The case report by Navarro-Lopez et al., (2023) in this issue describes a thorough differential diagnosis in an equine with acute neurological disease. Rabies was confirmed by direct fluorescent antibody test (DFA). Rabies virus (RABV) was isolated from brain tissue of the ill mare by intracerebral inoculation in sucking mice. Sequencing and phylogenetic inference allowed the identification of the rabies virus variant (RVV) associated with this case. Thus, Navarro-Lopez et al., reported that the rabid mare got infected with a rabies virus variant associated with skunks. This clinical commentary elaborates on the seemingly rare skunk rabies across North America (NA) highlighting its relevance in human and animal health that have remained somehow neglected

Previous studies have established the association of sex with gene and protein expression. This study investigated the association of sex with the abundance of endogenous urinary peptides, using capillary electrophoresis-coupled to mass spectrometry datasets from 2008 healthy individuals and patients with type II diabetes, divided in one discovery and two validation cohorts. Statistical analysis using the Mann-Whitney test, adjusted for multiple testing, revealed 143 sex-associated peptides in the discovery cohort. Of these, 90 peptides were associated with sex in at least one of the validation cohorts and showed agreement in their regulation trends across all cohorts. The 90 sex-associated peptides were fragments of 29 parental proteins. Comparison with previously published transcriptomics data demonstrated that the genes encoding 16 of these parental proteins had sex-biased expression. The 143 sex-associated peptides were combined into a support vector machine-based classifier that could discriminate males from females in two independent sets of healthy individuals and patients with type II diabetes, with an AUC of 89% and 81%, respectively. Collectively, the urinary peptidome contains multiple sex-associated differences, which may enable a better understanding of sex-biased molecular mechanisms and the development of more accurate diagnostic, prognostic or predictive classifiers for each individual sex.

Variation in fitness components can be linked in some cases to variation of key traits. Metric traits that lie at the intersection of development, defense, and ecological interactions may be expected to experience strong environmental selection, informing our understanding of evolutionary and ecological processes. Here, we use quantitative genetic and population genomic methods to investigate disease dynamics in hybrid and non-hybrid populations. We focus our investigation on morphological and ecophysiological traits which inform our understanding of physiology, growth, and defense against a pathogen. In particular, we investigate stomata, microscopic pores on the surface of a leaf which regulate gas exhange during photosynthesis and are sites of entry for various plant pathogens. Stomatal patterning traits were highly predictive of disease risk. Admixture mapping identified a polygenic basis of disease resistance. Candidate genes for stomatal and disease resistance map to the same genomic regions, and are experienceing positive selection. Genes with functions for guard cell homeostasis, the plant immune system, components of constitutive defenses, and growth related transcription factors were identified. Our results indicate positive selection is filtering genetic variance from one of the parental species maladpated to a novel pathogen, and changing suites of stomatal traits which contribute to disease variation in natural populations.

INTRODUCTIONCharles Bonnet Syndrome(CBS) was first described in 1760 by Naturalist and philosopher Charles Bonnet, who first observed lifelike complex visual hallucinations in his grandfather Charles Lullis after bilateral cataract surgery(1); it was a neurologist George de Morsier who coined the term in 1938 after Charles Bonnet himself developed the condition(2). CBS, also known as ”phantom image”, is characterized by recurrent or persistent complex visual hallucinations in people with a disease of the visual system with intact insight, intellectual function and normal cognitive functioning without primary psychiatric disorders(3,4). With limited knowledge of CBS among physicians, the prevalence of CBS is underreported(4) even though 41-59% of the visually impaired experience elementary visual phenomena, and 11-15% exhibit complex hallucinations, due to a medical condition or artificially produced, such as in preparation for cataract surgery(5,6). The presence of varying inclusion criteria, inconsistent depth of questioning and limited patient disclosure for fear of being ridiculed may all contribute to underreporting(3,5). Visual hallucinations could be a sign of psychiatric disorders, neurological diseases, metabolic abnormalities, and the use or abuse of specific drugs(7). Both elementary forms(3) and complex visual hallucinations are reported in CBS(8); while glaucoma,cataract and age-related macular degeneration are the most common associated disorders, any ophthalmological conditions can lead to CBS(7), especially in significant visual impairment(9). A pituitary adenoma is rarely associated with CBS (10); however, reduced visual acuity or a visual field deficit can occur from the benign tumour’s compressing optic chiasm affecting one or both eyes(11).There are three main theories associated with the pathogenesis of CBS, and these are; the sensory deprivation or deafferentiation theory related to spontaneous excitation due to a loss of visual input to the brain(12), the release theory associated with excessive excitation and the consequent release of visual hallucinations(13,14), and the ”irritative theory” due to distal provocative injuries transmit abnormal input to the visual cortex leading to abnormal excitatory activity to the temporal and occipital lobes(15,16).Charles Bonnet syndrome is treated multifacetedly with pharmacotherapy, psychosocial therapy, maintaining appropriate eye care, and sensory stimulation. Generally, CBS is treated with antipsychotics and antidepressants(5), and in some cases, antiepileptic medications have also been used with variable benefits (17).An 81-year-old blind male presented with a three-year history of visual hallucinations after a recurrence of pituitary macroadenoma. His past psychiatric history is uneventful, and he has intact insight with no cognitive impairment. He improved on a low haloperidol dosage, with a few relapses, when he stops the medications.

