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- Bozzola, Tiago, et al.
(author)
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Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth
- 2022
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In: Acs Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 17:7, s. 1890-1900
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Journal article (peer-reviewed)abstract
- Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.
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| 2. |
- Sorelius, Karl, et al.
(author)
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The Microbiology of Infective Native Aortic Aneurysms in a Population-Based Setting
- 2022
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In: Annals of Vascular Surgery. - : Elsevier. - 0890-5096 .- 1615-5947. ; 78, s. 112-122
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Journal article (peer-reviewed)abstract
- Objective: The aim was to describe the microbiology of surgically treated infective native (mycotic) aortic aneurysms (INAAs), and associated survival and development of infection-related complications (IRCs). Methods: Data were pooled from 2 nationwide studies on surgically treated patients with INAAs in Sweden, between 1994 - 2016. Patients were grouped and analyzed according to culture results: 1) Staphylococcus aureus, 2) Streptococcus species (sp.), 3) Salmonella sp., 4) Enterococcus sp., 5) Gram-negative intestinal bacteria, 6) Other sp. (all other species found in culture), and 7) Negative cultures. Results: A sum of 182 patients were included, mean age 71 years (standard deviation; SD: 8.9). The median follow-up was 50.3 months (range 0 - 360). 128 (70.3%) patients had positive blood and/or tissue culture; Staphylococcus aureus n = 38 (20.9%), Streptococcus sp. n = 37 (20.3%), Salmonella sp. n = 19 (10.4%), Enterococcus sp. n = 16 (8.8%), Gram-negative intestinal bacteria n = 6, (3.3%), Other sp. n = 12 (6.6%) and Negative cultures n = 54 (29.7%). The estimated survival for the largest groups at 2-years after surgery was: Staphylococcus aureus 62% (95% Confidence interval 53.9 - 70.1), Streptococcus sp. 74.7% (67.4 - 82.0), Salmonella sp. 73.7% (63.6 - 83.8), Enterococcus sp. 61.9% (49.6 - 74.2), and Negative cultures 89.8% (85.5 - 94.1), P =.051. There were 37 IRCs (20.3%), and 19 (51.4%) were fatal, the frequency was insignificant between the groups. The majority of IRCs, 30/37 (81%), developed during the first postoperative year. Conclusion: In this assessment of microbiological findings of INAAs in Sweden, 50% of the pathogens were Staphylococcus aureus, Streptococcus sp., or Salmonella sp.. The overall 20%-frequency of IRCs, and its association with high mortality, motivates long-term antibiotic treatment regardless of microbial findings.
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| 3. |
- Currie, Michael J., et al.
(author)
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Structural and biophysical analysis of a Haemophilus influenzae tripartite ATP-independent periplasmic (TRAP) transporter
- 2024
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In: ELIFE. - 2050-084X. ; 12
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Journal article (peer-reviewed)abstract
- Tripartite ATP-independent periplasmic (TRAP) transporters are secondary-active transporters that receive their substrates via a soluble-binding protein to move bioorganic acids across bacterial or archaeal cell membranes. Recent cryo-electron microscopy (cryo-EM) structures of TRAP transporters provide a broad framework to understand how they work, but the mechanistic details of transport are not yet defined. Here we report the cryo-EM structure of the Haemophilus influenzae N-acetylneuraminate TRAP transporter (HiSiaQM) at 2.99 & Aring; resolution (extending to 2.2 & Aring; at the core), revealing new features. The improved resolution (the previous HiSiaQM structure is 4.7 & Aring; resolution) permits accurate assignment of two Na+ sites and the architecture of the substrate-binding site, consistent with mutagenic and functional data. Moreover, rather than a monomer, the HiSiaQM structure is a homodimer. We observe lipids at the dimer interface, as well as a lipid trapped within the fusion that links the SiaQ and SiaM subunits. We show that the affinity (K-D) for the complex between the soluble HiSiaP protein and HiSiaQM is in the micromolar range and that a related SiaP can bind HiSiaQM. This work provides key data that enhances our understanding of the 'elevator-with-an-operator' mechanism of TRAP transporters.
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| 4. |
- Escudero-Martnez, I, et al.
