a more global view on the mode of action of CmC, transcriptomics and proteomics of cervimycin treated versus untreated
S. aureus
cells were performed. Interestingly, 3 × MIC of cervimycin did not induce characteristic responses, which would indicate disturbance of the DNA gyrase activity
in vivo
. Instead, cervimycin induced the expression of the CtsR/HrcA heat shock operon and the expression of autolysins, exhibiting similarity to the ribosome-targeting antibiotic gentamicin. In summary, we identified the DNA gyrase as a target, but at low concentrations, electron microscopy and omics data revealed a more complex mode of action of cervimycin, which comprised induction of the heat shock response, indicating protein stress in the cell.

IMPORTANCE

Antibiotic resistance of Gram-positive bacteria is an emerging problem in modern medicine, and new antibiotics with novel modes of action are urgently needed. Secondary metabolites from
Streptomyces
species are an important source of antibiotics, like the cervimycin complex produced by
Streptomyces tendae
HKI 0179. The phenotypic response of
Bacillus subtilis
and
Staphylococcus aureus
toward cervimycin C indicated a chromosome segregation and septum formation defect. This effect was at first attributed to an interaction between cervimycin C and the DNA gyrase. However, omics data of cervimycin treated versus untreated
S. aureus
cells indicated a different mode of action, because the stress response did not include the SOS response but resembled the response toward antibiotics that induce mistranslation or premature chain termination and cause protein stress. In summary, these results point toward a possibly novel mechanism that generates protein stress in the cells and subsequently leads to defects in cell and chromosome segregation.
GDP-mannose pyrophosphorylase is an efficient target in
Xanthomonas citri
for citrus canker control
Authors: Alexandrino André Vessoni , Barcelos Mariana Pegrucci , Federico Leonardo Bruno , da Silva Tamiris Garcia , Cavalca Lúcia Bonci , de Moraes Carlos Henrique Alves , Ferreira Henrique , Taft Carlton Anthony , Behlau Franklin , de Paula Silva Carlos Henrique Tomich , Novo-Mansur Maria Teresa Marques
Published: May 2024

Xanthomonas citri
subsp.
citri
(Xcc) is a bacterium that causes citrus canker, an economically important disease that results in premature fruit drop and reduced yield of fresh fruit. In this study, we demonstrated the involvement of XanB, an enzyme with phosphomannose isomerase (PMI) and guanosine diphosphate-mannose pyrophosphorylase (GMP) activities, in Xcc pathogenicity. Additionally, we found that XanB inhibitors protect the host against Xcc infection. Besides being deficient in motility, biofilm production, and ultraviolet resistance, the
xanB
deletion mutant was unable to cause disease, whereas
xanB
complementation restored wild-type phenotypes. XanB homology modeling allowed
in silico
virtual screening of inhibitors from databases, three of them being suitable in terms of absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties, which inhibited GMP (but not PMI) activity of the Xcc recombinant XanB protein in more than 50%. Inhibitors reduced citrus canker severity up to 95%, similarly to copper-based treatment.
xanB
is essential for Xcc pathogenicity, and XanB inhibitors can be used for the citrus canker control.

IMPORTANCE

Xcc causes citrus canker, a threat to citrus production, which has been managed with copper, being required a more sustainable alternative for the disease control. XanB was previously found on the surface of Xcc, interacting with the host and displaying PMI and GMP activities. We demonstrated by
xanB
deletion and complementation that GMP activity plays a critical role in Xcc pathogenicity, particularly in biofilm formation. XanB homology modeling was performed, and
in silico
virtual screening led to carbohydrate-derived compounds able to inhibit XanB activity and reduce disease symptoms by 95%. XanB emerges as a promising target for drug design for control of citrus canker and other economically important diseases caused by
Xanthomonas
sp.
Deficiency of adenosine deaminase 2: a genetic autoinflammatory disorder mimicking childhood polyarteritis nodosa
Authors: Mhatre Shweta , Muranjan Mamta , Karande Sunil , Thirumalaiswamy Aparna
Published: May 2024

