Archivio Istituzionale della Ricerca - Università degli Studi di Pavia
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Alzheimer's Disease Continuum: Evaluating the Relationship between Fluid Biomarkers and Patients’ Phenotype and Profile
No full text: The measurement of fluid biomarkers such as phosphorylated tau at threonine 181 (pTAU181), amyloid-β 40 (Aβ40), and Aβ42 is a routine medical examination that contributes to achieving an accurate diagnosis within the Alzheimer's disease (AD) clinical continuum. The aim of this study is to compare the concentration of these biomarkers in CSF and plasma and determine their relationship with the patients' clinical variant and profile. Patients were diagnosed following the NIA-AA criteria. Plasma and CSF were obtained from healthy controls (HC), mild cognitive impairment (MCI non-AD), MCI displaying positive AD markers (MCI-AD), and AD patients. Biomarker levels were assessed using the LUMIPULSE® G600II instrument (Fujirebio, Japan). Data showed a significant increase in pTAU181 concentration, specifically in the progression from MCI non-AD to AD conditions. The opposite trend was observed for Aβ42 and Aβ42/Aβ40. Furthermore, these biomarker trends appeared to change consistently with variations in the MMSE score, highlighting the relevance of plasma in detecting changes in patients' cognitive function. Considering the clinical variant, atypical patients displayed the highest pTAU181 and lowest Aβ42 levels, consistent with their lower MMSE scores. Lastly, the posterior cortical atrophy (PCA) profile showed higher pTAU181 and lower Aβ42 levels when compared to other profiles. Nevertheless, these last results are to be cautiously interpreted given the limited number of samples included in the analysis. Hence, further analyses on larger cohorts are needed to better define the role of these biomarkers in distinguishing between patients' clinical variants
INTERFACING HERITAGES, CULTURES, & LANDSCAPES: PAVING CULTURAL SUSTAINABILITY - Vol.1
No full textWithin the system of complex interconnectedness and interactions among cultures, heritage, and landscapes and their role in making cultural sustainability—all that is rooted in the past together, we seek to search ways, paths, and means that are implied for framing and creating a base for the UN Sustainable Development Goals Target 11.4, focussing on ‘Transforming our World: The 2030 Agenda for Sustainable Development’. Together with community development, nature-based education, and pilgrimages, revealing the spirit of places is part of the cultural process of transforming landscapes—seen and visualised in the fabric of landscape architecture. These attributes can be examined in relation to the trends and perspectives of the emerging literature and regional representations. The inherent and manifested meanings, symbols, metaphors, aesthetics, etc., exemplify the representations. In contrast to the mundane environment, spirituality offers a bridge through transcendence and connection to the inherent power of serene nature, which is also reflected in architectural symbols. These attributes are clearly visible in the holyheritage cities. This paper presents an introductory review and appraisal of the entire journey and the resultant cultural landscapes, following the path of RWYC - Reconnecting With Your Culture, and attempts to lay out a pathway for cultural and sacred sustainability
Representation and outcomes of individuals with major depression in routine care who are ineligible for randomized controlled trials: a nationwide register‐based study
No full textRandomized controlled trials (RCTs) are the foundation of current clinical treatment guidelines. However, they may not reflect real-world populations, due to strict eligibility criteria. We determined the proportion of individuals with major depressive disorder (MDD) receiving maintenance antidepressant treatment in routine care who would be ineligible for RCTs, and compared their outcomes with those who were eligible. Utilizing specialized health care registers in Finland (2004-2018) and Sweden (2006-2021), we identified adults diagnosed with non-psychotic MDD (ICD-10: F32, F33) who were stabilized on maintenance antidepressant monotherapy. Through multidisciplinary expert consensus on latest meta-analytic evidence, we derived a standardized list of RCT inclusion and exclusion criteria. These criteria were systematically applied to classify individuals as RCT-eligible or RCT-ineligible. We then used Cox proportional models to derive hazard ratios (HRs) of a composite primary outcome of hospitalization due to any psychiatric reason or suicide attempt, and all-cause mortality, during