Rational development and application of biomarkers in the field of autoimmunity: A conceptual framework guiding clinicians and researchers.

Clear guidance is needed in the development and implementation of laboratory biomarkers in medicine. So far, no standardized phased approach is established that would pilot researchers and clinicians in this process. This leads to often incompletely validated biomarkers, which can bear the consequence of wrong applications, misinterpretation and inadequate management in the clinical context. In this conceptual article, we describe a stepwise approach to develop and comprehensively validate laboratory biomarkers. We will delineate basic steps including technical performance, pre-analytical issues, and biological variation, as well as advanced aspects of biomarker utility comprising interpretability, diagnostic and prognostic accuracy, and health-care outcomes. These aspects will be illustrated by using well-known examples from the field of immunology. The application of this conceptual framework will guide researchers in conducting meaningful projects to develop and evaluate biomarkers for the use in clinical practice. Furthermore, clinicians will be able to adequately interpret pre-clinical and clinical diagnostic literature and rationally apply biomarkers in clinical practice. Improvement in the implementation and application of biomarkers might relevantly change the management and outcomes of our patients for the better

Krotov: A Python implementation of Krotov's method for quantum optimal control

We present a new open-source Python package, krotov, implementing the quantum optimal control method of that name. It allows to determine time-dependent external fields for a wide range of quantum control problems, including state-to-state transfer, quantum gate implementation and optimization towards an arbitrary perfect entangler. Krotov's method compares to other gradient-based optimization methods such as gradient-ascent and guarantees monotonic convergence for approximately time-continuous control fields. The user-friendly interface allows for combination with other Python packages, and thus high-level customization

Mutation screening of the medium-chain acyl-CoA dehydrogenase (MCAD) and the ornithine transcarbamylase (OTC) genes by multiplex PCR amplification and sequencing

Background: Sequencing based mutation screening assays of genes encompassing large numbers of exons could be substantially optimized by multiplex PCR, which enables simultaneous amplification of many targets in one reaction. In the present study, a multiplex PCR protocol originally developed for fragment analysis was evaluated for sequencing based mutation screening of the ornithine transcarbamylase (OTC) and the medium-chain acyl-CoA dehydrogenase (MCAD) genes. Methods: Single exon and multiplex PCR protocols were applied to generate PCR templates for subsequent DNA sequencing of all exons of the OTC and the MCAD genes. For each PCR protocol and using the same DNA samples, 66 OTC and 98 MCAD sequence reads were generated. The sequences derived from the two different PCR methods were compared at the level of individual signal-to-noise ratios of the four bases and the proportion of high-quality base-signals. Results: The single exon and the multiplex PCR protocol gave qualitatively comparable results for the two genes. Conclusions: Many existing sequencing based mutation analysis protocols may be easily optimized with the proposed method, since the multiplex PCR protocol was successfully applied without any re-design of the PCR primers and other optimization steps for generating sequencing templates for the OTC and MCAD genes, respectively. Clin Chem Lab Med 2009;47:56-

The bloodstream form of Trypanosoma brucei displays non-canonical gluconeogenesis

Trypanosoma brucei is a causative agent of the Human and Animal African Trypanosomiases. The mammalian stage parasites infect various tissues and organs including the bloodstream, central nervous system, skin, adipose tissue and lungs. They rely on ATP produced in glycolysis, consuming large amounts of glucose, which is readily available in the mammalian host. In addition to glucose, glycerol can also be used as a source of carbon and ATP and as a substrate for gluconeogenesis. However, the physiological relevance of glycerol-fed gluconeogenesis for the mammalian-infective life cycle forms remains elusive. To demonstrate its (in)dispensability, first we must identify the enzyme(s) of the pathway. Loss of the canonical gluconeogenic enzyme, fructose-1,6-bisphosphatase, does not abolish the process hence at least one other enzyme must participate in gluconeogenesis in trypanosomes. Using a combination of CRISPR/Cas9 gene editing and RNA interference, we generated mutants for four enzymes potentially capable of contributing to gluconeogenesis: fructose-1,6-bisphoshatase, sedoheptulose-1,7-bisphosphatase, phosphofructokinase and transaldolase, alone or in various combinations. Metabolomic analyses revealed that flux through gluconeogenesis was maintained irrespective of which of these genes were lost. Our data render unlikely a previously hypothesised role of a reverse phosphofructokinase reaction in gluconeogenesis and preclude the participation of a novel biochemical pathway involving transaldolase in the process. The sustained metabolic flux in gluconeogenesis in our mutants, including a triple-null strain, indicates the presence of a unique enzyme participating in gluconeogenesis. Additionally, the data provide new insights into gluconeogenesis and the pentose phosphate pathway, and improve the current understanding of carbon metabolism of the mammalian-infective stages of T. brucei.</p

