bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACT

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

ABSTRACT

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.
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.1To 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

BackgroundIntranasal 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.MethodsThis 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.Results7 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.ConclusionsTreatment 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

ObjectiveThere 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.MethodsC-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+).ResultsAcross 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%).ConclusionsIn 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

BackgroundNon-synovial inflammation as detected by MRI is characteristic in polymyalgia rheumatica (PMR) with potentially high diagnostic value.ObjectiveThe objective is to describe inflammatory MRI findings in the shoulder girdle of patients with PMR and discriminate from other causes of shoulder girdle pain.MethodsRetrospective 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.ResultsA 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).ConclusionContrast-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

ObjectiveA 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.DesignSingle-centre, single-blinded placebo-controlled randomised controlled trial.SettingSingle-centre study.ParticipantsInclusion 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).Interventions120 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 measuresPrimary 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.ResultsThere 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.ConclusionsDenervation 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 numberNCT04786145.
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

AbstractMuon-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

AbstractWe 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.
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.
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 V1 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.