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1.
Nat Ecol Evol ; 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39009851

ABSTRACT

Protected area (PA) assessments rarely evaluate socio-economic and environmental impacts relative to competing land uses, limiting understanding of socio-environmental trade-offs from efforts to protect 30% of the globe by 2030. Here we assess deforestation and poverty outcomes (fiscal income, income inequality, sanitation and literacy) between 2000 and 2010 of strict PAs (SPAs), sustainable-use PAs (SUPAs) and Indigenous territories (ITs) compared with different land uses (agriculture and mining concessions) across ~5,500 census tracts in the Brazilian Legal Amazon. ITs reduced deforestation relative to all alternative land uses (48-83%) but had smaller socio-economic benefits compared with other protection types and land uses (18-36% depending on outcome), indicating that Indigenous communities experience socio-economic trade-offs. By contrast, SUPAs, and potentially SPAs, did not reduce deforestation relative to small-scale agriculture (landholdings <10 ha) but did so relative to larger agricultural landholdings (70-82%). Critically, these reductions in deforestation frequently occurred without negative socio-economic outcomes. By contrast, ITs and SUPAs protected against deforestation from mining, but at the cost of smaller improvements in income and inequality. Our results suggest that although PAs in the Brazilian Legal Amazon substantially reduced deforestation without compromising local socio-economic development, efforts to secure Indigenous rights need additional interventions to ensure these communities are not further disadvantaged.

2.
Cureus ; 16(4): e57858, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38721185

ABSTRACT

INTRODUCTION: Recent clinical studies confirmed that whole-body electromyostimulation (WB-EMS) training is a safe and time-efficient therapeutic method for patients with nonspecific chronic back pain (NSCBP). However, significant variations in initial pain intensity among subjects in these studies have been observed. This study aims to determine if patients with differing initial pain intensities experience varying degrees of benefit from WB-EMS and to assess the overall correlation between initial pain levels and pain reduction. METHODS: Pain intensity datasets from two studies were combined. The pooled data included 121 NSCBP patients (38 males and 83 females) with an average age of 55.1 years (±11.8 years). Data was categorized by baseline pain intensity on the numeric rating scale (NRS) into seven groups: 0 to 2, >2 to 3, >3 to 4, >4 to 5, >5 to 6, >6 to 7, and >7. Both absolute and relative changes were analyzed. Additionally, a Spearman rho correlation test was performed on the entire dataset to evaluate the relationship between initial pain level and pain reduction. RESULTS: Significant improvements were noted across all NRS11 categories, with strong effect sizes (p) in all classes above 2, ranging from 0.56 to 0.90. The >7 category exhibited the highest rate of clinically significant changes (80%) and an average improvement of 3.72 points. The overall group from >1 to 10 showed an average improvement of 1.33 points, with 37% of the participants experiencing clinically significant improvements. The Spearman rho correlation test revealed a moderate positive relationship between initial pain level and pain reduction (r_s = 0.531, p < 0.001), indicating that, generally, higher initial pain levels are associated with greater pain reduction. CONCLUSION: The findings support the hypothesis that NSCBP patients with higher baseline NRS values benefit more substantially from WB-EMS. Those with NRS values above 7 show the greatest improvement and highest rate of clinical significance. The overall positive correlation between initial pain intensity and pain reduction further underscores the efficacy of WB-EMS in managing NSCBP across different pain intensities.

