Ancient Sheep Genomes reveal four Millennia of North European Short-Tailed Sheep in the Baltic Sea region.

Sheep are among the earliest domesticated livestock species, with a wide variety of breeds present today. However, it remains unclear how far back this diversity goes, with formal documentation only dating back a few centuries. North European short-tailed (NEST) breeds are often assumed to be among the oldest domestic sheep populations, even thought to represent relicts of the earliest sheep expansions during the Neolithic period reaching Scandinavia less than 6000 years ago. This study sequenced the genomes (up to 11.6X) of five sheep remains from the Baltic islands of Gotland and Åland, dating from Late Neolithic (∼4100 calBP) to historical times (∼1600 CE). Our findings indicate that these ancient sheep largely possessed the genetic characteristics of modern NEST breeds, suggesting a substantial degree of long-term continuity of this sheep type in the Baltic Sea region. Despite the wide temporal spread, population genetic analyses show high levels of affinity between the ancient genomes and they also exhibit relatively high genetic diversity when compared to modern NEST breeds, implying a loss of diversity in most breeds during the last centuries associated with breed formation and recent bottlenecks. Our results shed light on the development of breeds in Northern Europe specifically as well as the development of genetic diversity in sheep breeds, and their expansion from the domestication center in general.

NKG2C+CD57+ natural killer with senescent features cells are induced in cutaneous leishmaniasis and accumulate in patients with lesional healing impairment.

Natural killer (NK) cells include different subsets with diverse effector capacities that are poorly understood in the context of parasitic diseases. Here, we investigated inhibitory and activating receptor expression on NK cells in patients with cutaneous leishmaniasis (CL) and explored their phenotypic and functional heterogeneity based on CD57 and NKG2C expression. The expression of CD57 identified NK cells that accumulated in CL patients and exhibited features of senescence. The CD57+ cells exhibited heightened levels of the activating receptor NKG2C and diminished expression of the inhibitory receptor NKG2A. RNA sequencing analyses based on NKG2C transcriptome have revealed two distinct profiles among CL patients associated with cytotoxic and functional genes. The CD57+NKG2C+ subset accumulated in the blood of patients and presented conspicuous features of senescence, including the expression of markers such as p16, yH2ax, and p38, as well as reduced proliferative capacity. In addition, they positively correlated with the number of days until lesion resolution. This study provides a broad understanding of the NK cell biology during Leishmania infection and reinforces the role of senescent cells in the adverse clinical outcomes of cutaneous leishmaniasis.

Population Genomic History of the Endangered Anatolian and Cyprian Mouflons in Relation to Worldwide Wild, Feral, and Domestic Sheep Lineages.

Once widespread in their homelands, the Anatolian mouflon (Ovis gmelini anatolica) and the Cyprian mouflon (Ovis gmelini ophion) were driven to near extinction during the 20th century and are currently listed as endangered populations by the International Union for Conservation of Nature. While the exact origins of these lineages remain unclear, they have been suggested to be close relatives of domestic sheep or remnants of proto-domestic sheep. Here, we study whole genome sequences of n = 5 Anatolian mouflons and n = 10 Cyprian mouflons in terms of population history and diversity, comparing them with eight other extant sheep lineages. We find reciprocal genetic affinity between Anatolian and Cyprian mouflons and domestic sheep, higher than all other studied wild sheep genomes, including the Iranian mouflon (O. gmelini). Studying diversity indices, we detect a considerable load of short runs of homozygosity blocks (<2 Mb) in both Anatolian and Cyprian mouflons, reflecting small effective population size (Ne). Meanwhile, Ne and mutation load estimates are lower in Cyprian compared with Anatolian mouflons, suggesting the purging of recessive deleterious variants in Cyprian sheep under a small long-term Ne, possibly attributable to founder effects, island isolation, introgression from domestic lineages, or differences in their bottleneck dynamics. Expanding our analyses to worldwide wild and feral Ovis genomes, we observe varying viability metrics among different lineages and a limited consistency between viability metrics and International Union for Conservation of Nature conservation status. Factors such as recent inbreeding, introgression, and unique population dynamics may have contributed to the observed disparities.

Tumor-treating fields dosimetry in glioblastoma: Insights into treatment planning, optimization, and dose-response relationships.