a 6-month follow-up. Secondary outcomes were treatment changes (i.e., discontinuation, switch or augmentation) and psychiatric sick leave ≥2 weeks. A total of 73,720 individuals in Finland and 135,092 in Sweden were included. More than one third of patients with MDD (33.5% in Finland and 35.3% in Sweden) were found to be ineligible for RCTs. The most common reasons for ineligibility were comorbidities (serious somatic disease, other psychiatric disorders, or substance use disorder). RCT-ineligible individuals had more than twice the risk of the composite primary outcome compared to eligible individuals (HR=2.44, 95% CI: 2.15-2.76 in Finland; HR=2.61, 95% CI: 2.37-2.87 in Sweden). Approximately one third of the composite primary outcome was attributable to RCT-ineligibility factors (32.5%, 95% CI: 27.9-37.1 for Finland; 36.2%, 95% CI: 32.6-39.8 for Sweden). Risk of treatment change was slightly but significantly higher in ineligible individuals. Findings were consistent in a wide range of sensitivity analyses. We conclude that more inclusive eligibility criteria for RCTs, and their integration with real-world data, are needed to improve the generalizability of antidepressant trial evidence and MDD clinical treatment guidelines
Intraventricular neurocytoma presenting as Kleine-Levin syndrome: resolution after resection and review of neurosurgical conditions associated with hypersexuality. Illustrative case
No full textBackground: Kleine-Levin syndrome (KLS) is a rare disorder characterized by recurrent episodes of hypersomnia associated with one or more of the following: cognitive impairment, hyperphagia, hypersexuality, apathy, and derealization/altered perception. Headache and/or vomiting may precede the onset of hypersomnia. KLS secondary to lesions of neurosurgical interest is extremely rare and has been described once after hemorrhage complicating the endoscopic removal of a colloid cyst. Observations: A 25-year-old man, with no personal or family history of neuropsychiatric disorders, developed hypersomnia, apathy, and hypersexual behavior. Six months after the onset of the symptoms he became unable to stand without help and was admitted to the authors' hospital. Contrast-enhanced CT performed at admission and later contrast-enhanced MRI revealed an intraventricular mass extending from the right lateral ventricle to the third ventricle. The tumor was removed through a right frontal transcortical approach, and the pathological diagnosis was atypical neurocytoma. After surgery, all symptoms suggestive of KLS disappeared. Lessons: Compression by an intraventricular mass on the septal area, diencephalon, and hypothalamus may induce secondary KLS (sKLS). Tumor removal can relieve the syndrome. Hypersexualty and sKLS were reported more frequently with neurosurgical diseases of the right hemisphere, but the number of cases reported is insufficient to reach a conclusion and further observations are needed. https://thejns.org/doi/10.3171/CASE25800
A Novel Virulence Mechanism in Staphylococcus aureus: FnBPA Cross-Linking to Fibrin(ogen) and Fibronectin by Bacterially Activated FXIII and TG2
No full textStaphylococcus aureus is a versatile opportunistic pathogen capable of causing a spectrum of infections, from superficial skin lesions to life-threatening systemic diseases. Its capacity to evade host immune responses and establish persistent infections is critically dependent on its ability to adhere to and colonize host tissues. Central to this process is the interaction of S. aureus surface proteins with extracellular matrix (ECM) components, particularly fibronectin (Fn) and fibrinogen (Fbg). This thesis investigates a novel pathogenic mechanism by which S. aureus exploits host transglutaminases, specifically Factor XIII (FXIII) and tissue transglutaminase 2 (TG2), to covalently anchor itself to host proteins through the multifunctional surface adhesin Fibronectin Binding Protein A (FnBPA), with the bacterial coagulase von Willebrand factor-binding protein (vWbp) playing a central activating role.
The study begins by examining the expression profile and localization of vWbp during S. aureus growth, revealing that the protein is secreted during the exponential phase and subsequently rebinds to the bacterial surface via interactions with lipoteichoic acid (LTA) and peptidoglycan (PPG). Functionally, surface-associated vWbp non-proteolytically activates prothrombin, leading to fibrin formation and subsequent activation of FXIII. In this environment, bacterially-activated FXIII catalyzes the formation of ε-(γ-glutamyl)-lysine isopeptide bonds between Fbg and FnBPA, embedding the bacterium within a stable fibrin scaffold.
