Miracle-dz/UniFAR-FTUs huggingface dataset:
Variable hybridization between two Lake Tanganyikan cichlid species in recent secondary contact

Closely related taxa frequently exist in sympatry before the evolution of robust reproductive barriers, which can lead to substantial gene flow. Post‐divergence gene flow can promote several disparate trajectories of divergence ranging from the erosion of distinctiveness and eventual collapse of the taxa to the strengthening of reproductive isolation. Among many relevant factors, understanding the demographic history of divergence (e.g. divergence time and extent of historical gene flow) can be particularly informative when examining contemporary gene flow between closely related taxa because this history can influence gene flow's prevalence and consequences. Here, we used genotyping‐by‐sequencing data to investigate speciation and contemporary hybridization in two closely related and sympatrically distributed Lake Tanganyikan cichlid species in the genus Petrochromis. Demographic modelling supported a speciation scenario involving divergence in isolation followed by secondary contact with bidirectional gene flow. Further investigation of this recent gene flow found evidence of ongoing hybridization between the species that varied in extent between different co‐occurring populations. Relationships between abundance and the degree of admixture across populations suggest that the availability of conspecific mates may influence patterns of hybridization. These results, together with the observation that sets of recently diverged cichlid taxa are generally geographically separated in the lake, suggest that ongoing speciation in Lake Tanganyikan cichlids relies on initial spatial isolation. Additionally, the spatial heterogeneity of admixture between the Petrochromis species illustrates the complexities of hybridization when species are in recent secondary contact.
Array genotyping as diagnostic approach in medical genetics

Genotyping arrays are by far the most widely used genetic tests but are not generally utilized for diagnostic purposes in a medical context. In the present study, we examined the diagnostic value of a standard genotyping array (Illumina Global Screening Array) for a range of indications. Applications included stand‐alone testing for specific variants (32 variants in 10 genes), first‐tier array variant screening for monogenic conditions (10 different autosomal recessive metabolic diseases), and diagnostic workup for specific conditions caused by variants in multiple genes (suspected familial breast and ovarian cancer, and hypercholesterolemia). Our analyses showed a high analytical sensitivity and specificity of array‐based analyses for validated and non‐validated variants, and identified pitfalls that require attention. Ethical‐legal assessment highlighted the need for a software solution that allows for individual indication‐based consent and the reliable exclusion of non‐consented results. Cost/time assessment revealed excellent performance of diagnostic array analyses, depending on indication, proband data, and array design. We have implemented some analyses in our diagnostic portfolio, but array optimization is required for the implementation of other indications.
Dirac's Quantum Phase Problem

In 1927 the great physicist Paul A. M. Dirac failed to provide a consistent quantum description of the phase of a radiation field. Only one year later, he developed the famous Dirac theory of the electron, which led to the anti-particle -- the positron. We show that the reason for Dirac's failure with the phase problem bears a striking resemblance to his ingenious insight into the nature of the electron. For a correct quantum description of the phase of a radiation field it is necessary to take the polarisation into account. Similarly to the introduction of the anti-particle of the electron, the inclusion of the second polarisation resolves the inconsistency of the quantum phase problem. This also leads to new insight into the quantum measurement problem of time.
Undecidability and completeness results for process algebras with alternative with alternative quantification over data

textabstractWe define a class of process algebras with a generalised operation $sum$ that allows explicit treatment of emph{alternative quantification over data, and investigate the specific subclass formed by the algebras of finite processes modulo strong bisimulation. We prove that, in such algebras, equality between process terms is definable by means of a first-order data formula, and that, if the data is computable and has a built-in equality predicate, any $Pi^0_4$ data formula is definable as an equation between ground process terms. From these results we work to the conclusion that equality in strong bisimulation algebras with a computable data part is $Pi^0_4$-hard. We also investigate a restricted version of alternative quantification: the input prefix mechanism of Parrow and Sangiorgi (1995) and Hennessy and Lin (1996). We show that this restriction yields a less expressive formalism if the data is computable and has a built-in equality predicate: equality between input prefix processes coincides with the universal fragment of first-order logic for the data. That is, the input prefix mechanism gives rise to strong bisimulation algebras for which equality is complete in $Pi^0_1$. Finally, we give a ground complete axiomatisation for those strong bisimulation algebras of which the data part has built-in equality and Skolem functions.
On modeling and simulation of surfactants in diffuse interface flow

An existing phase-field model of two immiscible fluids with a single soluble surfactant present is discussed in detail. We analyze the well-posedness of the model and show that it is mathematically ill-posed for a large set of physically relevant parameters. As a consequence, critical modifications to the model are suggested that substantially increase the domain of validity. Carefully designed numerical simulations offer informative demonstrations as to the sharpness of our theoretical results and the qualities of the physical model. A fully coupled hydrodynamic test-case demonstrates the potential to capture also non-trivial effects on the overall flow.
Pediatic code blue event anaylsis: Performance of non-acute health-care providers

