The molecular mechanisms of microbial virulence and host defense are most often studied using animal models and Koch's molecular postulates. A common rationale for these types of experiments is to ...identify therapeutic targets based on the assumption that microbial or host factors that confer extreme animal model survival phenotypes represent critical virulence and host defense factors. Yet null mutant strains of microbial (or host) factors often yield extreme survival curve phenotypes because they fail to establish an infection. The lack of infection and disease establishment prevents true assessment of the given factor's role(s) in disease progression. Here, we posit that the emphasis on extreme survival curve phenotypes in fungal infectious disease models is leading to missed opportunities to identify new fungal and host factors critical for disease progression. We simply do not yet have a sufficient understanding of fungal virulence and host defense mechanisms throughout the temporal course of an infection. We propose that there is a need to develop new approaches and to revisit tried and true methods to define infection site biology beyond the analysis of survival curve phenotypes. To stimulate these new approaches, we propose the (new) terms "disease initiation factor" and "disease progression factor" to distinguish functional roles at distinct temporal stages of an infection and give us targets to foster new discoveries.
We analyse, in NLO, the physical properties of the discrete eigenvalue solution for the BFKL equation. We show that a set of eigenfunctions with positive eigenvalues,
ω
, together with a small ...contribution from a continuum of eigenfunctions with negative
ω
, provide an excellent description of high-precision HERA
F
2
data in the region,
x
<
0.001
,
Q
2
>
6
GeV
2
. The phases of the eigenfunctions can be obtained from a simple parametrisation of the pomeron spectrum, which has a natural motivation within BFKL. The data analysis shows that the first eigenfunction decouples completely or almost completely from the proton. This suggests that there exists an additional ground state, which is naturally saturated and may have the properties of the soft pomeron.
Previous work has shown that environmental and clinical isolates of Aspergillus fumigatus represent a diverse population that occupies a variety of niches, has extensive genetic diversity, and ...exhibits virulence heterogeneity in a number of animal models of invasive pulmonary aspergillosis (IPA). However, mechanisms explaining differences in virulence among A. fumigatus isolates remain enigmatic. Here, we report a significant difference in virulence of two common lab strains, CEA10 and AF293, in the murine triamcinolone immunosuppression model of IPA, in which we previously identified severe low oxygen microenvironments surrounding fungal lesions. Therefore, we hypothesize that the ability to thrive within these lesions of low oxygen promotes virulence of A. fumigatus in this model. To test this hypothesis, we performed in vitro fitness and in vivo virulence analyses in the triamcinolone murine model of IPA with 14 environmental and clinical isolates of A. fumigatus Among these isolates, we observed a strong correlation between fitness in low oxygen in vitro and virulence. In further support of our hypothesis, experimental evolution of AF293, a strain that exhibits reduced fitness in low oxygen and reduced virulence in the triamcinolone model of IPA, results in a strain (EVOL20) that has increased hypoxia fitness and a corresponding increase in virulence. Thus, the ability to thrive in low oxygen correlates with virulence of A. fumigatus isolates in the context of steroid-mediated murine immunosuppression.
Aspergillus fumigatus occupies multiple environmental niches, likely contributing to the genotypic and phenotypic heterogeneity among isolates. Despite reports of virulence heterogeneity, pathogenesis studies often utilize a single strain for the identification and characterization of virulence and immunity factors. Here, we describe significant variation between A. fumigatus isolates in hypoxia fitness and virulence, highlighting the advantage of including multiple strains in future studies. We also illustrate that hypoxia fitness correlates strongly with increased virulence exclusively in the nonleukopenic murine triamcinolone immunosuppression model of IPA. Through an experimental evolution experiment, we observe that chronic hypoxia exposure results in increased virulence of A. fumigatus We describe here the first observation of a model-specific virulence phenotype correlative with in vitro fitness in hypoxia and pave the way for identification of hypoxia-mediated mechanisms of virulence in the fungal pathogen A. fumigatus.
A golden age for heavy-quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The ...early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the
B
-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations at BESIII, the LHC, RHIC, FAIR, the Super Flavor and/or Tau–Charm factories, JLab, the ILC, and beyond. The list of newly found conventional states expanded to include
h
c
(1
P
),
χ
c
2
(2
P
),
, and
η
b
(1
S
). In addition, the unexpected and still-fascinating
X
(3872) has been joined by more than a dozen other charmonium- and bottomonium-like “
XYZ
” states that appear to lie outside the quark model. Many of these still need experimental confirmation. The plethora of new states unleashed a flood of theoretical investigations into new forms of matter such as quark–gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of
,
, and
bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. Lattice QCD has grown from a tool with computational possibilities to an industrial-strength effort now dependent more on insight and innovation than pure computational power. New effective field theories for the description of quarkonium in different regimes have been developed and brought to a high degree of sophistication, thus enabling precise and solid theoretical predictions. Many expected decays and transitions have either been measured with precision or for the first time, but the confusing patterns of decays, both above and below open-flavor thresholds, endure and have deepened. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark–gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.
IntroductionLong COVID-19, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms ...are fatigue, postexertional malaise and cognitive dysfunction. There is currently no effective treatment and the underlying mechanisms are unknown, although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in long COVID-19. This randomised, placebo-controlled clinical trial will explore HBOT as a potential treatment for long COVID-19. The primary objective is to evaluate if HBOT improves health-related quality of life (HRQoL) for patients with long COVID-19 compared with placebo/sham. The main secondary objective is to evaluate whether HBOT improves endothelial function, objective physical performance and short-term HRQoL.Methods and analysisA randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to long COVID-19, with low HRQoL. Clinical data, HRQoL questionnaires, blood samples, objective tests and activity metre data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over 6 weeks. Assessments for safety and efficacy will be performed at 6, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND 36-Item Health Survey) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent data safety monitoring board.Ethics and disseminationThe trial is approved by the Swedish National Institutional Review Board (2021–02634) and the Swedish Medical Products Agency (5.1-2020-36673). Positive, negative and inconclusive results will be published in peer-reviewed scientific journals with open access.Trial registration numberNCT04842448.