3.
Article in English | MEDLINE | ID: mdl-38717168

ABSTRACT

BACKGROUND AND OBJECTIVES: Robotics are becoming increasingly widespread within various neurosurgical subspecialties, but data pertaining to their feasibility in vascular neurosurgery are limited. We present our novel attempt to evaluate the learning curve of a robotic platform for microvascular anastomoses. METHODS: One hundred and sixty one sutures were performed and assessed. Fourteen anastomoses (10 robotic [MUSA-2 Microsurgical system; Microsure] and 4 hand-sewn) were performed by the senior author on 1.5-mm caliber tubes and recorded with the Kinevo 900 (Zeiss) operative microscope. We separately compared interrupted sutures (from needle insertion until third knot) and running sutures (from needle insertion until loop pull-down). Average suture timing across all groups was compared using an unpaired Student's t test. Exponential smoothing (α = 0.2) was then applied to the robotic data sets for validation and a second set of t tests were performed. RESULTS: We compared 107 robotic sutures with 54 hand-sewn sutures. There was a significant difference between the average time/stitch for the robotic running sutures (n = 55) and the hand-sewn running sutures (n = 31) (31.2 seconds vs 48.3 seconds, respectively; P-value = .00052). Exponential smoothing (α = 0.2) reinforced these results (37.6 seconds vs 48.3 seconds; P-value = .014625). Average robotic running times surpassed hand-sewn by the second anastomosis (38.8 seconds vs 48.3 seconds) and continued to steadily decrease with subsequent stitches. The average of the robotic interrupted sutures (n = 52) was significantly longer than the hand-sewn (n = 23) (171.3 seconds vs 70 seconds; P = .000024). Exponential smoothing (α = 0.2) yielded similar results (196.7 seconds vs 70 seconds; P = .00001). However, average robotic interrupted times significantly decreased from the first to the final anastomosis (286 seconds vs 105.2 seconds; P = .003674). CONCLUSION: Our results indicate the learning curve for robotic microanastomoses is short and encouraging. The use of robotics warrants further study for potential use in cerebrovascular bypass procedures.

5.
bioRxiv ; 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38559057

ABSTRACT

Clostridioides difficile, the leading cause of antibiotic-associated diarrhea, relies primarily on 3-3 crosslinks created by L,D-transpeptidases (LDTs) to fortify its peptidoglycan (PG) cell wall. This is unusual, as in most bacteria the vast majority of PG crosslinks are 4-3 crosslinks, which are created by penicillin-binding proteins (PBPs). Here we report the unprecedented observation that 3-3 crosslinking is essential for viability in C. difficile. We also report the discovery of a new family of LDTs that use a VanW domain to catalyze 3-3 crosslinking rather than a YkuD domain as in all previously known LDTs. Bioinformatic analyses indicate VanW domain LDTs are less common than YkuD domain LDTs and are largely restricted to Gram-positive bacteria. Our findings suggest that LDTs might be exploited as targets for antibiotics that kill C. difficile without disrupting the intestinal microbiota that is important for keeping C. difficile in check.

6.
Elife ; 132024 Apr 19.
Article in English | MEDLINE | ID: mdl-38639995

ABSTRACT

Mechanisms by which Mycobacterium tuberculosis (Mtb) evades pathogen recognition receptor activation during infection may offer insights for the development of improved tuberculosis (TB) vaccines. Whilst Mtb elicits NOD-2 activation through host recognition of its peptidoglycan-derived muramyl dipeptide (MDP), it masks the endogenous NOD-1 ligand through amidation of glutamate at the second position in peptidoglycan side-chains. As the current BCG vaccine is derived from pathogenic mycobacteria, a similar situation prevails. To alleviate this masking ability and to potentially improve efficacy of the BCG vaccine, we used CRISPRi to inhibit expression of the essential enzyme pair, MurT-GatD, implicated in amidation of peptidoglycan side-chains. We demonstrate that depletion of these enzymes results in reduced growth, cell wall defects, increased susceptibility to antibiotics, altered spatial localization of new peptidoglycan and increased NOD-1 expression in macrophages. In cell culture experiments, training of a human monocyte cell line with this recombinant BCG yielded improved control of Mtb growth. In the murine model of TB infection, we demonstrate that depletion of MurT-GatD in BCG, which is expected to unmask the D-glutamate diaminopimelate (iE-DAP) NOD-1 ligand, yields superior prevention of TB disease compared to the standard BCG vaccine. In vitro and in vivo experiments in this study demonstrate the feasibility of gene regulation platforms such as CRISPRi to alter antigen presentation in BCG in a bespoke manner that tunes immunity towards more effective protection against TB disease.