Fermentation monitoring is a powerful tool for bioprocess development and optimisation. On-line metabolomics is a technology that is starting to gain attention as a bioprocess monitoring tool, allowing the direct measurement of many compounds in the fermentation broth at a very high time resolution. In this work, targeted on-line metabolomics was used to monitor 40 metabolites of interest during three Escherichia coli succinate production fermentation experiments every 5 minutes with a triple quadrupole mass spectrometer. This allowed capturing high time resolution biological data that can provide critical information for process optimisation. For 9 of these metabolites, simple univariate regression models were used to model compound concentration from their on-line mass spectrometry peak area. These on-line metabolomics univariate models performed comparably to vibrational spectroscopy multivariate PLS regressions models reported in the literature, which typically are much more complex and time consuming to build. In conclusion, this work shows how on-line metabolomics can be used to directly monitor many bioprocess compounds of interest and obtain rich biological and bioprocess data.

Background Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life (EHL) factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients ≥12 years of age. Aim Assess the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real world data. Methods We collected prospective and retrospective data from patients with haemophilia B (FIX activity level ≤5 IU/dL) treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kingdom (UK)-EHL Outcome Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A novel population PK model was constructed using nonlinear mixed-effects modelling. Results Real world data was obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were <12 years of age. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error (PE) of -48.8%. The novel model showed a lower median PE (3.4%) and better described rFIX-Fc PK, especially for children <12 years of age. In the novel model, an increase in age was correlated with a decrease in clearance (p<0.01). Conclusion The published population PK model significantly underpredicted FIX activity levels. The novel model better describes rFIX-Fc PK, especially for children <12 years of age. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.

Numerous biodiversity–ecosystem functioning (BEF) experiments have shown that plant community productivity typically increases with species diversity. In these studies, diversity is generally quantified using metrics of taxonomic, phylogenetic, or functional differences among community members. Research has also shown that the relationships between species diversity and functioning depends on the spatial scale considered, primarily because larger areas may contain different ecosystem types and span gradients in environmental conditions, which result in a turnover of the species set present locally. A fact that has received little attention, however, is that ecological systems are hierarchically structured, from genes to individuals to communities to entire landscapes, and that additional biological variation occurs at levels of organization above and below those typically considered in BEF research. Here, we present cases of diversity effects at different hierarchical levels of organization and compare these to the species-diversity effects traditionally studied. We argue that when this evidence is combined across levels, a general framework emerges that allows the transfer of insights and concepts between traditionally disparate disciplines. Such a framework presents an important step towards a better understanding of the functional importance of diversity in complex, real-world systems.

By multiplying with the continuous factor (CF), the conventional Class- F / F - 1 , Class-J power amplifier (PA) can be expanded to their corresponding continuous modes, resulting in a great degree of freedom for broadband design. However, this method can hardly apply to other types of PAs. In view of this problem, the continuous mode is deeply analyzed from the perspective of equation solving for the first time, and a general theory for high-efficiency broadband continuous PA design is proposed. In this theory, the continuous impedance space does not rely on a mapping relationship achieved by multiplying with the CF, but on a direct solution of the high-efficiency equations to obtain the broadband design space. This approach is simpler and has the potential to provide greater design space. As a validation, this theory is used for the analysis of Class-E PAs and a new continuous Class-E (NC-E) PA is presented. With knee-point voltage and finite harmonics taken into account, this type of PA greatly expands the broadband design space of Class-E PAs, and also has the advantage of harmonic matching. The NC-E PA is designed and manufactured using GaN HEMT CGH40010F, which achieves 40.6∼41.6dBm output power and 66.2%∼74.2% drain efficiency (DE) in the frequency band of 2.5-3.8GHz.

