Miracle-dz/UniFAR-FTUs huggingface dataset:
A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer

Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade. Patients and Methods: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink. Results: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1–7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3–4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3–5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki-67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood. Conclusions: We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.
The association of milk-solid production during the current lactation with liver damage due to presumptive ingestion of spores from Pithomyces chatarum by dairy cattle

ABSTRACT Aims To determine the association between production of milk solids (MS) and liver damage from facial eczema (FE) in dairy cattle during autumn and to determine the most practical cut-off for serum gamma-glutamyl transferase (GGT) activity in predicting production loss. Methods Farm history and Pithomyces chartarum spore counts identified herds likely to be affected by raised GGT activity in serum during autumn 2018 or 2019. In these herds, a pilot blood sample from 30 cattle was collected, followed by a full herd blood test within 2 weeks if in those 30 cattle one or more had GGT activities >300 IU/L. Individual MS production was measured within −5 – +12 days of a full herd blood test. Information about feeding Brassica spp. was collected from the farmer. Pooled sera from 10 randomly selected cattle from 10/11 farms with GGT >40 IU/L were tested for anti-Fasciola antibodies. Statistical analysis The association of liver damage and production of MS was analysed using mixed linear regression. Potential risk factors included farm, cow age, MS at last herd test before the likely FE risk period, breed of cow and GGT activity. Subsequently, GGT activity thresholds, from 40–400 IU/L, were used to indicate varying severities of liver damage. For each threshold, a mixed linear model using herd test data produced estimated marginal mean differences in MS production for cows above or below threshold. The prevalence of animals above threshold was multiplied by the per cow loss to obtain the reduction in MS/day/100 cows for each cut-off. Results The prevalence of animals with GGT activities > 40 IU/L ranged between farms from 11% (45/488) to 96% (139/145), and GGT activities for individual cows ranged from 3 – 6001 IU/L. From the model, an increase of 100 IU/L in GGT activity was associated with a decrease of 0.011 (95% CI = 0.010–0.012) kg MS/cow/day. A GGT activity threshold of 40 IU/L identified the largest association with MS production of 6.14 kg MS/day/100 cows. No evidence of significant liver fluke or brassica toxicosis was found. Conclusion and clinical relevance Liver damage was most likely caused by sporidesmin toxicity and was associated with substantial linear reduction in MS., When assessing the impact liver damage has on herd milk production, threshold and prevalence of animals exceeding threshold should be considered by the practitioner in assessing economically significant facial eczema.
Enhancement of Photoacoustic Signal Strength with Continuous Wave Optical Pre-Illumination: A Non-Invasive Technique

Use of portable and affordable pulse light sources (light emitting diodes (LED) and laser diodes) for tissue illumination offers an opportunity to accelerate the clinical translation of photoacoustic imaging (PAI) technology. However, imaging depth in this case is limited because of low output (optical) power of these light sources. In this work, we developed a noninvasive technique for enhancing strength (amplitude) of photoacoustic (PA) signal. This is a photothermal-based technique in which a continuous wave (CW) optical beam, in addition to short-pulse ~ nsec laser beam, is employed to irradiate and, thus, raise the temperature of sample material selectively over a pre-specified region of interest (we call the process as pre-illumination). The increase in temperature, in turn enhances the PA-signal strength. Experiments were conducted in methylene blue, which is one of the commonly used contrast agents in laboratory research studies, to validate change in temperature and subsequent enhancement of PA-signal strength for the following cases: (1) concentration or optical absorption coefficient of sample, (2) optical power of CW-optical beam, and (3) time duration of pre-illumination. A theoretical hypothesis, being validated by numerical simulation, is presented. To validate the proposed technique for clinical and/or pre-clinical applications (diagnosis and treatments of cancer, pressure ulcers, and minimally invasive procedures including vascular access and fetal surgery), experiments were conducted in tissue-mimicking Agar phantom and ex-vivo animal tissue (chicken breast). Results demonstrate that pre-illumination significantly enhances PA-signal strength (up to ~70% (methylene blue), ~48% (Agar phantom), and ~40% (chicken tissue)). The proposed technique addresses one of the primary challenges in the clinical translation of LED-based PAI systems (more specifically, to obtain a detectable PA-signal from deep-seated tissue targets).
A Combined Method for MEMS Gyroscope Error Compensation Using a Long Short-Term Memory Network and Kalman Filter in Random Vibration Environments