Biochemical analysis identified Gln103 in the N1 subdomain of FnBPA's N-terminal Region A as the key reactive glutamine residue essential for vWbp-activated FXIII mediated crosslinking. Recombinant FnBPA mutants lacking Gln103 (Q103A) retained non-covalent binding to Fbg via the classical Dock, Lock, and Latch (DLL) mechanism but failed to form covalent complexes with fibrin(ogen). This specificity was confirmed using whole bacterial cells expressing Q103A FnBPA, which demonstrated impaired incorporation into fibrin matrices. Also, bacterial virulence was significantly reduced in a murine subcutaneous infection model in presence of the Q103A mutation, as evidenced by smaller dermonecrotic lesions and lower bacterial loads compared to wild-type strains. In addition, this study also establishes that TG2, a transglutaminase expressed in various tissues and induced during inflammation, can catalyze the same crosslinking reaction, broadening the physiological relevance of this mechanism beyond sites of coagulation.
Beyond Fbg, this work demonstrates that Fn is also a substrate for FnBPA-mediated covalent crosslinking to host proteins in the presence of vWbp-activated FXIII. Interestingly, this function is conferred not by the N1N2N3 region, but by the C-terminal repeat region (RR) of FnBPA, which forms high-molecular-weight complexes with both full-length Fn and the N-terminal 29 kDa fragment of Fn. The RR region is already known to mediate non-covalent interactions with Fn through a tandem β-zipper mechanism, highlighting its dual role in adhesive processes.
In summary, this thesis uncovers a novel virulence mechanism whereby S. aureus utilizes vWbp to hijack host transglutaminase activity, resulting in covalent stabilization of bacterial-host protein complexes via FnBPA. These findings not only deepen our understanding of S. aureus adhesion biology and immune evasion but also identify FnBPA-mediated covalent crosslinking as a promising therapeutic target, particularly in the context of antibiotic-resistant infections and biofilm-associated diseases.Staphylococcus aureus is a versatile opportunistic pathogen capable of causing a spectrum of infections, from superficial skin lesions to life-threatening systemic diseases. Its capacity to evade host immune responses and establish persistent infections is critically dependent on its ability to adhere to and colonize host tissues. Central to this process is the interaction of S. aureus surface proteins with extracellular matrix (ECM) components, particularly fibronectin (Fn) and fibrinogen (Fbg). This thesis investigates a novel pathogenic mechanism by which S. aureus exploits host transglutaminases, specifically Factor XIII (FXIII) and tissue transglutaminase 2 (TG2), to covalently anchor itself to host proteins through the multifunctional surface adhesin Fibronectin Binding Protein A (FnBPA), with the bacterial coagulase von Willebrand factor-binding protein (vWbp) playing a central activating role.
The study begins by examining the expression profile and localization of vWbp during S. aureus growth, revealing that the protein is secreted during the exponential phase and subsequently rebinds to the bacterial surface via interactions with lipoteichoic acid (LTA) and peptidoglycan (PPG). Functionally, surface-associated vWbp non-proteolytically activates prothrombin, leading to fibrin formation and subsequent activation of FXIII. In this environment, bacterially-activated FXIII catalyzes the formation of ε-(γ-glutamyl)-lysine isopeptide bonds between Fbg and FnBPA, embedding the bacterium within a stable fibrin scaffold.
Biochemical analysis identified Gln103 in the N1 subdomain of FnBPA's N-terminal Region A as the key reactive glutamine residue essential for vWbp-activated FXIII mediated crosslinking. Recombinant FnBPA mutants lacking Gln103 (Q103A) retained non-covalent binding to Fbg via the classical Dock, Lock, and Latch (DLL) mechanism but failed to form covalent complexes with fibrin(ogen). This specificity was confirmed using whole bacterial cells expressing Q103A FnBPA, which demonstrated impaired incorporation into fibrin matrices. Also, bacterial virulence was significantly reduced in a murine subcutaneous infection model in presence of the Q103A mutation, as evidenced by smaller dermonecrotic lesions and lower bacterial loads compared to wild-type strains. In addition, this study also establishes that TG2, a transglutaminase expressed in various tissues and induced during inflammation, can catalyze the same crosslinking reaction, broadening the physiological relevance of this mechanism beyond sites of coagulation.