A girl in the early adolescent age group presented with multisystem manifestations in the form of periodic fever, recurrent abdominal pain, hypertension, seizure, skin lesions over the chest and gangrene over the left ring and middle fingertips. Her condition had remained undiagnosed for 11 years. On evaluation, she had features of polyarteritis nodosa (PAN) (multiple aneurysms, symmetric sensorimotor peripheral neuropathy, superficial ulcers, digital necrosis, myalgia, hypertension and proteinuria). As childhood PAN is a phenocopy of adenosine deaminase 2 with a different management strategy, whole-exome sequencing was performed, which revealed a pathogenic variant inADA2gene. The child was treated with TNF alpha inhibitors and showed improvement in the Paediatric Vasculitis Activity Score. The paper highlights the gratifying consequences of correct diagnosis with disease-specific therapy that ended the diagnostic odyssey, providing relief to the patient from debilitating symptoms and to the family from the financial burden of continued out-of-pocket health expenditure.
Overexposure to ultraviolet radiation in solar urticaria
Authors: Ross Hannah Elizabeth , Parkin Donna , Ayer Jean
Published: May 2024

A man in his 50s was diagnosed with solar urticaria following monochromated light testing that demonstrated exquisite photosensivity to ultraviolet (UV) A, UV B (UVB) and visible light.

Treatment options for this photodermatosis are limited; UVB phototherapy is one modality that can be appropriate in some patients. This is administered at very low doses in a controlled environment to induce skin hardening.1

To self-treat his condition, the patient used a commercial sunbed on two occasions several days apart. He noted an immediate flare of solar urticaria after first use with associated dizziness. Following the second use, he felt generally unwell and was witnessed to lose consciousness and displayed jerky movements of his limbs while a passenger in a car. Investigations including a head MRI and an EEG were normal; an anoxic seizure caused by a flare of solar urticaria was later confirmed.

Solar urticaria is a rare photodermatosis that is poorly understood and difficult to treat. The condition has a significant impact on the quality of life of patients. Severe cases can be associated with systemic symptoms that could be life-threatening.
Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury
Authors: Yang Yang , Xu Long , Atkins Constance , Kuhlman Lily , Zhao Jie , Jeong Jong-Min , Wen Yankai , Moreno Nicolas , Kim Kang Ho , An Yu A , Wang Fenfen , Bynon Steve , Villani Vincenzo , Gao Bin , Brombacher Frank , Harris Raymond , Eltzschig Holger K , Jacobsen Elizabeth , Ju Cynthia
Published: May 2024

Objective

Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair.

Design

Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf).

Result

We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury.

Conclusion

Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.
Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson’s disease
Authors: Jiang Shenzhong , Wang Han , Yang Chengxian , Feng Feng , Xu Dan , Zhang Mengyu , Xie Manqing , Cui Ruixue , Zhu Zhaohui , Jia Chenhao , Liu Linwen , Wang Lin , Yang Xunzhe , Yang Yingmai , Hao Honglin , Liu Zhaoxi , Wu Zhihong , Leng Ling , Li Xiaoxin , Sun Xicai , Zhao Xiongfei , Xu Jinfang , Zhang Yi , Wan Xinhua , Bao Xinjie , Wang Renzhi
Published: May 2024

Background

Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson’s disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial.

Methods

This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy.

Results

7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels.

Conclusions

Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.
Long-term clinical outcomes of certolizumab pegol treatment in non-radiographic axial spondyloarthritis stratified by baseline MRI and CRP status
Authors: Rudwaleit Martin , Deodhar Atul , Bauer Lars , Gensler Lianne , Hoepken Bengt , Kumke Thomas , Auteri Simone Emanuele , Kim Mindy , Maksymowych Walter
Published: May 2024

Objective

There is a paucity of data on long-term clinical responses in patients with non-radiographic axial spondyloarthritis (nr-axSpA) based on their baseline objective signs of inflammation such as MRI or C-reactive protein (CRP) levels. This study reports clinical outcomes up to 3 years of the C-axSpAnd trial, including safety follow-up extension (SFE) from Weeks 52 to 156, stratified by patients’ baseline MRI and CRP status.

Methods

C-axSpAnd (NCT02552212) was a phase 3, multicentre study that evaluated certolizumab pegol (CZP) in patients with active nr-axSpA who had active sacroiliitis on MRI and/or elevated CRP. In this post hoc analysis, efficacy outcomes are reported to Week 156 of C-axSpAnd for patients stratified according to their MRI and CRP status at Week 0 (MRI+/CRP−, MRI−/CRP+ and MRI+/CRP+).