ABSTRACT In-hospital pediatric cardiopulmonary arrest is rare. With more than 50% of patients not surviving to discharge following cardiopulmonary arrest, it is important that health-care providers (HCPs) respond appropriately to deteriorating patients. Our study evaluated the performance of basic life support skills using non-acute HCPs during pediatric inpatient resuscitation events. We conducted a retrospective chart review of all code blue team (CBT) activations in non-acute care areas of a tertiary care children’s hospital from 2008 to 2017. The main outcomes were frequency of life support algorithmic assessments and interventions (critical actions) performed by non-acute HCPs prior to the arrival of CBT. CBT activation and outcome data were summarized descriptively. Logistic regression was used to assess for an association of outcomes with the presence of established leadership. A total of 60 CBT activations were retrieved, 48 of which had data available on isolated non-acute HCP performance. Most children (93%) survived to discharge. Critical action performance review revealed that an airway, breathing and pulse assessment was documented to have occurred in 33%, 69% and 29% of cases, respectively. A full primary assessment was documented in 6% of cases. The presence of established leadership was associated with the performance of a partial ABC assessment. Our results suggest that resuscitation performance of pediatric inpatient non-acute HCPs often does not adhere to standard life support guidelines. These results highlight the need to reconsider the current approaches used for non-acute HCP resuscitation training.
Distinct distribution patterns of exercise-induced natural killer cell mobilisation into the circulation and tumor tissue of patients with prostate cancer.

The mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune responsive tumor entities.
Edge-preserving models and efficient algorithms for ill-posed inverse problems in image processing

The goal of this research is to develop detail and edge-preserving image models to characterize natural images. Using these image models, we have developed efficient unsupervised algorithms for solving ill-posed inverse problems in image processing applications. The first part of this research deals with parameter estimation of fixed resolution Markov random field (MRF) models. This is an important problem since without a method to estimate the model parameters in an unsupervised fashion, one has to reconstruct the unknown image for several values of the model parameters and then visually choose between the results. We have shown that for a broad selection of MRF models and problem settings, it is possible to estimate the model parameters directly from the data using the EM algorithm. We have proposed a fast simulation technique and an extrapolation method to compute the estimates in a few iterations. Experimental results indicate that these fast algorithms substantially reduce computation and result in good parameter estimates for real tomographic data sets. The second part of this research deals with formulating a functional substitution approach for efficient computation of the MAP estimate for emission and transmission tomography. The new method retains the fast convergence of a recently proposed Newton-Raphson method and is globally convergent. The third part of this research deals with formulating non-homogeneous models. Non-homogeneous models have been largely ignored in the past since there was no effective means of estimating the large number of model parameters. We have tackled this problem in the multiresolution framework, where the space-varying model parameters at any resolution are estimated from the coarser resolution image. Experimental results on real tomographic data sets and optical flow estimation results on real image sequences demonstrate that the multiresolution non-homogeneous model results in cleaner and sharper images as compared to the fixed resolution homogeneous model. Moreover, the superior quality is achieved at no additional computational cost. The last part of this research deals with efficient image reconstruction from time-resolved diffusion data, which employs a finite-difference approach to solve the diffusion equation and adjoint differentiation to compute the gradient of the cost criterion. The intended application is medical optical tomography.
High platelet reactivity is a predictor of left ventricular remodelling in patients with acute myocardial infarction

Acute myocardial infarction (AMI) is associated with left ventricular remodelling (LVR), which leads to progressive heart failure. Platelets play a pivotal role in promoting systemic and cardiac inflammatory responses during the complex process of myocardial wound healing or repair following AMI. This study aimed to investigate the impact of platelet reactivity immediately after primary percutaneous coronary intervention (PCI) on LVR in AMI patients with ST‐segment (STEMI) and non‐ST‐segment elevation (NSTEMI).
LPS O Antigen Plays a Key Role in Klebsiella pneumoniae Capsule Retention