Variable supply voltage-clustered voltage scaling (VS-CVS) is an effective way to decrease power consumption without compromising performance. One of the major challenges in VS-CVS design is that level converting flip-flops(LCFFs) not only need to have low power consumption but also high performance. In this paper, we propose two new structures of LCFF: the data branch sharing LCFF based on conditional charging (DBS-LCFFCC) and the data branch sharing LCFF based on precharging (DBS-LCFFP).The new structures adopt a data branch sharing scheme to improve the speed of the circuit as well as to reduce the number of transistors. Based on simulation results using HSPICE with PTM 32nm CMOS technology, the proposed LCFFs show an improvement of 19.2% to 67.2% and 41.6% to 76.3% in power-delay-product (PDP) at 50% data switching activity, respectively, compared to other advanced LCFFs.

In this paper, for standalone and grid-connected PV systems, a three-phase simplified split-source inverter (SSI) is proposed and controlled using a model-predictive control (MPC). The maximum power point tracking (MPPT) approach used is an incremental conductance method based on a PI controller for both systems. The standalone system is composed of PV modules, a three-phase SSI, and a bidirectional power DC-DC converter that connects a battery bank and a DC-side capacitor. The output AC voltages of SSI are controlled using model-predictive control. The bidirectional power DC/DC converter regulates the DC-link voltage (DCLV). The grid-connected system consists of PV modules, a three-phase SSI, and an AC-side L-filter. The DC-link PI controller generates reference currents for the MPC algorithm. The MPC uses these reference currents to adjust and deliver the PV power to the grid while regulating the DCLV. The PI controllers’ parameters are selected for both systems using the Harris Hawks optimization method. Both PV systems simulation results show that under various operating conditions, they have succeeded in fixing a DCLV and producing a high-quality AC output voltage and current at low THD. Experimental results for the three-phase standalone PV system used to verify the system’s performance.

Monitoring population dynamics is of fundamental importance in conservation but assessing trends in abundance can be costly, especially in large and rough areas. Obtaining trend estimations from counts performed in only a portion of the total area (sample counts) can be a cost-effective method to improve the monitoring and conservation of species difficult to count. We tested the effectiveness of sample counts in monitoring population trends of wild animals, using as a model population the Alpine ibex (Capra ibex) in Gran Paradiso National Park (Italy), both with computer simulations and using historical census data collected over the last 65 years. Despite sample counts could fail to correctly estimate the true population abundance, sampling half of the target area could reliably monitor the trend of the target population. In case of strong changes in abundance, an even lower proportion of the total area could be sufficient to identify the direction of the population trend. However, when there is a high yearly trend variability, the required number of samples increases and even counting in the entire area can be ineffective to monitor population dynamics. Lastly, the effect of other parameters (such as which portion of the area is sampled or the detectability) was marginal, but these should be tested case by case. Sample counts could therefore constitute a viable alternative to assess population trends, allowing for important, cost-effective improvements in the monitoring of wild animals of conservation interest.

Teduglutide in Amyloidosis-associated Intestinal FailureClara Luhn§(1), Hermine Agis§(2), Elisabeth Hütterer(3), Ingrid Simonitsch-Klupp(4), Christopher Dawoud(1), Anton Stift(1), Felix Harpain(1)(1) Department of Surgery, Division of General Surgery, Medical University Vienna, Austria(2) Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria(3) Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, Austria(4) Department of Pathology, Medical University of Vienna, Austria§ contributed equally

IntroductionCarotidodynia or Fay’ syndrome is characterized as neck pain near the carotid bifurcation (1). Three main differential diagnoses can be responsible for carotidodynia : carotid dissection, cervical osteoarthritis and large vessel vasculitis ie Takayasu disease, giant cell arteritis. The definition of carotidodynia has evolved in the past century: initially classified in the International Classification of Headache Disorders (ICHD) in 1988 and then declassified due to unspecific clinical signs in 2004 (2).Over the last decade, reports of perivascular inflammation of the carotid artery have been described in patients with neck pain called TIPIC syndrome: Transient Perivascular Inflammation of the Carotid Artery. The diagnostic criteria for this rare vascular disorder were established by Lecler et al. in 2017 : acute neck pain directly around the level of the carotid bifurcation, eccentric pericarotidian infiltration on imaging, exclusion of another vascular or nonvascular diagnosis with imaging and improvement within 14 days either spontaneously or with anti-inflammatory treatment (1). A recent multicenter retrospective study of 72 patients with TIPIC syndrome confirmed the benign nature of this disorder and that recurrence may occur in up to 20% of cases (Micieli E et al. Transient perivascular inflammation of the carotid artery (TIPIC) syndrome; Vasa 2022). However, TIPIC pathophysiology and triggers remain poorly understood.We report herein the case of a myelodysplastic syndrome (MDS) patient with granulocyte colony stimulating factor (GCSF) induced TIPIC syndrome.