In applications such as carrier attitude control and mobile device navigation, a micro-electro-mechanical-system (MEMS) gyroscope will inevitably be affected by random vibration, which significantly affects the performance of the MEMS gyroscope. In order to solve the degradation of MEMS gyroscope performance in random vibration environments, in this paper, a combined method of a long short-term memory (LSTM) network and Kalman filter (KF) is proposed for error compensation, where Kalman filter parameters are iteratively optimized using the Kalman smoother and expectation-maximization (EM) algorithm. In order to verify the effectiveness of the proposed method, we performed a linear random vibration test to acquire MEMS gyroscope data. Subsequently, an analysis of the effects of input data step size and network topology on gyroscope error compensation performance is presented. Furthermore, the autoregressive moving average-Kalman filter (ARMA-KF) model, which is commonly used in gyroscope error compensation, was also combined with the LSTM network as a comparison method. The results show that, for the x-axis data, the proposed combined method reduces the standard deviation (STD) by 51.58% and 31.92% compared to the bidirectional LSTM (BiLSTM) network, and EM-KF method, respectively. For the z-axis data, the proposed combined method reduces the standard deviation by 29.19% and 12.75% compared to the BiLSTM network and EM-KF method, respectively. Furthermore, for x-axis data and z-axis data, the proposed combined method reduces the standard deviation by 46.54% and 22.30% compared to the BiLSTM-ARMA-KF method, respectively, and the output is smoother, proving the effectiveness of the proposed method.
Changes in porosity and microaggregation in clayey Ferralsols of the Brazilian Cerrado on clearing for pasture

Ferralsols have a macrostructure that is weak to moderate and a strong microstructure consisting of near spherical microaggregates. We have studied the evolution of the structure under changing land use in two Ferralsols under a native Cerrado and under pasture sowed after recent clearing by measuring bulk density. We studied the microaggregates' characteristics and resulting porosity using scanning electron microscopy and mercury porosimetry, respectively. Microaggregates 50–300 μm in diameter are attributed to termites. They were in a much closer arrangement from the surface to 1 m depth under pasture than under Cerrado. Larger microaggregates, 500–1000 μm in diameter, that are closely packed, resulted from earthworm activity. They were more numerous under pasture than under Cerrado. Thus within a few years, clearing and grazing have caused a dramatic decrease in microstructure that is one of the rare favourable characteristics of Ferralsols for agriculture. This evolution that affects the subsoil to 80–90 cm cannot be attributed to compaction by mechanical deforestation alone but seems to result from a change in the faunal activity in the soil. Finally, the packing of the clay particles within the microaggregates was similar whatever the type of microaggregate and land use. Our results accord with earlier studies showing that the porosity resulting from clay packing varies little in Ferralsols in which the fine material is mainly kaolinite.
Molecular dynamics of targeting CD38 in multiple myeloma

Multiple functions of CD38 need exploring to expand clinical application of anti‐CD38 antibodies in multiple myeloma (MM). We investigated membrane dynamics of MM cells and subsequent events when CD38 is targeted by therapeutic antibodies. Human MM cells (BF01) were co‐cultured in vitro with therapeutic antibody (or control immunoglobulin G) and analysed using gene expression profiling. Microvesicles from antibody‐exposed cells were analysed for differential gene and microRNA (miRNA) expression, and for phenotypic characterisation. Exposure of BF01 cells to anti‐CD38 antibody resulted in CD38 membrane redistribution, upregulation of metabolism‐related genes and downregulation of genes involved in cell cycle processes. Microvesicles derived from antibody‐exposed cells showed increased CD73 and CD39 expression, presence of programmed death‐ligand 1 and significant up‐/down‐modulation of miRNAs. Microvesicles accumulated around immunoglobulin Fc receptor‐positive (FcR+) cells. Upon internalisation, natural killer cells displayed significantly increased expression of genes related to activation and immune response, and downregulation of genes involved in the cell cycle. Cells may use microvesicles to transmit signals distally as part of a survival strategy. Microvesicles are equipped on their surface with enzymatic machinery leading to production of tolerogenic adenosine. Further, they are internalised in FcR+ cells with significant functional modifications. These observations have relevance for improving anti‐CD38 therapeutic antibodies through targeting this mechanism and its sequelae.
From Gaze Perception to Social Cognition: The Shared-Attention System