Tumor-treating fields (TTFields) are currently a Category 1A treatment recommendation by the US National Comprehensive Cancer Center for patients with newly diagnosed glioblastoma. Although the mechanism of action of TTFields has been partly elucidated, tangible and standardized metrics are lacking to assess antitumor dose and effects of the treatment. This paper outlines and evaluates the current standards and methodologies in the estimation of the TTFields distribution and dose measurement in the brain and highlights the most important principles governing TTFields dosimetry. The focus is on clinical utility to facilitate a practical understanding of these principles and how they can be used to guide treatment. The current evidence for a correlation between TTFields dose, tumor growth, and clinical outcome will be presented and discussed. Furthermore, we will provide perspectives and updated insights into the planning and optimization of TTFields therapy for glioblastoma by reviewing how the dose and thermal effects of TTFields are affected by factors such as tumor location and morphology, peritumoral edema, electrode array position, treatment duration (compliance), array "edge effect," electrical duty cycle, and skull-remodeling surgery. Finally, perspectives are provided on how to optimize the efficacy of future TTFields therapy.

A Systematic Review and Meta-Analysis of the Effects of Various Sources and Amounts of Copper on Nursery Piglets.

This study evaluated the impact of different dietary levels and sources of copper on the growth performance of nursery piglets through a combination of systematic review and meta-analysis. The database for this study was created using articles selected from major electronic databases. Data analysis involved forest plots and analysis of variance using mixed-effects models. The database included 63 articles published between 1990 and 2021, comprising 21,113 piglets in 946 treatments. Positive effects of supranutritional levels of copper from both inorganic and organic sources on the growth performance of nursery piglets were detected using Forest plots and analysis of variance (p < 0.001). Using mixed models, it was observed that piglet performance is influenced by body weight (p < 0.001), age (p < 0.001), and copper intake (p < 0.001). Both organic and inorganic sources of copper at supranutritional levels (>81 mg Cu/kg of diet) improved the performance of nursery piglets, but levels higher than 201 mg Cu/kg of diet did not further improve growth performance compared to 80-200 mg Cu/kg of diet. The feed conversion was worse in piglets fed with inorganic Cu sources (p < 0.001). In conclusion, dietary Cu supplementation influenced the weight gain and feed conversion rate in weaned piglets, particularly during the first few weeks post-weaning. Levels of 81 and 200 mg Cu/kg improved growth performance, but no further benefits were obtained for higher levels.

Non-fungible tokens in healthcare: a scoping review.

Introduction: Non-Fungible Tokens (NFTs) are digital assets that are verified using blockchain technology to ensure authenticity and ownership. NFTs have the potential to revolutionize healthcare by addressing various issues in the industry. Method: The goal of this study was to identify the applications of NFTs in healthcare. Our scoping review was conducted in 2023. We searched the Scopus, IEEE, PubMed, Web of Science, Science Direct, and Cochrane scientific databases using related keywords. The article selection process was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: After applying inclusion and exclusion criteria, a total of 13 articles were chosen. Then extracted data was summarized and reported. The most common application of NFTs in healthcare was found to be in health data management with 46% frequency, followed by supply chain management with 31% frequency. Furthermore, Ethereum is the main blockchain platform that is applied in NFTs in healthcare with 70%. Discussion: The findings from this review indicate that the NFTs that are currently used in healthcare could transform it. Also, it appears that researchers have not yet investigated the numerous potentials uses of NFTs in the healthcare field, which could be utilized in the future.

Demographic reconstruction of the Western sheep expansion from whole-genome sequences.

As one of the earliest livestock, sheep (Ovis aries) were domesticated in the Fertile Crescent about 12,000-10,000 years ago and have a nearly worldwide distribution today. Most of our knowledge about the timing of their expansions stems from archaeological data but it is unclear how the genetic diversity of modern sheep fits with these dates. We used whole-genome sequencing data of 63 domestic breeds and their wild relatives, the Asiatic mouflon (O. gmelini, previously known as O. orientalis), to explore the demographic history of sheep. On the global scale, our analysis revealed geographic structuring among breeds with unidirectional recent gene flow from domestics into Asiatic mouflons. We then selected 4 representative breeds from Spain, Morocco, the United Kingdom, and Iran to build a comprehensive demographic model of the Western sheep expansion. We inferred a single domestication event around 11,000 years ago. The subsequent westward expansion is dated to approximately 7,000 years ago, later than the original Neolithic expansion of sheep and slightly predating the Secondary Product Revolution associated with wooly sheep. We see some signals of recent gene flow from an ancestral population into Southern European breeds which could reflect admixture with feral European mouflon. Furthermore, our results indicate that many breeds experienced a reduction of their effective population size during the last centuries, probably associated with modern breed development. Our study provides insights into the complex demographic history of Western Eurasian sheep, highlighting interactions between breeds and their wild counterparts.