Bacterial capsules, typically comprised of complex sugars, enable pathogens to avoid key host responses to infection, including phagocytosis. These capsules are synthesized within the bacteria, exported through the outer envelope, and then secured to the external surface of the organism by a force or forces that are incompletely described. ABSTRACT Despite the importance of encapsulation in bacterial pathogenesis, the biochemical mechanisms and forces that underpin retention of capsule by encapsulated bacteria are poorly understood. In Gram-negative bacteria, there may be interactions between lipopolysaccharide (LPS) core and capsule polymers, between capsule polymers with retained acyl carriers and the outer membrane, and in some bacteria, between the capsule polymers and Wzi, an outer membrane protein lectin. Our transposon studies in Klebsiella pneumoniae B5055 identified additional genes that, when insertionally inactivated, resulted in reduced encapsulation. Inactivation of the gene waaL, which encodes the ligase responsible for attaching the repeated O antigen of LPS to the LPS core, resulted in a significant reduction in capsule retention, measured by atomic force microscopy. This reduction in encapsulation was associated with increased sensitivity to human serum and decreased virulence in a murine model of respiratory infection and, paradoxically, with increased biofilm formation. The capsule in the WaaL mutant was physically smaller than that of the Wzi mutant of K. pneumoniae B5055. These results suggest that interactions between surface carbohydrate polymers may enhance encapsulation, a key phenotype in bacterial virulence, and provide another target for the development of antimicrobials that may avoid resistance issues associated with growth inhibition. IMPORTANCE Bacterial capsules, typically comprised of complex sugars, enable pathogens to avoid key host responses to infection, including phagocytosis. These capsules are synthesized within the bacteria, exported through the outer envelope, and then secured to the external surface of the organism by a force or forces that are incompletely described. This study shows that in the important hospital pathogen Klebsiella pneumoniae, the polysaccharide capsule is retained by interactions with other surface sugars, especially the repeated sugar molecule of the LPS molecule in Gram-negative bacteria known as “O antigen. ” This O antigen is joined to the LPS molecule by ligation, and loss of the enzyme responsible for ligation, a protein called WaaL, results in reduced encapsulation. Since capsules are essential to the virulence of many pathogens, WaaL might provide a target for new antimicrobial development, critical to the control of pathogens like K. pneumoniae that have become highly drug resistant.
Enhanced Robustness of the Mouse Retinal Circadian Clock Upon Inherited Retina Degeneration

Daily biological rhythms are fundamental to retinal physiology and visual function. They are generated by a local circadian clock composed of a network of cell type/layer-specific, coupled oscillators. Animal models of retinal degeneration have been instrumental in characterizing the anatomical organization of the retinal clock. However, it is still unclear, among the multiple cell-types composing the retina, which ones are essential for proper circadian function. In this study, we used a previously well-characterized mouse model for autosomal dominant retinitis pigmentosa to examine the relationship between rod degeneration and the retinal circadian clock. This model carries the P23H mutation in rhodopsin, which induces mild rod degeneration in heterozygous and rapid loss of photoreceptors in homozygous genotypes. By measuring PER2::LUC bioluminescence rhythms, we show that the retinal clock in P23H/+ heterozygous mice displays circadian rhythms with significantly increased robustness and amplitude. By treating retinal explants with L-α aminoadipic acid, we further provide evidence that this enhanced rhythmicity might involve activation of Müller glial cells.
Central regulation of body fluid homeostasis

Extracellular fluids, including blood, lymphatic fluid, and cerebrospinal fluid, are collectively called body fluids. The Na+ concentration ([Na+]) in body fluids is maintained at 135–145 mM and is broadly conserved among terrestrial animals. Homeostatic osmoregulation by Na+ is vital for life because severe hyper- or hypotonicity elicits irreversible organ damage and lethal neurological trauma. To achieve “body fluid homeostasis” or “Na homeostasis”, the brain continuously monitors [Na+] in body fluids and controls water/salt intake and water/salt excretion by the kidneys. These physiological functions are primarily regulated based on information on [Na+] and relevant circulating hormones, such as angiotensin II, aldosterone, and vasopressin. In this review, we discuss sensing mechanisms for [Na+] and hormones in the brain that control water/salt intake behaviors, together with the responsible sensors (receptors) and relevant neural pathways. We also describe mechanisms in the brain by which [Na+] increases in body fluids activate the sympathetic neural activity leading to hypertension.
Characterization of Treponema denticola Major Surface Protein (Msp) by Deletion Analysis and Advanced Molecular Modeling