Microbial populations form intricate macroscopic colonies with diverse morphologies whose functions remain to be fully understood. Despite fungal colonies isolated from environmental and clinical ...samples revealing abundant intraspecies morphological diversity, it is unclear how this diversity affects fungal fitness and disease progression. Here we observe a notable effect of oxygen tension on the macroscopic and biofilm morphotypes of the human fungal pathogen Aspergillus fumigatus. A hypoxia-typic morphotype is generated through the expression of a subtelomeric gene cluster containing genes that alter the hyphal surface and perturb interhyphal interactions to disrupt in vivo biofilm and infection site morphologies. Consequently, this morphotype leads to increased host inflammation, rapid disease progression and mortality in a murine model of invasive aspergillosis. Taken together, these data suggest that filamentous fungal biofilm morphology affects fungal-host interactions and should be taken into consideration when assessing virulence and host disease progression of an isolated strain.
Prurigo nodualris (PN) is a chronic condition with highly pruritic, hyperkeratotic papules or nodules arising in the setting of chronic pruritus. While PN may serve as a phenotypic presentation of ...several underlying conditions such as atopic dermatitis, chronic kidney disease-related pruritus, and neurological diseases, it represents a distinct clinical entity that may persist despite the removal of the underlying cause, if one is identified. Neuronal proliferation, eosinophils, mast cells, and small-fiber neuropathy play a role in the production of pruritus in PN, although the exact mechanism has not yet been established. Identifying an underlying cause, if present, is essential to prevent recurrence of PN. Due to often present comorbidities, treatment is typically multimodal with utilization of topical and systemic therapies. We performed a PubMed/MEDLINE search for PN and present a review of recent developments in the treatment of PN. Treatment typically relies on the use of topical or intralesional steroids, though more severe or recalcitrant cases often necessitate the use of phototherapy or systemic immunosuppressives. Thalidomide and lenalidomide can both be used in severe cases; however, their toxicity profile makes them less favorable. Opioid receptor antagonists and neurokinin-1 receptor antagonists represent two novel families of therapeutic agents which may effectively treat PN with a lower toxicity profile than thalidomide or lenalidomide.
The genus
encompasses human pathogens such as
and industrial powerhouses such as
In both cases,
biofilms have consequences for infection outcomes and yields of economically important products. ...However, the molecular components influencing filamentous fungal biofilm development, structure, and function remain ill defined. Macroscopic colony morphology is an indicator of underlying biofilm architecture and fungal physiology. A hypoxia-locked colony morphotype of
has abundant colony furrows that coincide with a reduction in vertically oriented hyphae within biofilms and increased low oxygen growth and virulence. Investigation of this morphotype has led to the identification of the causative gene,
(
), a small cryptic open reading frame within a subtelomeric gene cluster. BafA is sufficient to induce the hypoxia-locked colony morphology and biofilm architecture in
Analysis across a large population of
isolates identified a larger family of
genes, all of which have the capacity to modulate hyphal architecture, biofilm development, and hypoxic growth. Furthermore, introduction of
into
is sufficient to generate the hypoxia-locked colony morphology, biofilm architecture, and increased hypoxic growth. Together, these data indicate the potential broad impacts of this previously uncharacterized family of small genes to modulate biofilm architecture and function in clinical and industrial settings.
The manipulation of microbial biofilms in industrial and clinical applications remains a difficult task. The problem is particularly acute with regard to filamentous fungal biofilms for which molecular mechanisms of biofilm formation, maintenance, and function are only just being elucidated. Here, we describe a family of small genes heterogeneously expressed across
strains that are capable of modifying colony biofilm morphology and microscopic hyphal architecture. Specifically, these genes are implicated in the formation of a hypoxia-locked colony morphotype that is associated with increased virulence of
Synthetic introduction of these gene family members, here referred to as biofilm architecture factors, in both
and
additionally modulates low oxygen growth and surface adherence. Thus, these genes are candidates for genetic manipulation of biofilm development in aspergilli.
Falls in older adults are a significant and growing public health concern. There are multiple risk factors associated with falls that may be addressed within the scope of chiropractic training and ...licensure. Few attempts have been made to summarize existing evidence on multimodal chiropractic care and fall risk mitigation. Therefore, the broad purpose of this review was to summarize this research to date. BODY: Systematic review was conducted following PRISMA guidelines. Databases searched included PubMed, Embase, Cochrane Library, PEDro, and Index of Chiropractic Literature. Eligible study designs included randomized controlled trials (RCT), prospective non-randomized controlled, observational, and cross-over studies in which multimodal chiropractic care was the primary intervention and changes in gait, balance and/or falls were outcomes. Risk of bias was also assessed using the 8-item Cochrane Collaboration Tool. The original search yielded 889 articles; 21 met final eligibility including 10 RCTs. One study directly measured the frequency of falls (underpowered secondary outcome) while most studies assessed short-term measurements of gait and balance. The overall methodological quality of identified studies and findings were mixed, limiting interpretation regarding the potential impact of chiropractic care on fall risk to qualitative synthesis.
Little high-quality research has been published to inform how multimodal chiropractic care can best address and positively influence fall prevention. We propose strategies for building an evidence base to inform the role of multimodal chiropractic care in fall prevention and outline recommendations for future research to fill current evidence gaps.
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