Tuberculosis is the leading cause of death from an infectious disease worldwide, partially due to a lack of access to drug treatments in certain countries where the disease is common. The only available tuberculosis vaccine ­ known as the BCG vaccine ­ is useful for preventing cases in young children, but is ineffective in teenagers and adults. So, there is a need to develop new vaccines that offer better, and longer lasting, durable protection in people of all ages. During an infection, our immune system recognizes markers known as PAMPs on the surface of bacteria, viruses or other disease-causing pathogens. The recognition of PAMPs by the immune system enables the body to distinguish foreign invading organisms from its own cells and tissues, thus triggering a response that fights the infection. If the body encounters the infectious agent again in the future, the immune system is able to quickly recognize and eliminate it before it can cause disease. Vaccines protect us by mimicking the appearance of the pathogen to trigger the first immune response without causing the illness. The BCG vaccine contains live bacteria that are closely related to the bacterium responsible for tuberculosis called Mycobacterium tuberculosis. Both M. tuberculosis and the live bacteria used in the BCG vaccine are able to hide an important PAMP, known as the NOD-1 ligand, from the immune system, making it harder for the body to detect them. The NOD-1 ligand forms part of the bacterial cell wall and modifying the BCG bacterium so it cannot disguise this PAMP may lead to a new, more effective vaccine. To investigate this possibility, Shaku et al. used a gene editing approach to develop a modified version of the BCG bacterium which is unable to hide its NOD-1 ligand when treated with a specific drug. Immune cells trained with the modified BCG vaccine were more effective at controlling the growth of M. tuberculosis than macrophages trained using the original vaccine. Furthermore, mice vaccinated with the modified BCG vaccine were better able to limit M. tuberculosis growth in their lungs than mice that had received the original vaccine. These findings offer a new candidate vaccine in the fight against tuberculosis. Further studies will be needed to modify the vaccine for use in humans. More broadly, this work demonstrates that gene editing can be used to expose a specific PAMP present in a live vaccine. This may help develop more effective vaccines for other diseases in the future.


Subject(s)
BCG Vaccine , Mycobacterium tuberculosis , Peptidoglycan , Tuberculosis , Animals , Peptidoglycan/metabolism , Mice , BCG Vaccine/immunology , Mycobacterium tuberculosis/immunology , Tuberculosis/prevention & control , Tuberculosis/immunology , Tuberculosis/microbiology , Humans , Mice, Inbred C57BL , Macrophages/immunology , Macrophages/microbiology , Macrophages/metabolism , Female , Nod1 Signaling Adaptor Protein/metabolism , Nod1 Signaling Adaptor Protein/genetics , Disease Models, Animal , Bacterial Proteins/metabolism , Bacterial Proteins/genetics
7.
Bioconjug Chem ; 35(4): 489-498, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38591251

ABSTRACT

The role of the intestinal microbiota in host health is increasingly revealed in its contributions to disease states. The host-microbiome interaction is multifactorial and dynamic. One of the factors that has recently been strongly associated with host physiological responses is peptidoglycan from bacterial cell walls. Peptidoglycan from gut commensal bacteria activates peptidoglycan sensors in human cells, including the nucleotide-binding oligomerization domain-containing protein 2. When present in the gastrointestinal tract, both the polymeric form (sacculi) and depolymerized fragments can modulate host physiology, including checkpoint anticancer therapy efficacy, body temperature and appetite, and postnatal growth. To utilize this growing area of biology toward therapeutic prescriptions, it will be critical to directly analyze a key feature of the host-microbiome interaction from living hosts in a reproducible and noninvasive way. Here we show that metabolically labeled peptidoglycan/sacculi can be readily isolated from fecal samples collected from both mice and humans. Analysis of fecal samples provided a noninvasive route to probe the gut commensal community including the metabolic synchronicity with the host circadian clock. Together, these results pave the way for noninvasive diagnostic tools to interrogate the causal nature of peptidoglycan in host health and disease.


Subject(s)
Gastrointestinal Microbiome , Microbiota , Humans , Animals , Mice , Peptidoglycan , Bacteria/metabolism
9.
Nature ; 627(8004): 646-655, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38418879

ABSTRACT

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.