When two people look at the same object in the environment and are aware of each other’s attentional state, they find themselves in a shared-attention episode. This can occur through intentional or incidental signaling and, in either case, causes an exchange of information between the two parties about the environment and each other’s mental states. In this article, we give an overview of what is known about the building blocks of shared attention (gaze perception and joint attention) and focus on bringing to bear new findings on the initiation of shared attention that complement knowledge about gaze following and incorporate new insights from research into the sense of agency. We also present a neurocognitive model, incorporating first-, second-, and third-order social cognitive processes (the shared-attention system, or SAS), building on previous models and approaches. The SAS model aims to encompass perceptual, cognitive, and affective processes that contribute to and follow on from the establishment of shared attention. These processes include fundamental components of social cognition such as reward, affective evaluation, agency, empathy, and theory of mind.
Global progress in incorporating climate adaptation into land protection for biodiversity since Aichi targets

Climate adaptation strategies are being developed and implemented to protect biodiversity from the impacts of climate change. A well‐established strategy involves the identification and addition of new areas for conservation, and most countries agreed in 2010 to expand the global protected area (PA) network to 17% by 2020 (Aichi Biodiversity Target 11). Although great efforts to expand the global PA network have been made, the potential of newly established PAs to conserve biodiversity under future climate change remains unclear at the global scale. Here, we conducted the first global‐extent, country‐level assessment of the contribution of PA network expansion toward three key land prioritization approaches for biodiversity persistence under climate change: protecting climate refugia, protecting abiotic diversity, and increasing connectivity. These approaches avoid uncertainties of biodiversity predictions under climate change as well as the issue of undescribed species. We found that 51% of the countries created new PAs in locations with lower mean climate velocity (representing better climate refugia) and 58% added PAs in areas with higher mean abiotic diversity compared to the available, non‐human‐dominated lands not chosen for protection. However, connectivity among PAs declined in 53% of the countries, indicating that many new PAs were located far from existing PAs. Lastly, we identified potential improvements for climate adaptation, showing that 94% of the countries have the opportunity to improve in executing one or more approaches to conserve biodiversity. Most countries (60%) were associated with multiple opportunities, highlighting the need for integrative strategies that target multiple land protection approaches. Our results demonstrate that a global improvement in the protection of climate refugia, abiotic diversity, and connectivity of reserves is needed to complement land protection informed by existing and projected species distributions. Our study also provides a framework for countries to prioritize land protection for climate adaptation using publicly available data.
Uncovering the Hidden Credentials of Brucella Virulence

Bacteria in the genus Brucella are important human and veterinary pathogens. The abortion and infertility they cause in food animals produce economic hardships in areas where the disease has not been controlled, and human brucellosis is one of the world’s most common zoonoses. Brucella strains have also been isolated from wildlife, but we know much less about the pathobiology and epidemiology of these infections than we do about brucellosis in domestic animals. SUMMARY Bacteria in the genus Brucella are important human and veterinary pathogens. The abortion and infertility they cause in food animals produce economic hardships in areas where the disease has not been controlled, and human brucellosis is one of the world’s most common zoonoses. Brucella strains have also been isolated from wildlife, but we know much less about the pathobiology and epidemiology of these infections than we do about brucellosis in domestic animals. The brucellae maintain predominantly an intracellular lifestyle in their mammalian hosts, and their ability to subvert the host immune response and survive and replicate in macrophages and placental trophoblasts underlies their success as pathogens. We are just beginning to understand how these bacteria evolved from a progenitor alphaproteobacterium with an environmental niche and diverged to become highly host-adapted and host-specific pathogens. Two important virulence determinants played critical roles in this evolution: (i) a type IV secretion system that secretes effector molecules into the host cell cytoplasm that direct the intracellular trafficking of the brucellae and modulate host immune responses and (ii) a lipopolysaccharide moiety which poorly stimulates host inflammatory responses. This review highlights what we presently know about how these and other virulence determinants contribute to Brucella pathogenesis. Gaining a better understanding of how the brucellae produce disease will provide us with information that can be used to design better strategies for preventing brucellosis in animals and for preventing and treating this disease in humans.
Supplementation Effect of Oleuropein Extract Combined with Betaine, Magnesium, and Vitamin E on Pigs’ Performance and Meat Quality Characteristics