The bloodstream form of Trypanosoma brucei displays non-canonical gluconeogenesis

Trypanosoma brucei is a causative agent of the Human and Animal African Trypanosomiases. The mammalian stage parasites infect various tissues and organs including the bloodstream, central nervous system, skin, adipose tissue and lungs. They rely on ATP produced in glycolysis, consuming large amounts of glucose, which is readily available in the mammalian host. In addition to glucose, glycerol can also be used as a source of carbon and ATP and as a substrate for gluconeogenesis. However, the physiological relevance of glycerol-fed gluconeogenesis for the mammalian-infective life cycle forms remains elusive. To demonstrate its (in)dispensability, first we must identify the enzyme(s) of the pathway. Loss of the canonical gluconeogenic enzyme, fructose-1,6-bisphosphatase, does not abolish the process hence at least one other enzyme must participate in gluconeogenesis in trypanosomes. Using a combination of CRISPR/Cas9 gene editing and RNA interference, we generated mutants for four enzymes potentially capable of contributing to gluconeogenesis: fructose-1,6-bisphoshatase, sedoheptulose-1,7-bisphosphatase, phosphofructokinase and transaldolase, alone or in various combinations. Metabolomic analyses revealed that flux through gluconeogenesis was maintained irrespective of which of these genes were lost. Our data render unlikely a previously hypothesised role of a reverse phosphofructokinase reaction in gluconeogenesis and preclude the participation of a novel biochemical pathway involving transaldolase in the process. The sustained metabolic flux in gluconeogenesis in our mutants, including a triple-null strain, indicates the presence of a unique enzyme participating in gluconeogenesis. Additionally, the data provide new insights into gluconeogenesis and the pentose phosphate pathway, and improve the current understanding of carbon metabolism of the mammalian-infective stages of T. brucei.</p

Clinical Validity of Anti-Proteinase 3 Antibodies in Patients with Inflammatory Bowel Disease: A Short Meta-Analysis.

Anti-neutrophil cytoplasmic antibodies (ANCA) directed to proteinase 3 (PR3) represent highly established markers for patients with ANCA-associated vasculitis (AAV). PR3-ANCA have also demonstrated utility in the management of inflammatory bowel disease (IBD). More specifically, PR3-ANCA discriminate individuals with ulcerative colitis (UC) from Crohn's disease (CD) patients and are associated with disease severity, activity, and treatment non-response. Here, we aim to summarize the current data on the diagnostic utility of PR3-ANCA in IBD. A structured, systematic literature review, including three electronic databases, was conducted on June 6th, 2023, to identify studies assessing the diagnostic accuracy of the QUANTA Flash® PR3 assay in UC vs. CD patients. Electronic searches were supplemented by hand searching. A hierarchical, bivariate, mixed-effect meta-analysis was conducted using the metandi function, as per the Cochrane collaboration recommendations. Study quality was assessed using the QUADAS-2 tool, which considers the risk of bias and applicability. Six out of a hundred and eleven citations met the inclusion criteria and reported QUANTA Flash® PR3 diagnostic accuracy in UC vs. CD (UC, n = 667, CD, n = 682 patients). The sensitivity/specificity point estimate for UC was 34.9%/95.9%. This resulted in a Diagnostic Odds Ratio (DOR) of 12.6. The risk of bias was low in the index test and reference standard domains. Four of the six studies (67%) showed an unclear risk of bias in patient selection and in flow and timing domains. All studies had low concerns about applicability in all the domains. PR3-ANCA measured with the QUANTA Flash® PR3 assay represent novel diagnostic markers in IBD and enables discrimination between UC and CD