Subject(s)
Antibodies, Monoclonal , Antineoplastic Agents , B7-H1 Antigen , Myeloid Cells , Neoplasms , Receptors, Immunologic , T-Lymphocytes, Regulatory , Animals , Humans , Mice , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Drug Therapy, Combination , Immune Checkpoint Inhibitors/immunology , Immune Checkpoint Inhibitors/therapeutic use , Macrophage Activation , Myeloid Cells/immunology , Neoplasms/drug therapy , Neoplasms/immunology , Receptors, IgG/immunology , Receptors, Immunologic/immunology , T-Lymphocytes, Regulatory/immunology , Tumor Microenvironment/immunology , Tumor-Associated Macrophages/immunology
10.
J Neurol Surg A Cent Eur Neurosurg ; 85(2): 117-125, 2024 Mar.
Article in English | MEDLINE | ID: mdl-36828012

ABSTRACT

BACKGROUND: The global trend toward increased life expectancy because of remarkable improvements in health care quality has drawn increased attention to osteoporotic fractures and degenerative spine diseases. Cement-augmented pedicle screw fixation has been established as the mainstay treatment for patients with poor bone quality. This study aimed to determine the number of patients with cement leakage and pulmonary cement embolism (PCE) as detected on thoracic computed tomography (CT), and to assess the potential risk factors for PCE. METHODS: Patients undergoing cement-augmented pedicle screw placement in our institution between May 2008 and December 2020 were included. Data regarding baseline characteristics, complications, and cement leakage rates were collected. Indications for the performance of a postoperative thoracic CT due to the suspicion of PCE were intra- or postoperative complications, or postoperative oxygen supplementation. Moreover, PCE was accidently diagnosed because the thoracic CT was performed for medical reasons other than the suspicion of PCE (tumor staging, severe pneumonia, or exacerbated chronic pulmonary obstructive disease). RESULTS: A total of 104 patients with a mean age of 72.8 years (standard deviation of 6.7) were included. Of 802 screws, 573 were cement augmented. Of the 104 patients, 44 (42.3%) underwent thoracic CT scans to diagnose PCE; additionally, 67 (64.4%) demonstrated cement leakage, of whom 27 developed PCE and 4 were symptomatic. Cement-augmented thoracic screws were a risk factor for PCE (odds ratio: 1.5; 95% confidence interval: 1.2-2.1; p = 0.004). CONCLUSIONS: This study showed a high prevalence of cement leakage after cement-augmented pedicle screw insertion, with a relatively frequent incidence of PCE, as tracked by thoracic CT scans. Cement-augmented thoracic screw placement was a unique risk factor for PCE.


Subject(s)
Osteoporotic Fractures , Pedicle Screws , Pulmonary Embolism , Humans , Aged , Pedicle Screws/adverse effects , Lumbar Vertebrae/surgery , Bone Cements/adverse effects , Osteoporotic Fractures/diagnostic imaging , Osteoporotic Fractures/surgery , Osteoporotic Fractures/complications , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/epidemiology , Pulmonary Embolism/etiology
11.
J Clin Endocrinol Metab ; 109(3): e1061-e1071, 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-37930769

ABSTRACT

CONTEXT: In clinical trials, burosumab ameliorates symptoms of pain, fatigue, and stiffness and improves performance on certain muscle function studies in patients with X-linked hypophosphatemia (XLH). OBJECTIVE: This work aimed to determine if burosumab increases adenosine triphosphate (ATP) synthesis in skeletal muscle of treatment-naive adults with XLH, and if so, whether that correlates with improved muscle function. METHODS: Ten untreated, symptomatic adults with XLH had ATP synthesis rates measured in the right calf using the 31P magnetic resonance spectroscopy saturation transfer technique. Baseline muscle function tests and symptoms of pain, fatigue, stiffness, and lower-extremity joint pain were quantified. All participants were treated with burosumab, 1 mg/kg every 4 weeks for 12 weeks. ATP synthesis rates and muscle function tests were repeated 2 weeks ("peak") and 4 weeks ("trough") after the third dose of burosumab. RESULTS: All symptoms improved with treatment. Performance on the 6-Minute Walk Test (6MWT) and Sit to Stand (STS) tests also improved. Muscle strength and ATP synthesis rates did not change over the 3 months of the study. When individuals whose performances on the 6MWT and STS test were at or better than the median outcome for those tests were compared to those whose outcomes were below the median, no difference was observed in the rate of change in ATP synthesis. Intracellular muscle concentrations of phosphate were normal. CONCLUSION: The improvement in the 6MWT and STS test without changes in muscle strength or ATP synthesis rates suggests that reductions in pain, fatigue, and stiffness may partly explain the improved performance. Intracellular phosphate in skeletal muscle is insulated from hypophosphatemia in XLH.