Simple Summary Oleuropein, betaine, magnesium, and vitamin E show antioxidant and/or metabolic effects on the organism that are reflected, in many cases, in performances and meat quality. This study evaluated whether the combination of these nutrients at two doses manifest different effects on the final product. Both combinations were enough to improve the oxidative status of pigs, although performances were not affected. However, the higher doses increased n-6 and n-3 PUFA in the triglycerides and free fatty acid fractions that resulted in meat that was more susceptible to oxidation. Abstract This study evaluates the effect of the dietary combination of oleuropein extract (1200 mg/kg) and betaine (1000 mg/kg), magnesium oxide (600 mg/kg), and α–tocopheryl acetate (400 mg/kg), or a half-dose of these compounds, on pigs’ performance, oxidative status, and meat quality characteristics (drip loss, TBARS, and texture and fatty acid profile of intramuscular fat). Sixty-six barrows and females were slaughtered at 120 kg of BW. Performance and carcass yield were not changed by treatments. The high-dose mixture resulted in higher serum ferric reducing/antioxidant power (p = 0.0026), lower glucose (p = 0.03) and a tendency to have lower serum TBARS (p = 0.07) when compared to control. Percentage of drip loss, moisture content, intramuscular fat, or texture parameters were not modified by dietary treatments. Pigs supplemented with the high-dose mixture had higher PUFA (p = 0.0001), n-6 (p = 0.0001), n-3 (p = 0.0095) and lower MUFA (p = 0.0064) in the neutral lipid fraction of intramuscular fat. Free PUFA, mainly n-3 fatty acids (p = 0.0009), were also higher in the meat of pigs fed the high-dose mixture compared with the others. A higher mobilization (neutral to free fatty acids hydrolysis) of n-3 and MUFA fatty acids in the muscle from pigs fed the high-dose mixture was observed. However, dietary mixture supplementation tended to increase MUFA (p = 0.056) and decrease the total PUFA (p = 0.0074) proportions in muscle polar lipids. This specific fatty acid composition of meat from pigs supplemented with the high-dose mixture could be responsible for the higher meat lipid oxidation observed in this group when compared to the other groups. Consequently, the low-dose mixture would be more adequate for maintaining the oxidative status of pigs and, meat lipid stability.
Calprotectin in Lung Diseases

Calprotectin (CLP) is a heterodimer formed by two S-100 calcium-binding cytosolic proteins, S100A8 and S100A9. It is a multifunctional protein expressed mainly by neutrophils and released extracellularly by activated or damaged cells mediating a broad range of physiological and pathological responses. It has been more than 20 years since the implication of S100A8/A9 in the inflammatory process was shown; however, the evaluation of its role in the pathogenesis of respiratory diseases or its usefulness as a biomarker for the appropriate diagnosis and prognosis of lung diseases have only gained attention in recent years. This review aimed to provide current knowledge regarding the potential role of CLP in the pathophysiology of lung diseases and describe how this knowledge is, up until now, translated into daily clinical practice. CLP is involved in numerous cellular processes in lung health and disease. In addition to its anti-microbial functions, CLP also serves as a molecule with pro- and anti-tumor properties related to cell survival and growth, angiogenesis, DNA damage response, and the remodeling of the extracellular matrix. The findings of this review potentially introduce CLP in daily clinical practice within the spectrum of respiratory diseases.
Chitosan and Hydroxyapatite Based Biomaterials to Circumvent Periprosthetic Joint Infections

Every year, worldwide, millions of people suffering from joint pain undergo joint replacement. For most patients, joint arthroplasty reduces pain and improve function, though a small fraction will experience implant failure. One of the main reasons includes prosthetic joint infection (PJI), involving the prosthesis and adjacent tissues. Few microorganisms (MO) are required to inoculate the implant, resulting in the formation of a biofilm on its surface. Standard treatment includes not only removal of the infected prosthesis but also the elimination of necrotic bone fragments, local and/or systemic administration of antibiotics, and revision arthroplasty with a new prosthesis, immediately after the infection is cleared. Therefore, an alternative to the conventional therapeutics would be the incorporation of natural antimicrobial compounds into the prosthesis. Chitosan (Ch) is a potential valuable biomaterial presenting properties such as biocompatibility, biodegradability, low immunogenicity, wound healing ability, antimicrobial activity, and anti-inflammatory potential. Regarding its antimicrobial activity, Gram-negative and Gram-positive bacteria, as well as fungi are highly susceptible to chitosan. Calcium phosphate (CaP)-based materials are commonly utilized in orthopedic and dentistry for their excellent biocompatibility and bioactivity, particularly in the establishment of cohesive bone bonding that yields effective and rapid osteointegration. At present, the majority of CaP-based materials are synthetic, which conducts to the depletion of the natural resources of phosphorous in the future due to the extensive use of phosphate. CaP in the form of hydroxyapatite (HAp) may be extracted from natural sources as fish bones or scales, which are by-products of the fish food industry. Thus, this review aims to enlighten the fundamental characteristics of Ch and HAp biomaterials which makes them attractive to PJI prevention and bone regeneration, summarizing relevant studies with these biomaterials to the field.