Beyond Fbg, this work demonstrates that Fn is also a substrate for FnBPA-mediated covalent crosslinking to host proteins in the presence of vWbp-activated FXIII. Interestingly, this function is conferred not by the N1N2N3 region, but by the C-terminal repeat region (RR) of FnBPA, which forms high-molecular-weight complexes with both full-length Fn and the N-terminal 29 kDa fragment of Fn. The RR region is already known to mediate non-covalent interactions with Fn through a tandem β-zipper mechanism, highlighting its dual role in adhesive processes.
In summary, this thesis uncovers a novel virulence mechanism whereby S. aureus utilizes vWbp to hijack host transglutaminase activity, resulting in covalent stabilization of bacterial-host protein complexes via FnBPA. These findings not only deepen our understanding of S. aureus adhesion biology and immune evasion but also identify FnBPA-mediated covalent crosslinking as a promising therapeutic target, particularly in the context of antibiotic-resistant infections and biofilm-associated diseases
Impact of Spiroplasma infection on reproductive physiology and behavior in Glossina fuscipes fuscipes
No full textAfrican Trypanosomiasis is a vector-born disease of major public health and
veterinary importance in Sub-Saharan Africa. It is caused by the protozoa parasites
of the genus Trypanosoma, transmitted by tsetse flies (Glossina spp.). The disease
occurs in two forms: Human African Trypanosomiasis (HAT) better known as
sleeping sickness, and Animal African Trypanosomiasis (AAT), or Nagana, which
primarily affects livestock and cattle. According to World Health Organization
(WHO), nearly one thousand new cases of HAT are reported annually. No effective
vaccine is currently available, and existing drugs treatment are costly and difficult to
implement. Consequently, vector control remains the most effective strategy to limit
transmission. While conventional approaches such as insecticides and traps are still
in use, eco-friendly strategies like the Sterile Insect Technique represent powerful
alternatives (SIT).
Tsetse flies are unusual among insects due to their reproductive strategy of
adenotrophic viviparity: after egg fertilization, females nourish a single larva in utero,
giving birth to a fully developed third instar larva. Their microbiota is also highly
specialized, dominated by four main bacterial symbionts: the obligate endosymbiont
Wigglesworthia, the commensal Sodalis, the facultative Wolbachia and Spiroplasma.
These microbes play critical roles in host physiology, reproduction and vector
competence. Particularly, Spiroplasma, a member of the Mollicutes class, has
attracted growing interest because of its ability to confer refractoriness to
trypanosome co-infection, potentially reducing disease transmission. However, its
presence is restricted to certain Glossina species within the palpalis subgroup,
including Glossina fuscipes fuscipes (Gff), the principal vector of HAT in Uganda.
This thesis investigates the interaction between Spiroplasma and its tsetse fly host,
with a focus on reproductive outcomes and mating behavior.
Controlled mating experiments demonstrated that Spiroplasma infection increases
mating propensity and revealed evidence of non-random mating, suggesting a form
of pre-mating isolation linked to infection status. Furthermore, a horizontal
transmission of Spiroplasma, from infected males to females was observed during
copulation.
Transcriptomic analysis of Gff revealed that Spiroplasma infection exerts an overall
negative effect on male reproduction by reducing energy metabolism and
compromising sperm quality and motility.
In summary, this work provides new insight into the role of Spiroplasma in shaping
tsetse reproductive biology. These findings highlight the dual potential of
Spiroplasma as both a natural modifier of vector competence and a factor influencing
fly fitness, with important implications for future applications, such as the
development of innovative, symbiont-based biological control strategies against
tsetse flies
On a brain tumor growth model with lactate metabolism, viscoelastic effects, and tissue damage
No full textIn this paper, we study a nonlinearly coupled initial–boundary value problem describing the evolution of brain tumor growth, including lactate metabolism. In our modeling approach, we also take into account the viscoelastic properties of the tissues as well as the reversible damage effects that could occur, possibly caused by surgery. After introducing the PDE system, coupling a Fischer–Kolmogorov type equation for the tumor phase with a reaction–diffusion equation for the lactate, a quasi-static momentum balance with nonlinear elasticity and viscosity matrices, and a nonlinear differential inclusion for the damage, we prove the existence of global in time weak solutions under reasonable assumptions on the involved functions and data. Strengthening these assumptions, we subsequently prove further regularity properties of the solutions as well as their continuous dependence with respect to the data, entailing the well-posedness of the Cauchy problem associated with the nonlinear PDE system