Pairing in fermionic systems: A quantum information perspective

The notion of "paired" fermions is central to important condensed matter phenomena such as superconductivity and superfluidity. While the concept is widely used and its physical meaning is clear there exists no systematic and mathematical theory of pairing which would allow to unambiguously characterize and systematically detect paired states. We propose a definition of pairing and develop methods for its detection and quantification applicable to current experimental setups. Pairing is shown to be a quantum correlation different from entanglement, giving further understanding in the structure of highly correlated quantum systems. In addition, we will show the resource character of paired states for precision metrology, proving that the BCS states allow phase measurements at the Heisenberg limit.Comment: 23 pages, 4 figure

Iron–molybdenum-oxo complexes as initiators for olefin autoxidation with O2

The reaction between [(TPA)Fe(MeCN)2](OTf)2 and [nBu4N](Cp*MoO3) yields the novel tetranuclear complex [(TPA)Fe(μ-Cp*MoO3)]2(OTf)2, 1, with a rectangular [Mo–O–Fe–O–]2 core containing high-spin iron(II) centres. 1 proved to be an efficient initiator/(pre)catalyst for the autoxidation of cis-cyclooctene with O2 to give cyclooctene epoxide. To test, which features of 1 are essential in this regard, analogues with zinc(II) and cobalt(II) central atoms, namely [(TPA)Zn(Cp*MoO3)](OTf), 3, and [(TPA)Co(Cp*MoO3)](OTf), 4, were prepared, which proved to be inactive. The precursor compounds of 1, [(TPA)Fe(MeCN)2](OTf)2 and [nBu4N](Cp*MoO3) as well as Cp2*Mo2O5, were found to be inactive, too. Reactivity studies in the absence of cyclooctene revealed that 1 reacts both with O2 and PhIO via loss of the Cp* ligands to give the triflate salt 2 of the known cation [((TPA)Fe)2(μ-O)(μ-MoO4)]2+. The cobalt analogue 4 reacts with O2 in a different way yielding [((TPA)Co)2(μ-Mo2O8)](OTf)2, 5, featuring a Mo2O84− structural unit which is novel in coordination chemistry. The compound [(TPA)Fe(μ-MoO4)]2, 6, being related to 1, but lacking Cp* ligands failed to trigger autoxidation of cyclooctene. However, initiation of autoxidation by Cp* radicals was excluded via experiments including thermal dissociation of Cp2*

Endovascular repair of an actively hemorrhaging gunshot injury to the abdominal aorta

Endovascular stents have had a limited role in the management of trauma and vascular emergencies involving active hemorrhage. We describe a patient with delayed rupture of the infrarenal aorta after intra-abdominal sepsis caused the breakdown of a primary aortic repair. A stent-graft repair was performed, as concomitant injuries did not allow anterior access to the aorta. This report describes the successful endovascular repair of an actively hemorrhaging penetrating abdominal aortic injury. Endovascular approaches to aortic injuries may be valuable in settings where a hostile abdomen precludes traditional open repair

The Optimal Control Landscape for the Generation of Unitary Transformations with Constrained Dynamics

The reliable and precise generation of quantum unitary transformations is essential to the realization of a number of fundamental objectives, such as quantum control and quantum information processing. Prior work has explored the optimal control problem of generating such unitary transformations as a surface optimization problem over the quantum control landscape, defined as a metric for realizing a desired unitary transformation as a function of the control variables. It was found that under the assumption of non-dissipative and controllable dynamics, the landscape topology is trap-free, implying that any reasonable optimization heuristic should be able to identify globally optimal solutions. The present work is a control landscape analysis incorporating specific constraints in the Hamiltonian corresponding to certain dynamical symmetries in the underlying physical system. It is found that the presence of such symmetries does not destroy the trap-free topology. These findings expand the class of quantum dynamical systems on which control problems are intrinsically amenable to solution by optimal control.Comment: Submitted to Journal of Mathematical Physic