Subject(s)
Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal , Familial Hypophosphatemic Rickets , Adult , Humans , Antibodies, Monoclonal/therapeutic use , Familial Hypophosphatemic Rickets/diagnosis , Adenosine Triphosphate , Muscle, Skeletal , Polyphosphates/therapeutic use , Pain/drug therapy , Leg , Fatigue/drug therapy
13.
World Neurosurg ; 182: e245-e252, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38006939

ABSTRACT

OBJECTIVE: To examine the usefulness of carotid web (CW), carotid bifurcation and their combined angioarchitectural measurements in assessing stroke risk. METHODS: Anatomic data on the internal carotid artery (ICA), common carotid artery (CCA), and the CW were gathered as part of a retrospective study from symptomatic (stroke) and asymptomatic (nonstroke) patients with CW. We built a model of stroke risk using principal-component analysis, Firth regression trained with 5-fold cross-validation, and heuristic binary cutoffs based on the Minimal Description Length principle. RESULTS: The study included 22 patients, with a mean age of 55.9 ± 12.8 years; 72.9% were female. Eleven patients experienced an ischemic stroke. The first 2 principal components distinguished between patients with stroke and patients without stroke. The model showed that ICA-pouch tip angle (P = 0.036), CCA-pouch tip angle (P = 0.036), ICA web-pouch angle (P = 0.036), and CCA web-pouch angle (P = 0.036) are the most important features associated with stroke risk. Conversely, CCA and ICA anatomy (diameter and angle) were not found to be risk factors. CONCLUSIONS: This pilot study shows that using data from computed tomography angiography, carotid bifurcation, and CW angioarchitecture may be used to assess stroke risk, allowing physicians to tailor care for each patient according to risk stratification.


Subject(s)
Carotid Stenosis , Stroke , Humans , Female , Adult , Middle Aged , Aged , Male , Carotid Artery, Internal/diagnostic imaging , Retrospective Studies , Pilot Projects , Stroke/etiology , Stroke/complications , Carotid Artery, Common , Risk Assessment , Carotid Stenosis/complications
15.
J Endocr Soc ; 7(11): bvad116, 2023 Oct 09.
Article in English | MEDLINE | ID: mdl-37860221

ABSTRACT

Individuals with X-linked hypophosphatemia (XLH) are at greater risk for being overweight or obese. Whether there are underlying metabolic abnormalities that put patients with XLH at greater risk for excessive weight gain is largely unknown. Lipocalin-2 (LCN2) has recently received attention as a factor regulating energy consumption and specifically is postulated to be anorexigenic and to improve insulin sensitivity. In a retrospective study, circulating levels of LCN2, leptin, and insulin were measured in 32 patients with XLH, ages 2-60 years, all of whom were being treated with burosumab, and 38 control subjects. Control subjects were chosen who were close in age to those with XLH, with a similar number of participants of each sex. Subjects were analyzed in 3 age cohorts, 2-10 years, 11-18 years, and 20-60 years. In all age groups LCN2 levels were lower in the patients with XLH than in controls but when adjusted for weight class (normal, overweight, obese) the differences were not significant. In contrast, serum leptin levels were significantly lower in children with XLH compared to controls in the 2-10 years age cohort. Serum levels of insulin were also significantly lower in the 2-10-year-old children with XLH when compared with controls. We conclude that changes in expression of lipocalin-2 in children and adolescents with XLH is unlikely to contribute to their risk for obesity in adulthood. It is unclear if lower circulating levels of leptin in these children plays a role in the higher prevalence of obesity among adults with XLH.