(author)
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Association of cholesterol levels with hemorrhagic transformation and cerebral edema after reperfusion therapies
- 2023
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In: European stroke journal. - : SAGE Publications. - 2396-9881 .- 2396-9873. ; 8:1, s. 294-300
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Journal article (peer-reviewed)abstract
- The association between cholesterol levels and cerebral edema (CED) or hemorrhagic transformation (HT) as an expressions of blood-brain barrier (BBB) dysfunction after ischemic stroke is not well established. The aim of this study is to determine the association of total cholesterol (TC) levels with the incidence of HT and CED after reperfusion therapies. Methods: We analyzed SITS Thrombolysis and Thrombectomy Registry data from January 2011 to December 2017. We identified patients with data on TC levels at baseline. TC values were categorized in three groups (reference group ⩾200 mg/dl). The two primary outcomes were any parenchymal hemorrhage (PH) and moderate to severe CED on follow up imaging. Secondary outcomes included death and functional independence (mRS 0–2) at 3 months. Multivariable logistic regression analysis adjusted for baseline factors including statin pretreatment was used to assess the association between TC levels and outcomes. Results: Of 35,314 patients with available information on TC levels at baseline, 3372 (9.5%) presented with TC levels ⩽130 mg/dl, 8203 (23.2%) with TC 130–200 mg/dl and 23,739 (67.3%) with TC ⩾ 200 mg/dl. In the adjusted analyses, TC level as continuous variable was inversely associated with moderate to severe CED (OR 0.99, 95% CI 0.99–1.00, p = 0.025) and as categorical variable lower TC levels were associated with a higher risk of moderate to severe CED (aOR 1.24, 95% CI 1.10–1.40, p = 0.003). TC levels were not associated with any PH, functional independence, and mortality at 3 months. Conclusions: Our findings indicate an independent association between low levels of TC and higher odds of moderate/severe CED. Further studies are needed to confirm these findings.
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| 5. |
- Stea, T. H., et al.
(author)
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Mapping the Concept, Content, and Outcome of Family-Based Outdoor Therapy for Children and Adolescents with Mental Health Problems : A Scoping Review
- 2022
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In: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 19:10
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Research review (peer-reviewed)abstract
- Outdoor therapy and family-based therapy are suggested to be promising interventions for the treatment of mental health problems. The aim of the present scoping review was to systematically map the concept, content, and outcome of combining family-and outdoor-based therapy for children and adolescents with mental health problems. The Joanna Briggs Institute methodology and PRISMA guidelines were applied. Eligible qualitative and quantitative studies were screened, included, and extracted for data. Seven studies were included. Findings from these studies indicated that family-based outdoor therapy programs have a positive impact on family-and peer relationships, adolescent behavior, mental health, self-perceptions (self-concept), school success, social engagement, and delinquency rates. However, participant characteristics, study design, and content and mode of delivery of the interventions varied substantially, hence preventing detailed comparison of outcomes across studies. In addition, most of the studies included few participants and lacked population diversity and comparable control groups. Although important ethical concerns were raised, such as non-voluntary participation in some of the programs, there was a lack of reporting on safety. This review indicates that a combination of family-and outdoor-based therapy may benefit mental health among children and adolescents, but due to the limited number of studies eligible for inclusion and high levels of heterogeneity, it was difficult to draw firm conclusions. Thus, future theory-based studies using robust designs are warranted.
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| 15. |
- Nyberger, K., et al.
(author)
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Epidemiology of firearm injuries in Sweden
- 2022
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In: European Journal of Trauma and Emergency Surgery. - : Springer Science and Business Media LLC. - 1863-9933 .- 1863-9941. ; 48:3, s. 2349-2357
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Journal article (peer-reviewed)abstract
- Background Gun violence is a global health problem. Population-based research on firearm-related injuries has been relatively limited considering the burden of disease. The aim of this study was to analyze nationwide epidemiological trends of firearm injuries. Methods This is a retrospective nationwide epidemiological study including all patients with firearm injuries from the Swedish Trauma Registry (SweTrau) during the period 2011 and 2019. Registry data were merged with data from the Swedish National Council for Crime Prevention and the Swedish Police Authority. Results There were 1010 patients admitted with firearm injuries, 96.6% men and 3.4% women, median age 26.0 years [IQR 22.0-36.3]. The overall number of firearm injuries increased on a yearly basis (P < 0.001). The most common anatomical injury location was lower extremity (29.7%) followed by upper extremity (13.8%), abdomen (13.8%), and chest (12.5%). The head was the most severely injured body region with a median abbreviated injury scale (AIS) of 5 [IQR 3.2-5]. Vascular injuries were mainly located to the lower extremity (42%; 74/175). Majority of patients (51.3%) had more than one anatomic injury location. The median hospital length of stay was 3 days [IQR 2-8]. 154 patients (15.2%) died within 24 h of admission. The 30-day and 90-day mortality was 16.7% (169/1010) and 17.5% (177/1010), respectively. There was an association between 24-h mortality and emergency department systolic blood pressure < 90 mmHg [OR 30.3, 95% CI 16.1-56.9] as well as the following injuries with AIS >= 3; head [OR 11.8, 95% CI 7.5-18.5], chest [OR 2.3, 95% CI 1.3-4.1], and upper extremity [OR 3.6, CI 1.3-10.1]. Conclusions This nationwide study shows an annual increase of firearm-related injuries and fatalities. Firearm injuries affect people of all ages but more frequently young males in major cities. One in six patients succumbed from their injuries within 30 days with most deaths occurring within 24 h of hospital admission. Given the impact of firearm-related injuries on society additional research on a national level is critical.