The Treponema denticola gene encoding its major surface protein (Msp) is an ortholog of the T. pallidum tprA to -K gene family that includes tprK, whose remarkable in vivo hypervariability is proposed to contribute to T. pallidum immune evasion. Using a combined strategy of fine-scale mutagenesis and advanced predictive molecular modeling, we characterized the Msp protein and present a high-confidence model of its structure as an oligomer embedded in the outer membrane. ABSTRACT Treponema denticola, a keystone pathogen in periodontitis, is a model organism for studying Treponema physiology and host-microbe interactions. Its major surface protein Msp forms an oligomeric outer membrane complex that binds fibronectin, has cytotoxic pore-forming activity, and disrupts several intracellular processes in host cells. T. denticola msp is an ortholog of the Treponema pallidum tprA to -K gene family that includes tprK, whose remarkable in vivo hypervariability is proposed to contribute to T. pallidum immune evasion. We recently identified the primary Msp surface-exposed epitope and proposed a model of the Msp protein as a β-barrel protein similar to Gram-negative bacterial porins. Here, we report fine-scale Msp mutagenesis demonstrating that both the N and C termini as well as the centrally located Msp surface epitope are required for native Msp oligomer expression. Removal of as few as three C-terminal amino acids abrogated Msp detection on the T. denticola cell surface, and deletion of four residues resulted in complete loss of detectable Msp. Substitution of a FLAG tag for either residues 6 to 13 of mature Msp or an 8-residue portion of the central Msp surface epitope resulted in expression of full-length Msp but absence of the oligomer, suggesting roles for both domains in oligomer formation. Consistent with previously reported Msp N-glycosylation, proteinase K treatment of intact cells released a 25 kDa polypeptide containing the Msp surface epitope into culture supernatants. Molecular modeling of Msp using novel metagenome-derived multiple sequence alignment (MSA) algorithms supports the hypothesis that Msp is a large-diameter, trimeric outer membrane porin-like protein whose potential transport substrate remains to be identified. IMPORTANCE The Treponema denticola gene encoding its major surface protein (Msp) is an ortholog of the T. pallidum tprA to -K gene family that includes tprK, whose remarkable in vivo hypervariability is proposed to contribute to T. pallidum immune evasion. Using a combined strategy of fine-scale mutagenesis and advanced predictive molecular modeling, we characterized the Msp protein and present a high-confidence model of its structure as an oligomer embedded in the outer membrane. This work adds to knowledge of Msp-like proteins in oral treponemes and may contribute to understanding the evolutionary and potential functional relationships between T. denticola Msp and the orthologous T. pallidum Tpr proteins.
Alprazolam-related deaths in Scotland, 2004–2020

Background: The benzodiazepine drug alprazolam, a fast-acting tranquiliser, cannot be prescribed on the National Health Service in the United Kingdom. Illicit alprazolam supply and consumption have increased. Concern about increasing numbers of alprazolam-related fatalities started circulating in 2018. However, statistics on this issue are very limited. This study examined patterns in such mortality in Scotland. Methods: Statistics on deaths where alprazolam was mentioned in the ‘cause of death’ were obtained from official mortality registers. Anonymised Scottish case-level data were obtained. Data were examined in respect of the characteristics of decedents and deaths using descriptive statistics. Results: Scotland registered 370 deaths in 2004–2020; 366 of these occurred in 2015–2020: most involved males (77.1%); mean age 39.0 (SD 12.6) years. The principal underlying cause of death was accidental poisoning: opiates/opioids (77.9%); sedatives/hypnotics (15.0%). Two deaths involved alprazolam alone. Main drug groups implicated: opiates/opioids (94.8%), ‘other benzodiazepines’ (67.2%), gabapentinoids (42.9%), stimulants (30.1%), antidepressants (15.0%). Two-thirds (64.2%) involved combinations of central nervous system (CNS) depressants. Discussion: Alprazolam-related deaths are likely due to an increasing illicit supply. The fall in deaths in 2019–2020 is partially due to increased use of designer benzodiazepines. Treatment for alprazolam dependence is growing. Clinicians need to be aware of continuing recreational alprazolam use. When such consumption occurs with CNS depressants, overdose and death risks increase. Conclusions: More awareness of alprazolam contributing to deaths, especially in conjunction with other CNS depressants, is needed by consumers and clinicians. Improved monitoring of illicit supplies could identify emerging issues of medicines’ abuse.
Design and analysis of cluster randomized trials with time‐to‐event outcomes under the additive hazards mixed model

A primary focus of current methods for cluster randomized trials (CRTs) has been for continuous, binary, and count outcomes, with relatively less attention given to right‐censored, time‐to‐event outcomes. In this article, we detail considerations for sample size requirement and statistical inference in CRTs with time‐to‐event outcomes when the intervention effect parameter is specified through the additive hazards mixed model (AHMM), which includes a frailty term to explicitly account for the dependency between the failure times. First, we discuss improved inference for the treatment effect parameter via bias‐corrected sandwich variance estimators and randomization‐based test under AHMM, addressing potential small‐sample biases in CRTs. Next, we derive a new sample size formula for AHMM analysis of CRTs accommodating both equal and unequal cluster sizes. When the cluster sizes vary, our sample size formula depends on the mean and coefficient of variation of cluster sizes, based on which we articulate the impact of cluster size variation in CRTs with time‐to‐event outcomes. Furthermore, we obtain the insight that the classical variance inflation factor for CRTs with a non‐censored outcome can in fact apply to CRTs with a time‐to‐event outcome, providing that an appropriate definition of the intraclass correlation coefficient is considered under AHMM. Simulation studies are carried out to illustrate key design and analysis considerations in CRTs with a small to moderate number of clusters. The proposed sample size procedure and analytical methods are further illustrated using the context of the STrategies to Reduce Injuries and Develop Confidence in Elders CRT.