Monitoring bacterial composition and assemblage in the Gulf of Corcovado, southern Chile: Bacteria associated with harmful algae.

Harmful Algal Blooms (HABs) have caused damage to the marine environment in Isla San Pedro in the Gulf of Corcovado, Chile. While rising water temperature and artificial eutrophication are the most discussed topics as a cause, marine bacteria is a recent attractive parameter as an algal bloom driver. This study monitored algal and bacterial compositions in the water of Isla San Pedro for one year using microscopy and 16S rRNA metabarcoding analysis, along with physicochemical parameters. The collected data were analyzed with various statistical tools to understand how the particle-associated bacteria (PA) and the free-living (FL) bacteria were possibly involved in algal blooms. Both FL and PA fractions maintained a stable bacterial composition: the FL fraction was dominated by Proteobacteria (α-Proteobacteria and γ-Proteobacteria), and Cyanobacteria dominated the PA fraction. The two fractions contained equivalent bacterial taxonomic richness (c.a. 8,000 Operational Taxonomic Units) and shared more than 50% of OTU; however, roughly 20% was exclusive to each fraction. The four most abundant algal genera in the Isla San Pedro water were Thalassiosira, Skeletonema, Chaetoceros, and Pseudo-nitzchia. Statistical analysis identified that the bacterial species Polycyclovorans algicola was correlated with Pseudo-nitzschia spp., and our monitoring data recorded a sudden increase of particle-associated Polycyclovorans algicola shortly after the increase of Pseudo-nitzschia, suggesting that P. algicola may have regression effect on Pseudo-nitzschia spp. The study also investigated the physicochemical parameter effect on algal-bacterial interactions. Oxygen concentration and chlorophyll-a showed a strong correlation with both FL and PA bacteria despite their assemblage differences, suggesting that the two groups had different mechanisms for interacting with algal species.

An Approach to Canonical Correlation Analysis Based on Rényi's Pseudodistances.

Canonical Correlation Analysis (CCA) infers a pairwise linear relationship between two groups of random variables, X and Y. In this paper, we present a new procedure based on Rényi's pseudodistances (RP) aiming to detect linear and non-linear relationships between the two groups. RP canonical analysis (RPCCA) finds canonical coefficient vectors, a and b, by maximizing an RP-based measure. This new family includes the Information Canonical Correlation Analysis (ICCA) as a particular case and extends the method for distances inherently robust against outliers. We provide estimating techniques for RPCCA and show the consistency of the proposed estimated canonical vectors. Further, a permutation test for determining the number of significant pairs of canonical variables is described. The robustness properties of the RPCCA are examined theoretically and empirically through a simulation study, concluding that the RPCCA presents a competitive alternative to ICCA with an added advantage in terms of robustness against outliers and data contamination.

Lumbar trans-spinal direct current stimulation: A modeling-experimental approach to dorsal root ganglia stimulation.

Introduction: The excitability of spinal motor neurons (MN) can be altered through subthreshold currents, such as transcutaneous spinal direct-current stimulation (tsDCS). Current evidence shows that tsDCS can interfere with ascending somatosensory pathways and lower motor neurons' (LMN) excitability, which points to its therapeutic potential for repairing altered spinal responses. We aim to define the best tsDCS montage for maximizing the electric field (E-field) in the lumbar spinal cord (L-SC) by computer modeling; and to apply this montage to measure the effect on LMN excitability and somatosensory evoked potentials (SSEP). Methods: A human volume conductor model was obtained from an available database. The E-field distribution was calculated considering three different electrode settings aiming at maximizing the field at L-SC and right dorsal root ganglia (DRG). The best electrode setting was then selected and applied in a blind crossover pseudo-randomized study including 14 subjects. tsDCS was delivered for 15 min (cathodal vs. sham) over L2 vertebra level (4 mA, 144 mC/cm2), and its effect on F-waves, H-reflex (including homosynaptic depression, HD) and SSEPs was investigated in the lower limbs. Results: All simulated montages showed higher current density and E-field magnitudes between the electrodes (>0.15 V/m), with a major longitudinal component and with rostral-caudal direction. The induced E-field involved the sensory ganglia and was maximum in the right T8-left L2 montage, which was the one selected for the experimental protocol. We disclosed a statistically significant increase of the H-reflex amplitude at 0.1 Hz, after cathodal tsDCS (c-tsDCS) on both sides. No other significant change was observed. Discussion: Our results can suggest the c-tsDCS applied to the L-SC and DRG can modulate synaptic efficiency increasing lower motor neurons response to Ia fibers excitation. The possible implications of our findings for treating clinical conditions will be addressed in future studies.