Results

Across all outcome measures, including major improvement in Ankylosing Spondylitis Disease Activity Score (ASDAS-MI) and Assessment of SpondyloArthritis international Society criteria ≥40% response (ASAS40), outcomes were generally sustained in SFE patients from Week 52 to Week 156. MRI+/CRP+ patients showed numerically higher or comparable responses relative to MRI−/CRP+ and MRI+/CRP− patients at Weeks 52 and 156; however, all three subgroups demonstrated substantial improvements from Week 0 (in CZP-randomised patients, ASDAS-MI at Week 156 [observed case]: MRI+/CRP+: 73.1%, MRI–/CRP+: 52.2%, MRI+/CRP–: 30.4%; ASAS40: MRI+/CRP+: 76.9%, MRI–/CRP+: 62.5%, MRI+/CRP–: 65.2%).

Conclusions

In patients with nr-axSpA and objective signs of inflammation, long-term clinical outcomes achieved after 1 year were generally sustained at 3 years across MRI+/CRP+, MRI−/CRP+ and MRI+/CRP− subgroups.
MRI of shoulder girdle in polymyalgia rheumatica: inflammatory findings and their diagnostic value
Authors: Fruth Martin , Künitz Lucie , Martin-Seidel Philipp , Tsiami Styliani , Baraliakos Xenofon
Published: May 2024

Background

Non-synovial inflammation as detected by MRI is characteristic in polymyalgia rheumatica (PMR) with potentially high diagnostic value.

Objective

The objective is to describe inflammatory MRI findings in the shoulder girdle of patients with PMR and discriminate from other causes of shoulder girdle pain.

Methods

Retrospective study of 496 contrast-enhanced MRI scans of the shoulder girdle from 122 PMR patients and 374 non-PMR cases. Two radiologists blinded to clinical and demographic information evaluated inflammation at six non-synovial plus three synovial sites for the presence or absence of inflammation. The prevalence of synovial and non-synovial inflammation, both alone and together with clinical information, was tested for its ability to differentiate PMR from non-PMR.

Results

A high prevalence of non-synovial inflammation was identified as striking imaging finding in PMR, in average 3.4±1.7, mean (M)±SD, out of the six predefined sites were inflamed compared with 1.1±1.4 (M±SD) in non-PMR group, p<0.001, with excellent discriminatory effect between PMR patients and non-PMR cases. The prevalence of synovitis also differed significantly between PMR patients and non-PMR cases, 2.5±0.8 (M±SD) vs 1.9±1.1 (M±SD) out of three predefined synovial sites, but with an inferior discriminatory effect. The detection of inflammation at three out of six predefined non-synovial sites differentiated PMR patients from controls with a sensitivity/specificity of 73.8%/85.8% and overall better performance than detection of synovitis alone (sensitivity/specificity of 86.1%/36.1%, respectively).

Conclusion

Contrast-enhanced MRI of the shoulder girdle is a reliable imaging tool with significant diagnostic value in the assessment of patients suffering from PMR and differentiation to other conditions for shoulder girdle pain.
Cryoneurolysis versus radiofrequency ablation outcome on pain experience in chronic low back pain (COPE): a single-blinded randomised controlled trial
Authors: Truong Kamilla , Meier Kaare , Ahrens Lasse Cramer , Wichmann Thea Overgaard , Zaer Hamed , Tiroke Lasse Hubertus , Arvin Simon , Bazys Mindaugas , Duel Peter , Gudmundsdottir Gudrun , Carlsen Jakob Gram , Nikolajsen Lone , van Tulder Maurits , Sørensen Jens Christian Hedemann , Rasmussen Mikkel Mylius
Published: May 2024

Objective

A comparison of cryoneurolysis or radio frequency (RF) with placebo in patients with facetogenic chronic low back pain (LBP) for patient global impression of change (PGIC), pain intensity, function and quality of life, with 1-year follow-up.

Design

Single-centre, single-blinded placebo-controlled randomised controlled trial.

Setting

Single-centre study.

Participants

Inclusion from March 2020 to September 2022: consenting adults over 18 years of age, LBP>3 months, average Numeric Rating Scale LBP≥4 average last 14 days and a positive response to a diagnostic medial branch block (>50% pain reduction after 60 min).

Interventions

120 patients were block randomised 1:1:1 to cryoneurolysis, RF or placebo of the medial branch nerves. Physical therapy was added after 4 weeks for all groups.