The question of why socially monogamous females engage in extra-pair behaviour is long-standing in evolutionary biology. Recent theoretical work has moved away from the indirect-benefits hypothesis to explain female extra-pair behaviours, instead favouring suggestions that they are the result of pleiotropic effects. That is, a trait under strong positive selection in either or both sexes are genetically linked to another, often unrelated, trait. For example, where genes beneficial to female fecundity (contributing to within-pair solicitation of her social partner) are linked with extra-pair behaviour (soliciting copulations from extra-pair males). Here, we test two predictions from this hypothesis: We test the prediction that female divorce, measured from the number of social mates within a given year, is linked with (1) the number of extra-pair males and (2) the proportion of her offspring that are extra-pair. Our results suggest that females who frequently divorce social partners are more likely to produce extra-pair offspring than those who maintain social monogamy. However, by contrast, those females do not also have a higher proportion of extra-pair offspring. The number of broods initiated was also positively correlated with extra-pair males, probably through increased opportunity for extra-pair males to sire offspring over a longer breeding season. Our results provide an empirical example of a behavioural trait, beneficial to female fecundity, that is linked with extra-pair behaviour. These empirical results support the intrasexual pleiotropy hypothesis as a driver of female extra-pair behaviour.

The results of tertiary structure assessment at CASP15 are reported. For the first time, recognising the outstanding performance of AlphaFold 2 (AF2) at CASP14, all single chain predictions were assessed together, irrespective of whether a template was available. At CASP15 there was no single stand-out group, with most of the best-scoring groups - led by PEZYFoldings, UM-TBM and Yang Server - employing AF2 in one way or another. Many top groups paid special attention to generating deep Multiple Sequence Alignments (MSAs) and testing variant MSAs, thereby allowing them to successfully address some of the hardest targets. Such difficult targets, as well as lacking templates, were typically proteins with few homologues: small size, high α-helical content and monomeric structure were other likely aggravating factors. Local divergence between prediction and target correlated with localisation at crystal lattice or chain interfaces, and with regions exhibiting high B-factor factors in crystal structure targets, but should not necessarily be considered as representing error in the prediction. However, analysis of exposed and buried side chain accuracy showed room for improvement even in the latter. Nevertheless, a majority of groups, including those applying methods similar to those used to generate major resources such as the AlphaFold Protein Structure Database and the ESM Metagenomic atlas, produced high quality predictions for most targets which are valuable for experimental structure determination, functional analysis and many other tasks across biology.

Trans-activation response DNA binding protein of 43kDa (TDP-43) regulates a great variety of cellular processes in the nucleus and cytosol. In addition, a defined subset of neurodegenerative diseases is characterized by nuclear depletion of TDP-43 as well as cytosolic mislocalization and aggregation. To perform its diverse functions TDP-43 can associate with different ribonucleoprotein complexes. Combined with transcriptomics, MS interactome studies have unveiled associations between TDP-43 and the spliceosome machinery, polysomes and RNA granules. Moreover, the highly dynamic, low-valency interactions regulated by its low-complexity domain calls for innovative proximity labeling methodologies. In addition to protein partners, the analysis of posttranslational modifications showed that they may play a role in the nucleocytoplasmic shuttling, RNA binding, liquid-liquid phase separation and protein aggregation of TDP-43. Here we review the various TDP-43 ribonucleoprotein complexes characterized so far, how they contribute to the diverse functions of TDP-43, and roles of post-translational modifications. Further understanding of the fluid dynamic properties of TDP-43 in ribonucleoprotein complexes, RNA granules, and self-assemblies will advance the understanding of RNA processing in cells and perhaps help to develop novel therapeutic approaches for TDPopathies.