How the Number and Distance of Electrodes Change the Induced Electric Field in the Cortex during Multichannel tDCS.

Multichannel transcranial direct current stimulation (tDCS) is a promising approach to target neuromodulation of neural networks by making use of variable number of electrodes and distances to facilitate/inhibit specific connectivity patterns. Optimization of the electric field (EF) spatial distribution through computational models can provide a more accurate definition of the stimulation settings that are more effective. In this study, we investigate the effect of increasing the number of cathodes around a central anode placed over the target. We demonstrate that anode-cathode distance has the largest influence in the EF and using more than 3 cathodes did not result in considerable changes in the EF magnitude and direction. This could be relevant for simultaneous tDCS-electroencephalography (EEG) applications, by saving electrode positions for EEG acquisition. Clinical Relevance- This study demonstrates that distance between electrodes is more relevant than electrode number in determining the electric field distribution, and that a highly-focused stimulation can be equally effective with fewer electrodes.

Temperature and Impedance Variations During Tumor Treating Fields (TTFields) Treatment.

Tumor Treating Fields (TTFields) is an FDA-approved cancer treatment technique used for glioblastoma multiforme (GBM). It consists in the application of alternating (100-500 kHz) and low-intensity (1-3 V/cm) electric fields (EFs) to interfere with the mitotic process of tumoral cells. In patients, these fields are applied via transducer arrays strategically positioned on the scalp using the NovoTAL™ system. It is recommended that the patient stays under the application of these fields for as long as possible. Inevitably, the temperature of the scalp increases because of the Joule effect, and it will remain above basal values for most part of the day. Furthermore, it is also known that the impedance of the head changes throughout treatment and that it might also play a role in the temperature variations. The goals of this work were to investigate how to realistically account for these increases and to quantify their impact in the choice of optimal arrays positions using a realistic head model with arrays positions obtained through NovoTAL™. We also studied the impedance variations based on the log files of patients who participated in the EF-14 clinical trial. Our computational results indicated that the layouts in which the arrays were very close to each other led to the appearance of a temperature hotspot that limited how much current could be injected which could consequently reduce treatment efficacy. Based on these data, we suggest that the arrays should be placed at least 1 cm apart from each other. The analysis of the impedance showed that the variations seen during treatment could be explained by three main factors: slow and long-term variations, array placement, and circadian rhythm. Our work indicates that both the temperature and impedance variations should be accounted for to improve the accuracy of computational results when investigating TTFields.

Biogeographic Variation and Functional Pathways of the Gut Microbiota in Celiac Disease.

BACKGROUND & AIMS: Genes and gluten are necessary but insufficient to cause celiac disease (CeD). Altered gut microbiota has been implicated as an additional risk factor. Variability in sampling site may confound interpretation and mechanistic insight, as CeD primarily affects the small intestine. Thus, we characterized CeD microbiota along the duodenum and in feces and verified functional impact in gnotobiotic mice. METHODS: We used 16S rRNA gene sequencing (Illumina) and predicted gene function (PICRUSt2) in duodenal biopsies (D1, D2 and D3), aspirates, and stool from patients with active CeD and controls. CeD alleles were determined in consented participants. A subset of duodenal samples stratified according to similar CeD risk genotypes (controls DQ2-/- or DQ2+/- and CeD DQ2+/-) were used for further analysis and to colonize germ-free mice for gluten metabolism studies. RESULTS: Microbiota composition and predicted function in CeD was largely determined by intestinal location. In the duodenum, but not stool, there was higher abundance of Escherichia coli (D1), Prevotella salivae (D2), and Neisseria (D3) in CeD vs controls. Predicted bacterial protease and peptidase genes were altered in CeD and impaired gluten degradation was detected only in mice colonized with CeD microbiota. CONCLUSIONS: Our results showed luminal and mucosal microbial niches along the gut in CeD. We identified novel microbial proteolytic pathways involved in gluten detoxification that are impaired in CeD but not in controls carrying DQ2, suggesting an association with active duodenal inflammation. Sampling site should be considered a confounding factor in microbiome studies in CeD.