Main outcome measures

Primary outcome was PGIC 4 weeks after the intervention. Secondary outcomes included pain intensity (Numeric Rating Scale, NRS), quality of life (Short Form 36, EQ-5D-5L), disability (Oswestry Disability Index), depression (Major Depression Inventory) and catastrophising (Pain Catastrophising Scale). Outcomes were measured at 4 weeks, 3, 6 and 12 months.

Results

There was no statistically significant difference in PGIC at 4 weeks between cryoneurolysis and placebo (risk ratio (RR) 2; 95% CI 0.75 to 5.33, p=0.17) and RF and placebo (RR 1.6; 95% CI 0.57 to 4.49, p=0.37), except PGIC for cryoneurolysis at 6-month follow-up (RR 5.1; 95% CI 1.20 to 22.03, p=0.03). No statistically significant differences were found in secondary follow-up endpoints.

Conclusions

Denervation of the medial branch nerve by either cryoneurolysis or RF compared with placebo did not demonstrate significant improvement in PGIC, pain intensity, function and quality of life in patients with facetogenic chronic LBP at short-term or long-term follow-up.

Trial registration number

NCT04786145.
Muon-induced background in a next-generation dark matter experiment based on liquid xenon
Authors: Pěč Viktor , Kudryavtsev Vitaly A. , Araújo Henrique M. , Sumner Timothy J.
Published: May 2024

Muon-induced neutrons can lead to potentially irreducible backgrounds in rare event search experiments. We have investigated the implication of laboratory depth on the muon-induced background in a future dark matter experiment capable of reaching the so-called neutrino floor. Our simulation study focused on a xenon-based detector with 70 tonnes of active mass, surrounded by additional veto systems plus a water shield. Two locations at the Boulby Underground Laboratory (UK) were analysed as examples: an experimental cavern in salt at a depth of 2850 m w. e. (similar to the location of the existing laboratory), and a deeper laboratory located in polyhalite rock at a depth of 3575 m w. e. Our results show that no cosmogenic background events are likely to survive standard analysis cuts for 10 years of operation at either location. The largest background component we identified comes from beta-delayed neutron emission from $$^{17}$$

17

N which is produced from $$^{19}$$

19

F in the fluoropolymer components of the experiment. Our results confirm that a dark matter search with sensitivity to the neutrino floor is viable (from the point of view of cosmogenic backgrounds) in underground laboratories at these levels of rock overburden. This work was conducted in 2019–21 in the context of a feasibility study to investigate the possibility of developing the Boulby Underground Laboratory to host a next-generation dark matter experiment; however, our findings are also relevant for other underground laboratories.
Nonproportionality of NaI(Tl) scintillation detector for dark matter search experiments
Authors:   COSINE-100 Collaboration, Lee S. M. , Adhikari G. , Carlin N. , Cho J. Y. , Choi J. J. , Choi S. , Ezeribe A. C. , França L. E. , Ha C. , Hahn I. S. , Hollick S. J. , Jeon E. J. , Joo H. W. , Kang W. G. , Kauer M. , Kim B. H. , Kim H. J. , Kim J. , Kim K. W. , Kim S. H. , Kim S. K. , Kim S. W. , Kim W. K. , Kim Y. D. , Kim Y. H. , Ko Y. J. , Lee D. H. , Lee E. K. , Lee H. , Lee H. S. , Lee H. Y. , Lee I. S. , Lee J. , Lee J. Y. , Lee M. H. , Lee S. H. , Lee Y. J. , Leonard D. S. , Luan N. T. , Manzato B. B. , Maruyama R. H. , Neal R. J. , Nikkel J. A. , Olsen S. L. , Park B. J. , Park H. K. , Park H. S. , Park J. C. , Park K. S. , Park S. D. , Pitta R. L. C. , Prihtiadi H. , Ra S. J. , Rott C. , Shin K. A. , Cavalcante D. F. F. S. , Scarff A. , Son M. K. , Spooner N. J. C. , Truc L. T. , Yang L. , Yu G. H.
Published: May 2024