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| 17. |
- Pfaff, JAR, et al.
(author)
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The impact of the DWI-FLAIR-mismatch in the ECASS-4 trial - A post hoc analysis
- 2020
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In: European stroke journal. - : SAGE Publications. - 2396-9881 .- 2396-9873. ; 5:4, s. 370-373
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Journal article (peer-reviewed)abstract
- To investigate the impact of a mismatch between diffusion-weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) on functional outcome in patients with acute stroke in a prolonged time window or unknown time of symptom onset randomized to intravenous thrombolysis or placebo. Patients and Methods We performed a post-hoc analysis of the European Cooperative Acute Stroke Study-4 (ECASS-4) trial. ECASS-4 was an investigator driven, phase 3, multi-center, double-blind, placebo-controlled study which randomized ischemic stroke patients presenting within 4.5 and 9h of stroke onset or unknown time-window to either rt-PA or placebo after MR-imaging. Two subgroups “no mismatch” (nMM) and “any mismatch” (aMM) were created by applying a DWI-FLAIR-mismatch criterion. We calculated frequency of nMM and aMM and performed a univariate analysis (Fisher's Test) for excellent clinical outcome (mRS 0-1) and mortality (mRS=6). Results MR-Imaging of n=111/119 (93.2%) patients was suitable for this analysis. DWI-FLAIR mismatch was found in 49 patients (44.1%). Proportions of mismatch nMM and aMM were comparable in treatment-groups (aMM: Placebo 46.3%, Alteplase 42.1%; p=0.70). Patients with nMM showed no benefit of rt-PA-treatment (OR (95%CI) mRS 0-1: 0.95 (0.29-3.17)). Patients with aMM showed a point estimate of the odds ratio in favour of a treatment benefit of rt-PA (mRS 0-1: OR (95%CI) 2.62 (0.68-11.1)). Mortality within 90 days was not different in patients treated with rt-PA if nMM (15.2%) or aMM (12.5%) was present. Discussion In this analysis no significant evidence, but subtle indication towards patients treated with rt-PA in a prolonged time window reaching an excellent clinical outcome if a DWI-FLAIR-mismatch is present on initial stroke MR-imaging. Conclusion A DWI-FLAIR mismatch in the region of ischemia as imaging based surrogate parameter for patient selection for i.v. rt-PA should be strongly pursued.
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| 19. |
- Sahlén, Pelin, et al.
(author)
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Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis– and psoriasis-associated genes
- 2020
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In: Journal of Allergy and Clinical Immunology. - : Mosby Inc.. - 0091-6749 .- 1097-6825.
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Journal article (peer-reviewed)abstract
- Background: Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear. Objective: We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate. Methods: We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies. Results: We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis. Conclusions: Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.
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| 23. |
- Xiang, Y., et al.
(author)
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Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-beta-Lactamase 2 (VIM-2) Inhibitor
- 2020
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In: Biomolecules. - : MDPI AG. - 2218-273X. ; 10:1
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Journal article (peer-reviewed)abstract
- Inhibition of beta-lactamases presents a promising strategy to restore the beta-lactams antibacterial activity to resistant bacteria. In this work, we found that aromatic carboxyl substituted 2-triazolylthioacetamides 1a-j inhibited VIM-2, exhibiting an IC50 value in the range of 20.6-58.6 mu M. The structure-activity relationship study revealed that replacing the aliphatic carboxylic acid with aromatic carboxyl improved the inhibitory activity of 2-triazolylthioacetamides against VIM-2. 1a-j (16 mg/mL) restored the antibacterial activity of cefazolin against E. coli cell expressing VIM-2, resulting in a 4-8-fold reduction in MICs. The isothermal titration calorimetry (ITC) characterization suggested that the primary binding 2-triazolylthioacetamide (1b, 1c, or 1h) to VIM-2 was a combination of entropy and enthalpy contributions. Further, the crystal structure of VIM-2 in complex with 1b was obtained by co-crystallization with a hanging-drop vapour-diffusion method. The crystal structure analysis revealed that 1b bound to two Zn(II) ions of the enzyme active sites, formed H-bound with Asn233 and structure water molecule, and interacted with the hydrophobic pocket of enzyme activity center utilizing hydrophobic moieties; especially for the phenyl of aromatic carboxyl which formed pi-pi stacking with active residue His263. These studies confirmed that aromatic carboxyl substituted 2-triazolylthioacetamides are the potent VIM-2 inhibitors scaffold and provided help to further optimize 2-triazolylthioacetamides as VIM-2 even or broad-spectrum M beta Ls inhibitors.
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