How to correctly estimate the electric field in capacitively coupled systems for tissue engineering: a comparative study.

Capacitively Coupled (CCoupled) electric fields are used to stimulate cell cultures in Tissue Engineering. Knowing the electric field (E-Field) magnitude in the culture medium is fundamental to establish a relationship between stimulus strength and cellular effects. We analysed eight CCoupled studies and sought to corroborate the reported estimates of the E-Field in the culture medium. First, we reviewed the basic physics underlying CCoupled stimulation and delineated three approaches to estimate the E-field. Using these approaches, we found that the reported values were overestimated in five studies, four of which were based on incorrect assumptions. In all studies, insufficient information was provided to reproduce the setup exactly. Creating electrical models of the experimental setup should improve the accuracy of the E-field estimates and enhance reproducibility. For this purpose, we developed a free open-source tool, the E-field Calculator for CCoupled systems, which is available for download from an internet hosting platform.

Breast Implant-Associated Anaplastic Large Cell Lymphoma: Two Distinct Clinical Presentations.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare CD30 positive T cell lymphoma whose incidence has recently increased. Until 2020, 733 cases of BIA-ALCL and 36 deaths have been reported around the world, with only one confirmed case in Portugal. The authors describe two clinical cases of BIA-ALCL after breast cancer reconstruction using macrotextured implants. Case 1: A 45-year-old patient, who presented with a typical late-onset seroma five years after breast reconstruction and underwent capsulectomy, confirming localized disease to the capsule. Case 2: A 43-year-old patient presented with an atypical presentation of pleural effusion and tumor mass, 14 years after reconstruction. She underwent implant removal and chemotherapy, due to metastatic disease. These clinical cases illustrate two very distinct clinical presentations of BIA-ALCL. Early diagnosis of this entity allows for effective treatment of the disease, which should be approached in a multidisciplinary setting.

O linfoma anaplásico de grandes células associado aos implantes mamários é um linfoma T CD30 positivo raro, cuja incidência tem aumentado recentemente. Até 2020, estavam registados 733 casos de BIA-ALCL e 36 mortes, em todo o mundo e apenas um caso confirmado em Portugal. Os autores descrevem dois casos de BIA-ALCL, após reconstrução mamária por cancro de mama, com próteses macrotexturadas. Caso 1: Doente com 45 anos, que se apresentou com a manifestação típica de seroma tardio, cinco anos após a colocação da prótese, tendo sido submetida a capsulectomia, que confirmou doença localizada à cápsula. Caso 2: Doente de 43 anos, que se manifestou de forma atípica com derrame pleural e massa tumoral, 14 anos após a colocação da prótese. A doente foi submetida a remoção de prótese e quimioterapia, tendo em conta a doença metastática. Os casos clínicos descritos ilustram duas formas distintas de apresentação clínica de BIA-ALCL. O diagnóstico precoce desta patologia possibilita o seu tratamento de forma eficaz e deve ser abordado em equipa multidisciplinar.

Robust Test Statistics Based on Restricted Minimum Rényi's Pseudodistance Estimators.

The Rao's score, Wald and likelihood ratio tests are the most common procedures for testing hypotheses in parametric models. None of the three test statistics is uniformly superior to the other two in relation with the power function, and moreover, they are first-order equivalent and asymptotically optimal. Conversely, these three classical tests present serious robustness problems, as they are based on the maximum likelihood estimator, which is highly non-robust. To overcome this drawback, some test statistics have been introduced in the literature based on robust estimators, such as robust generalized Wald-type and Rao-type tests based on minimum divergence estimators. In this paper, restricted minimum Rényi's pseudodistance estimators are defined, and their asymptotic distribution and influence function are derived. Further, robust Rao-type and divergence-based tests based on minimum Rényi's pseudodistance and restricted minimum Rényi's pseudodistance estimators are considered, and the asymptotic properties of the new families of tests statistics are obtained. Finally, the robustness of the proposed estimators and test statistics is empirically examined through a simulation study, and illustrative applications in real-life data are analyzed.