We present a comprehensive study of the nonproportionality of NaI(Tl) scintillation detectors within the context of dark matter search experiments. Our investigation, which integrates COSINE-100 data with supplementary $$\gamma $$
γ
spectroscopy, measures light yields across diverse energy levels from full-energy $$\gamma $$
γ
peaks produced by the decays of various isotopes. These $$\gamma $$
γ
peaks of interest were produced by decays supported by both long and short-lived isotopes. Analyzing peaks from decays supported only by short-lived isotopes presented a unique challenge due to their limited statistics and overlapping energies, which was overcome by long-term data collection and a time-dependent analysis. A key achievement is the direct measurement of the 0.87 keV light yield, resulting from the cascade following electron capture decay of $$\mathrm {^{22}Na}$$

22

Na

from internal contamination. This measurement, previously accessible only indirectly, deepens our understanding of NaI(Tl) scintillator behavior in the region of interest for dark matter searches. This study holds substantial implications for background modeling and the interpretation of dark matter signals in NaI(Tl) experiments.
Effect of polarized colliding beam on Higgs boson production at the lepton collider
Authors: Ahmed Ijaz , Shakar Mashal , Ashraf M. U. , Muhammad Jamil , Khurshid Taimoor
Published: May 2024

Different production processes involving the Higgs boson, such as annihilation and W/Z boson fusion, will be observed in the International Linear Collider (ILC). The ILC operates at a center-of-mass (CM) energy of [Formula: see text]–1000[Formula: see text]GeV. The study reveals that the production cross-section can either be enhanced or reduced depending on the CM energy and the specific combination used, which has implications for selecting appropriate production processes. Additionally, this investigation highlights that by polarizing beams, the number of measurable observables increases. These observables, such as left–right asymmetry, detailed effective polarization, and adequate effective luminosity, are crucial to ascertain contemporary physical parameters in physics models absurdly the Standard Model (SM).
Separations in Proof Complexity and TFNP
Authors: Göös Mika , Hollender Alexandros , Jain Siddhartha , Maystre Gilbert , Pires William , Robere Robert , Tao Ran
Published: May 2024

It is well-known that Resolution proofs can be efficiently simulated by Sherali–Adams (SA) proofs. We show, however, that any such simulation needs to exploit huge coefficients: Resolution cannot be efficiently simulated by SA when the coefficients are written in unary. We also show that
Reversible Resolution
(a variant of MaxSAT Resolution) cannot be efficiently simulated by Nullstellensatz (NS).

These results have consequences for total NP search problems. First, we characterise the classes PPADS, PPAD, SOPL by unary-SA, unary-NS, and Reversible Resolution, respectively. Second, we show that, relative to an oracle,

\({\text{ PLS}} \not\subseteq {\text{ PPP}}\)

,

\({\text{ SOPL}} \not\subseteq {\text{ PPA}}\)

, and

\({\text{ EOPL}} \not\subseteq {\text{ UEOPL}}\)

. In particular, together with prior work, this gives a complete picture of the black-box relationships between all classical TFNP classes introduced in the 1990s.
An Observational View of Structure in Protostellar Systems
Authors: Tobin John J. , Sheehan Patrick D.
Published: May 2024

The envelopes and disks that surround protostars reflect the initial conditions of star and planet formation and govern the assembly of stellar masses. Characterizing these structures requires observations that span the near-IR to centimeter wavelengths. Consequently, the past two decades have seen progress driven by numerous advances in observational facilities across this spectrum, including the Spitzer Space Telescope, Herschel Space Observatory, the Atacama Large Millimeter/submillimeter Array, and a host of other ground-based interferometers and single-dish radio telescopes.
▪Nearly all protostars have well-formed circumstellar disks that are likely to be rotationally supported; the ability to detect a disk around a protostar is more a question of spatial resolution rather than whether or not a disk is present.▪The disks around protostars have inherently higher millimeter/submillimeter luminosities as compared to disks around more-evolved pre-main-sequence stars, though there may be systematic variations between star-forming regions.▪The envelopes around protostars are inherently asymmetric, and streamers emphasize that mass flow through the envelopes to the disks may not be homogeneous.▪The current mass distribution of protostars may be impacted by selection bias given that it is skewed toward solar-mass protostars, which is inconsistent with the stellar initial mass function.
Mapping the Human Cell Surface Interactome: A Key to Decode Cell-to-Cell Communication
Authors: Shilts Jarrod , Wright Gavin J.
Published: May 2024