16.
AJNR Am J Neuroradiol ; 44(11): 1302-1308, 2023 11.
Article in English | MEDLINE | ID: mdl-37857448

ABSTRACT

BACKGROUND AND PURPOSE: Arterial spin-labeling is a noninvasive MR imaging technique allowing direct and quantitative measurement of brain perfusion. Arterial spin-labeling is well-established in clinics for investigating the overall cerebral perfusion, but it is still occasionally employed during tasks. The typical contrast for functional MR imaging is blood oxygen level-dependent (BOLD) imaging, whose specificity could be biased in neurologic patients due to altered neurovascular coupling. This work aimed to validate the use of functional ASL as a noninvasive tool for presurgical functional brain mapping. This is achieved by comparing the spatial accuracy of functional ASL with transcranial magnetic stimulation as the criterion standard. MATERIALS AND METHODS: Twenty-eight healthy participants executed a motor task and received a somatosensory stimulation, while BOLD imaging and arterial spin-labeling were acquired simultaneously. Transcranial magnetic stimulation was subsequently used to define hand somatotopy. RESULTS: Functional ASL was found more adjacent to transcranial magnetic stimulation than BOLD imaging, with a significant shift along the inferior-to-superior direction. With respect to BOLD imaging, functional ASL was localized significantly more laterally, anteriorly, and inferiorly during motor tasks and pneumatic stimulation. CONCLUSIONS: Our results confirm the specificity of functional ASL in targeting the regional neuronal excitability. Functional ASL could be considered as a valid supplementary technique to BOLD imaging for presurgical mapping when spatial accuracy is crucial for delineating eloquent cortex.


Subject(s)
Brain Mapping , Brain , Humans , Spin Labels , Brain Mapping/methods , Brain/blood supply , Magnetic Resonance Imaging/methods , Arteries , Cerebrovascular Circulation/physiology
17.
Front Cell Infect Microbiol ; 13: 1205829, 2023.
Article in English | MEDLINE | ID: mdl-37692163

ABSTRACT

Introduction: Mycobacteria assemble a complex cell wall with cross-linked peptidoglycan (PG) which plays an essential role in maintenance of cell wall integrity and tolerance to osmotic pressure. We previously demonstrated that various hydrolytic enzymes are required to remodel PG during essential processes such as cell elongation and septal hydrolysis. Here, we explore the chemistry associated with PG cross-linking, specifically the requirement for amidation of the D-glutamate residue found in PG precursors. Methods: Synthetic fluorescent probes were used to assess PG remodelling dynamics in live bacteria. Fluorescence microscopy was used to assess protein localization in live bacteria and CRISPR-interference was used to construct targeted gene knockdown strains. Time-lapse microscopy was used to assess bacterial growth. Western blotting was used to assess protein phosphorylation. Results and discussion: In Mycobacterium smegmatis, we confirmed the essentiality for D-glutamate amidation in PG biosynthesis by labelling cells with synthetic fluorescent PG probes carrying amidation modifications. We also used CRISPRi targeted knockdown of genes encoding the MurT-GatD complex, previously implicated in D-glutamate amidation, and demonstrated that these genes are essential for mycobacterial growth. We show that MurT-rseGFP co-localizes with mRFP-GatD at the cell poles and septum, which are the sites of cell wall synthesis in mycobacteria. Furthermore, time-lapse microscopic analysis of MurT-rseGFP localization, in fluorescent D-amino acid (FDAA)-labelled mycobacterial cells during growth, demonstrated co-localization with maturing PG, suggestive of a role for PG amidation during PG remodelling and repair. Depletion of MurT and GatD caused reduced PG cross-linking and increased sensitivity to lysozyme and ß-lactam antibiotics. Cell growth inhibition was found to be the result of a shutdown of PG biosynthesis mediated by the serine/threonine protein kinase B (PknB) which senses uncross-linked PG. Collectively, these data demonstrate the essentiality of D-glutamate amidation in mycobacterial PG precursors and highlight the MurT-GatD complex as a novel drug target.