INTRODUCTION Pheochromocytoma, arising from the chromaffin cells of the adrenal medulla, can cause excessive catecholamines secretion and trigger pheochromocytoma crisis, characterized by high mortality rate up to 13%1. Pheochromocytoma crisis induced catecholaminergic cardiomyopathy may lead to multiple organ system damage or dysfunction, myocardial infarction, acute left ventricular failure, cardiogenic shock, and other fatal outcomes, commonly in undiagnosed or well-controlled pheochromocytoma2. Surgical resection is the primary treatment; however, the instability of perioperative hemodynamics poses a high risk of anesthesia and poses great challenges in treatment3. Currently, research on the diagnosis, treatment, and nursing care of such patients is mainly based on case reports. Veno-arterial extracorporeal membrane oxygenation (VA -ECMO) has been reported to stabilize circulation and extend the surgical window for patients with severe myocardial injury or circulatory failure4. In June 2021, we successfully treated a patient with pheochromocytoma presenting with cardiogenic shock as the first manifestation of multiple organ failure. This case report presents our experience in diagnosis, treatment, and nursing care of pheochromocytoma with various severe complications.

Cause for optimism in mild hypoxic ischaemic hypoxic encephalopathyWilliam M. Curtin, MD, corresponding authorDivision of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology & Pathology and Laboratory Medicine, Penn State College of Medicine, Penn State Health, Milton S. Hershey Medical Center, Hershey, PA, [email protected] code H103500 University Dr, PO Box 850Hershey, PA 17033-0850Maternal-Fetal Medicine, Rm C3620Phone 717-531-8142/Option #5Fax 717-531-0947Acknowledgements: noneDisclosure of Interests: The author has no conflicts nor competing interests to disclose, financial or otherwise, in connection with this manuscript.Contribution to Authorship: Dr. Curtin alone completed review of the Törn et al. final manuscript entitled “Outcomes in children after mild neonatal hypoxic ischaemic encephalopathy: A population-based cohort study” The writings and opinions expressed in his mini commentary are solely the work of Dr. Curtin.Details of Ethics Approval: not applicable at our institution’s IRB as a commentary is not considered research and does not involve human subjects.Funding: Dr. Curtin neither received nor utilized any funds in writing this mini commentary.The objective of the study by Törn et al. was to determine if mild hypoxic ischaemic encephalopathy (HIE) was associated with severe neurological outcomes utilizing a population-based approach facilitated by five linked Swedish national databases. The rationale given was that while moderate to severe HIE is known to be associated with significant neurological morbidity, long-term disability, and mortality in children, less is known about mild HIE. The authors note that half of the cases of HIE are mild and they cite a systematic review of 250 infants (Conway JM, et al. Early human development . 2018; 120:80-7) showing a 22% prevalence of abnormal neurological outcomes in this disorder. There is therefore potential for significant burden of disease in mild HIE. Törn et al. chose a primary composite outcome that included cerebral palsy, epilepsy, mental retardation and death in children with mild HIE and non HIE cohorts followed up to 6 years of age. With a median follow-up of 3.3 years of age, 17 of 414 (4.1%) and 4786 of 504,661 (0.95%), in the mild HIE and non HIE cohorts respectively, had the composite outcome with an adjusted hazard ratio of 3.85 (95% CI: 2.27-6.50)In 1976 Sarnat and Sarnat reported clinical and EEG features of 21 neonates at term who experienced ischaemic-anoxic encephalopathy (Sarnat HB et al. Arch Neurol. 1976; 33:696–705). This temporal classification divided the infants into three progressively deteriorating stages. Fast forward to the current millennium and Sarnat’s original classification is used to differentiate between infants with mild and moderate/severe HIE, the latter two categories benefiting from therapeutic hypothermia (Jacobs SE et al. Cochrane Database Syst Rev. 2013, Issue 1. Art. No.: CD003311). Seven infants with moderate or severe HIE is the number needed to treat (NNT) to prevent one adverse neurological outcome.Therapeutic hypothermia is not standard of care in mild HIE; however, in a survey of neonatal clinicians from 35 countries the vast majority would support a large randomized controlled trial to examine neurodevelopmental outcomes (Singla M, et al. Neonatology. 2022; 119:712-718). The results from this methodical Swedish cohort study provide data that can be used to direct further research. The composite outcomes in HIE are lower than expected, and one could infer similar outcomes in high resource settings. The data are reassuring and will be useful for clinicians in counseling and reassuring parents with infants affected by mild HIE. Regarding a randomized controlled trial of therapeutic hypothermia in mild HIE: it would appear, based on the data provided by Törn et al., if we hypothesize this therapy would result in a 50% reduction in the composite outcome, the NNT would be approximately 50. This compares unfavorably to the NNT of 7 in moderate/severe HIE. Perhaps, further insight could be gained by review of individual patient data, particularly with respect to antenatal and neonatal course, imaging, EEG, and biochemical data in order to identify a subset that might benefit from therapeutic hypothermia or other novel therapy.Word count: 490