Proteins on the surfaces of cells serve as physical connection points to bridge one cell with another, enabling direct communication between cells and cohesive structure. As biomedical research makes the leap from characterizing individual cells toward understanding the multicellular organization of the human body, the binding interactions between molecules on the surfaces of cells are foundational both for computational models and for clinical efforts to exploit these influential receptor pathways. To achieve this grander vision, we must assemble the full interactome of ways surface proteins can link together. This review investigates how close we are to knowing the human cell surface protein interactome. We summarize the current state of databases and systematic technologies to assemble surface protein interactomes, while highlighting substantial gaps that remain. We aim for this to serve as a road map for eventually building a more robust picture of the human cell surface protein interactome.
Communication and Deliberation for Environmental Governance
Authors: Erbaugh James T. , Chang Charlotte H. , Masuda Yuta J. , Ribot Jesse
Published: May 2024

Environmental governance occurs through and is shaped by communication. We propose a typology of public communication, classifying it by directionality (one-way or two-way) and objective (informational or operational). We then review how communication types influence individuals’ conceptual frames, values, and environmental behaviors. Though one-way communication is common, its impact is often limited to influencing conceptual frames. Research on two-way informational communication demonstrates a greater ability to align conceptual frames and values among individuals, and research on two-way operational communication demonstrates the greatest impact on conceptual frames, values, and environmental behaviors. Factors that affect the impact of communication include the medium through which it occurs, trust, timing, and social-material context. Among these, our review considers new directions in public communication research that focus on the role of digital platforms, misinformation, and disinformation. We conclude by synthesizing research on deliberative communication, a case of communication among citizens guided by democratic ideals.
Motor-evoked potentials in the human upper and lower limb do not increase after single 30-min sessions of acute intermittent hypoxia
Authors: Mathew Anandit J. , Finn Harrison T. , Carter Sophie G. , Gandevia Simon C. , Butler Jane E.
Published: May 2024

This is the first study that tests whether acute intermittent hypoxia (AIH) induces motor output facilitation in humans after two different doses of AIH (9% and 12% [Formula: see text]) and the reproducibility of participant responses after a repeat AIH intervention at 9% AIH. There was no motor output facilitation in response to either dose of AIH. The results question the effectiveness of a single 30-min session of AIH in inducing motor output facilitation, tested in this way.
Effect of glycocalyx-targeted therapy on vascular function in older adults: a randomized controlled trial
Authors: Gimblet Colin J. , Ernst Jackson W. , Bell Blair , Bos Kyle D. , Stroud Amy K. , Wendt Linder H. , Donato Anthony J. , Jalal Diana I. , Pierce Gary L.
Published: May 2024

Endothelial glycocalyx thickness and vascular endothelial function decline with advancing age. Endocalyx Pro is a glycocalyx-targeted therapy that may improve endothelial glycocalyx thickness and vascular endothelial function in older adults. This study demonstrated that 12-wk Endocalyx Pro supplementation did not improve overall endothelial glycocalyx thickness or flow-mediated dilation in older adults; however, Endocalyx Pro did increase capillary glycocalyx thickness in individuals not taking antihypertensive medication and improve flow-mediated dilation normalized to the shear stimulus.
The Impact of the Coexpression of MET and ESR Genes on Prognosticators and Clinical Outcomes of Breast Cancer: An Analysis for the METABRIC Dataset
Authors: Ayoub Nehad M. , Al-Taani Ghaith M. , Alkhalifa Amer E. , Ibrahim Dalia R. , Shatnawi Aymen
Published: May 2024