Subject(s)
Amides , Cell Wall , Glutamic Acid , Mycobacterium smegmatis , Peptidoglycan , Amides/metabolism , Glutamic Acid/metabolism , Mycobacterium smegmatis/growth & development , Mycobacterium smegmatis/metabolism , Cell Wall/chemistry , Cell Wall/metabolism , Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor/metabolism , Bacterial Proteins/metabolism , Peptidoglycan/metabolism
18.
bioRxiv ; 2023 Sep 02.
Article in English | MEDLINE | ID: mdl-37693563

ABSTRACT

The role of the intestinal microbiota in host health is increasingly revealed in its contributions to disease states. The host-microbiome interaction is multifactorial and dynamic. One of the factors that has recently been strongly associated with host physiological responses is peptidoglycan from bacterial cell walls. Peptidoglycan from gut commensal bacteria activate peptidoglycan sensors in human cells, including the Nucleotide-binding oligomerization domain containing protein 2 (NOD2). When present in the gastrointestinal tract, both the polymeric form (sacculi) and de-polymerized fragments can modulate host physiology, including checkpoint anticancer therapy efficacy, body temperature and appetite, and postnatal growth. To leverage this growing area of biology towards therapeutic prescriptions, it will be critical to directly analyze a key feature of the host-microbiome interaction from living hosts in a reproducible and non-invasive way. Here we show that metabolically labeled peptidoglycan/sacculi can be readily isolated from fecal samples collected from both mice and humans. Analysis of fecal samples provided a non-invasive route to probe the gut commensal community including the metabolic synchronicity with the host circadian clock. Together, these results pave the way for non-invasive diagnostic tools to interrogate the causal nature of peptidoglycan in host health and disease.

19.
CJC Open ; 5(9): 704-708, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37744655

ABSTRACT

Scale measuring the construct of "health security in chronic illness" (HSCI) was piloted in Canadian cardiac device patients (N = 176) enrolled in a remote-monitoring study at 2 timepoints. Analysis revealed a 2-factor solution, labeled as "support" and "certainty". Patients reported receiving less support over time, but consistent health certainty. Patients with implantable cardioverter defibrillators felt less secure over time and reported lower levels of health security in chronic illness than pacemaker patients.


Une échelle mesurant le concept de la « sécurité en matière de santé en présence d'une maladie chronique ¼ a fait l'objet d'un projet pilote auprès de patients canadiens porteurs de dispositifs cardiaques (N = 176) inscrits dans une étude de télésurveillance comportant deux évaluations. L'analyse a révélé une solution à deux facteurs, soit le soutien et la certitude. Les patients ont déclaré qu'ils recevaient moins de soutien au fil du temps, mais que la certitude quant à leur santé était constante. Les porteurs d'un défibrillateur cardioverteur implantable se sentaient moins en sécurité au fil du temps et signalaient de plus bas niveaux de sécurité en matière de santé, relativement à leur maladie chronique, que les porteurs d'un stimulateur cardiaque.

20.
J Pers Med ; 13(7)2023 Jul 10.
Article in English | MEDLINE | ID: mdl-37511733

ABSTRACT

Many head and neck cancer patients assigned to definitive or adjuvant chemoradiation treatment do not complete the concurrent cisplatin dose. We determined corresponding risk factors and developed a prognostic instrument to help identify these patients. Ten pre-treatment characteristics were retrospectively analyzed in 154 patients with head and neck cancer who were treated via chemoradiation with cisplatin. These pre-treatment characteristics included age, sex, Karnofsky performance score, tumor site, primary tumor stage, nodal stage, histologic grade, upfront surgery, human papilloma virus status, and history of smoking. The characteristics significantly associated with the completion of cisplatin-based treatment, the receipt of ≥80% cisplatin, or showing a strong trend of association after multivariate analyses were used for the prognostic instrument. For each characteristic, 0 points were assigned for worse outcomes, and 1 point was assigned for better outcomes. Patients' scores were calculated by adding these points. Age ≤ 60 years and a Karnofsky performance score of 90-100 were significantly associated with both endpoints after multivariate analysis, and male gender showed a trend for association with the receipt of ≥80% cisplatin. Patient scores were 0, 1, 2, and 3 points. The corresponding rates of completion of cisplatin-based treatment were 14%, 41%, 62%, and 72%, respectively (p = 0.004). The rates of receipt of ≥80% cisplatin were 29%, 54%, 72%, and 94%, respectively (p < 0.001). This new prognostic instrument helps to predict whether head and neck cancer patients scheduled for chemoradiation will receive cisplatin as planned.

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