Purpose. Breast cancer is a heterogeneous disease. Exploring new prognostic and therapeutic targets in patients with breast cancer is essential. This study investigated the expression of MET, ESR1, and ESR2 genes and their association with clinicopathologic characteristics and clinical outcomes in patients with breast cancer. Methods. The METABRIC dataset for breast cancer was obtained from the cBioPortal public domain. Gene expression data for MET, ESR1, and ESR2, as well as the putative copy number alterations (CNAs) for MET were retrieved. Results. The MET mRNA expression levels correlated inversely with the expression levels of ESR1 and positively with the expression levels of ESR2 (r = −0.379, p<0.001 and r = 0.066, and p=0.004, respectively). The ESR1 mRNA expression was significantly different among MET CNAs groups p<0.001. Patients with high MET/ESR1 coexpression had favorable clinicopathologic tumor characteristics and prognosticators compared to low MET/ESR1 coexpression in terms of greater age at diagnosis, reduced Nottingham Prognostic Index, lower tumor grade, hormone receptor positivity, HER2-negative status, and luminal subtype p<0.001. In contrast, patients with high MET/ESR2 coexpression had unfavorable tumor features and advanced prognosticators compared to patients with low MET/ESR2 coexpression p<0.001. No significant difference in overall survival was observed based on the MET/ESR coexpression status. However, when data were stratified based on the treatment type (chemotherapy and hormonal therapy), survival was significantly different based on the coexpression status of MET/ESR. Conclusions. Findings from our study add to the growing evidence on the potential crosstalk between MET and estrogen receptors in breast cancer. The expression of the MET/ESR genes could be a novel prognosticator and calls for future studies to evaluate the impact of combinational treatment approaches with MET inhibitors and endocrine drugs in breast cancer.
Chronic Kidney Disease in Patients with Hip Fracture: Prevalence and Outcomes
Authors: Fisher Alexander , Wang Jo-Wai Douglas , Smith Paul N.
Published: May 2024

Objective. Although the association between chronic kidney disease (CKD) and osteoporotic fractures is well established, data on CKD combined with hip fracture (HF) are scarce and controversial. We aimed to assess in patients with HF the prevalence of CKD, its impact on hospital mortality and length of stay (LOS) and to determine the prognostic value of CKD to predict hospital outcomes. Methods. Prospectively collected clinical data were analysed in 3623 consecutive HF patients aged ≥65 years (mean age 83.4 ± 7.50 [standard deviation] years; 74.4% females). Results. CKD among older patients with HF is highly prevalent (39.9%), has different clinical characteristics, a 2.5-fold higher mortality rate, and 40% greater risk of prolonged LOS. The strongest risk for a poor outcome was advanced age (>80 years). The risk of death substantially increases in combination with chronic disorders, especially coronary artery disease, anaemia, hyperparathyroidism, and atrial fibrillation; models based only on three variables—CKD stage, age >80, and presence of a specific chronic condition—predicted in-hospital death with good discrimination capability (AUC ≥ 0.700) and reasonable accuracy, the number needed to predict ranged between 5.7 and 14.5. Only 12% of HF patients received osteoporotic drugs prefracture. Conclusion. In HF patients with CKD, the risk of adverse outcomes largely increases in parallel with worsening kidney function and, especially, in combination with comorbidities; models based on three admission variables predict a fatal outcome. Assessment of renal function is essential to preventing osteoporotic fractures.
Adverse Health Effects of the Long-Term Simultaneous Exposure to Arsenic and Particulate Matter in a Murine Model
Authors: Rivas-Santiago Cesar , Gallegos-Bañuelos Maria , Trejo-Ramos Irving , Solís-Torres Nancy , Quintana-Belmares Raúl , Macías-Segura Noé , Gutiérrez-Bañuelos Héctor , Troncoso-Vazquez Lorena , Rivas-Santiago Bruno , Gonzalez-Curiel Irma
Published: May 2024

PM2.5 and arsenic are two of the most hazardous substances for humans that coexist worldwide. Independently, they might cause multiple organ damage. However, the combined effect of PM2.5 and arsenic has not been studied. Here, we used an animal model of simultaneous exposure to arsenic and PM2.5. Adult Wistar rats were exposed to PM2.5, As, or PM2.5 + As and their corresponding control groups. After 7, 14, and 28 days of exposure, the animals were euthanized and serum, lungs, kidneys, and hearts were collected. Analysis performed showed high levels of lung inflammation in all experimental groups, with an additive effect in the coexposed group. Besides, we observed cartilaginous metaplasia in the hearts of all exposed animals. The levels of creatine kinase, CK-MB, and lactate dehydrogenase increased in experimental groups. Tissue alterations might be related to oxidative stress through increased GPx and NADPH oxidase activity. The findings of this study suggest that exposure to arsenic, PM2.5, or coexposure induces high levels of oxidative stress, which might be associated with lung inflammation and heart damage. These findings highlight the importance of reducing exposure to these pollutants to protect human health.
Genetic Profile of Greek Indigenous Honey Bee Populations, Local Extinctions, Geographical Distinction, and Patterns, by Using mtDNA COI and Nuclear CSD Gene Analysis Markers
Authors: Zampakas Konstantinos , Alvanou Maria V. , Kalapouti Anastasia , Hatjina Fani , Tananaki Chrysoula , Melfou Katerina , Giantsis Ioannis A.
Published: May 2024

Evaluation and conservation of local genetic resources of the domestic honey bee populations is important, especially in regions with high diversity levels as well as high honey bee colony density. Greece is rich in honey bee biodiversity, hosting several subspecies, with the status of them being, though, doubtful. The purpose of the present study was to investigate the genetic relationships of both stationary and movable honey bee populations, originating from many location throughout Greece. Two molecular markers were utilized, namely, the conserved mitochondrial COI gene and the highly variable complementary sex determination (CSD) gene. Samples were collected from nine distant populations: eight populations from colonies that followed the traditional stationary beekeeping model and one following the modern migratory beekeeping model type, where the hives are transferred from place to place according to the season. Regardless the beekeeping model, all populations were characterized by sufficient genetic diversity indicating no signs of inbreeding or any bottleneck effects. Nevertheless, genetic differentiation and phylogenetic analysis in comparison with haplotypes obtained from GenBank revealed a genetic admixture pattern suggesting that movement causes genetic homogeneity, occasionally in the stable reared populations as well. Interestingly, two populations, namely, Kastoria and Protokklisi, belonging to A. m. macedonica population, were significantly differentiated, supporting the maintenance of their genetic integrity. Unfortunately, on the other hand, genetic structure of the populations from Crete (Sasalos population) provided evidence that the indigenous breed from the island, A. m. adami, has probably gone extinct. Future management strategies should focus on the conservation of the local genetic resources in which distinct genetic identity has been sustained.
Planar Graphs without Cycles of Length 3, 4, and 6 are (3, 3)-Colorable
Authors: Sittitrai Pongpat , Pimpasalee Wannapol
Published: May 2024

For non-negative integers d1 and d2, if V1 and V2 are two partitions of a graph G’s vertex set VG, such that

V

1

and V2 induce two subgraphs of G, called GV1 with maximum degree at most d1 and GV2 with maximum degree at most d2, respectively, then the graph G is said to be improper d1,d2-colorable, as well as d1,d2-colorable. A class of planar graphs without C3,C4, and C6 is denoted by C. In 2019, Dross and Ochem proved that G is 0,6-colorable, for each graph G in C. Given that d1+d2≥6, this inspires us to investigate whether G is d1,d2-colorable, for each graph G in C. In this paper, we provide a partial solution by showing that G is (3, 3)-colorable, for each graph G in C.
Table S2 from ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts
Authors: Hu Bomiao , Wiesehöfer Marc , de Miguel Fernando J. , Liu Zongzhi , Chan Lok-Hei , Choi Jungmin , Melnick Mary Ann , Arnal Estape Anna , Walther Zenta , Zhao Dejian , Lopez-Giraldez Francesc , Wurtz Anna , Cai Guoping , Fan Rong , Gettinger Scott , Xiao Andrew , Yan Qin , Homer Robert , Nguyen Don X. , Politi Katerina
Published: May 2024

WES Summary
Table S1 from ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts
Authors: Hu Bomiao , Wiesehöfer Marc , de Miguel Fernando J. , Liu Zongzhi , Chan Lok-Hei , Choi Jungmin , Melnick Mary Ann , Arnal Estape Anna , Walther Zenta , Zhao Dejian , Lopez-Giraldez Francesc , Wurtz Anna , Cai Guoping , Fan Rong , Gettinger Scott , Xiao Andrew , Yan Qin , Homer Robert , Nguyen Don X. , Politi Katerina
Published: May 2024

Patient Information
Figure S7 from ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts
Authors: Hu Bomiao , Wiesehöfer Marc , de Miguel Fernando J. , Liu Zongzhi , Chan Lok-Hei , Choi Jungmin , Melnick Mary Ann , Arnal Estape Anna , Walther Zenta , Zhao Dejian , Lopez-Giraldez Francesc , Wurtz Anna , Cai Guoping , Fan Rong , Gettinger Scott , Xiao Andrew , Yan Qin , Homer Robert , Nguyen Don X. , Politi Katerina
Published: May 2024

ASCL1 expression activates an EMT transcriptional program in permissive cellular contexts. Expression of individual EMT marker genes in mutant EGFR lung cancer cell lines and PDXs with or without ASCL1 overexpression.