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Background Natural killer (NK) cells are being extensively studied as a cell therapy for cancer. These cells are activated by recognition of ligands and antigens on tumor cells. Cytokine therapies, such as IL-15, are also broadly used to stimulate endogenous and adoptively transferred NK cells in patients with cancer. These stimuli activate the membrane protease ADAM17, which cleaves various cell-surface receptors on NK cells as a negative feedback loop to limit their cytolytic function. ADAM17 inhibition can enhance IL-15-mediated NK cell proliferation in vitro and in vivo. In this study, we investigated the underlying mechanism of this process.Methods Peripheral blood mononuclear cells (PBMCs) or enriched NK cells from human peripheral blood, either unlabeled or labeled with a cell proliferation dye, were cultured for up to 7 days in the presence of rhIL-15±an ADAM17 function-blocking antibody. Different fully human versions of the antibody were generated; Medi-1 (IgG1), Medi-4 (IgG4), Medi-PGLALA, Medi-F(ab′)2, and TAB16 (anti-ADAM17 and anti-CD16 bispecific) to modulate CD16A binding. Flow cytometry was used to assess NK cell proliferation and phenotypic markers, immunoblotting to examine CD16A signaling, and IncuCyte-based live cell imaging to measure NK cell antitumor activity.Results The ADAM17 function-blocking monoclonal antibody (mAb) Medi-1 markedly increased early NK cell activation by IL-15. By using different engineered versions of the antibody, we demonstrate involvement by CD16A, an activating Fcγ receptor and well-described ADAM17 substrate. Hence, Medi-1 when bound to ADAM17 on NK cells is engaged by CD16A and blocks its shedding, inducing and prolonging its signaling. This process did not promote evident NK cell fratricide or dysfunction. Synergistic signaling by Medi-1 and IL-15 enhanced the upregulation of CD137 on CD16A+ NK cells and augmented their proliferation in the presence of PBMC accessory cells or an anti-CD137 agonistic mAb.Conclusions Our data reveal for the first time that CD16A and CD137 underpin Medi-1 enhancement of IL-15-driven NK cell activation and proliferation, respectively, with the latter requiring PBMC accessory cells. The use of Medi-1 represents a novel strategy to enhance IL-15-driven NK cell proliferation, and it may be of therapeutic importance by increasing the antitumor activity of NK cells in patients with cancer.

Ethylenediaminetetraacetic acid (EDTA) is a well-known metal chelator and an attractive ligand for covalently modifying adsorbents for bioremediation. Cellulose, a naturally occurring biopolymer, has immense potential as an inexpensive, earth abundant, biocompatible scaffold for EDTA-facilitated environmental remediation; however, pretreatment of the material is required to achieve sufficient degrees of chemical modification. In this study, Natural Fiber Welding (NFW) is used to prepare commercial cotton Aida cloth for EDTA functionalization. Following NFW, the cotton scaffold was covalently modified with up to 0.56 mmol of EDTA per gram of adsorbent, a nearly 2.5-fold increase over native material. The welded EDTA-modified substrates were tested qualitatively against cobalt and quantitatively against nickel, reaching equilibrium binding capacities (qe) of up to 46 mg metal per g of adsorbent, on par with capacities reported from past work on EDTA-modified cellulose. In addition, adsorbent material could be regenerated using mild acid treatment with no significant loss in qe. Unlike the controls, the fiber-welded EDTA-Aida did not fray even after 3 chelation cycles, indicating enhanced textile robustness afforded through NFW treatment. Overall, NFW offers a new approach to converting commercially available, sustainable biomaterials into robust adsorbents for environmental remediation.

Millions of tonnes of polystyrene (PS) are produced annually, with only an estimated 12% being recycled. Herein, the upcycling of expanded or foamed PS waste into electromechanically responsive triboelectric laminates (TLs) is described. These TLs possess internal triboelectric dipoles offering an alternative to ferroelectric fluoropolymers, and, when manufactured into triboelectric nanogenerators (TENGs), are able to generate over 200 V and 12 μA from motion. This energy harvesting is enabled by electrospinning alternating layers of small and large diameter PS fibers, which upon friction establish an effective dipole moment within the TL. The PS‐TENG shows remarkable stability and is able to charge a 0.47 μF capacitor to 15 V in 200 s of vibration from same material contact electrification, with piezoelectric contact‐mode testing showing that a single PS laminate is comparable to state‐of‐the‐art piezoelectric fluoropolymers for overall electromechanical conversion.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson’s disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients’ quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety. Methods: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation. Results: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze. Conclusions: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD.

Introduction: To compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR) mutations. Methods: Patients with treatment-naive advanced EGFR-mutated lung cancer treated with first-line tyrosine kinase inhibitors (TKIs) were included. pEGFR were measured at baseline and first response assessment using ddPCR and NGS. Clearance of pEGFR was defined as undetectable levels after a positive baseline result. Results were correlated with time-to-treatment failure (TTF). In exploratory analysis, corresponding change in carcinoembryonic antigen (CEA) levels was evaluated. Results: Between January 1, 2020, and December 31, 2021, 27 patients were recruited. Ex19del comprised 74% (20 of 27) and L858R 26% (seven of 27). Osimertinib was used in 59% (16 of 27), dacomitinib 4% (one of 27), and gefitinib/erlotinib 37% (10 of 27). Sensitivity of ddPCR and NGS in detecting pEGFR mutation at baseline was 70% (19 of 27) and 78% (21 of 27), respectively (p = 0.16). All patients with detectable pEGFR by ddPCR were detected by NGS.At a median of 8 (range 3–24) weeks post-TKI initiation, clearance of pEGFR was achieved in 68% (13 of 19) and 71% (15 of 21) using ddPCR and NGS, respectively. Concordance between ddPCR and NGS was 79% (kappa = 0.513, p = 0.013). Clearance of pEGFR was associated with longer median TTF (not reached versus 6 months, p = 0.03) and median decrease in CEA levels by 70% from baseline.In another cohort of 124 patients, decrease in CEA levels by greater than 70% within 90 days of TKI initiation was associated with doubling of both TTF and overall survival. Conclusions: Plasma NGS trended toward higher sensitivity than ddPCR in detecting pEGFR, although both had similar concordance in detecting pEGFR clearance. Our results support using NGS at diagnosis and interchangeability of NGS and ddPCR for monitoring, whereas CEA could be explored as a surrogate for pEGFR clearance.

Supporting diabetes self-care in school is important for optimal glycemic control and mental health. The aim of this study was to investigate parental experiences of diabetes management in Danish schools, with an emphasis on the importance of school staff support in self-care. This cross-sectional study surveyed parents of schoolchildren with type 1 diabetes aged 6 to 16 years in Denmark. The parents were identified among members of the Danish Diabetes Association and were invited to complete an online questionnaire. A total of 252 parents of schoolchildren with type 1 diabetes answered the questionnaire. Only 28% of the children had a designated staff member responsible for support in diabetes self-care during school hours. Having a designated staff member responsible for support in self-care was positively associated with parental experiences of better school–parent cooperation (p < 0.001), better experience of diabetes management in school (p < 0.001), and larger proportions of children and parents feeling comfortable in school (p = 0.022 and p = 0.049, respectively). School staff support was positively associated with better parental experience of diabetes management and with some parameters of mental health in schoolchildren with type 1 diabetes and their parents in Denmark.

An optogenetic, spatial self-stimulation task in mice reveals how information carried by distinct inputs to the nucleus accumbens shell is potentially integrated to drive behavioural responses.

Abstract Biodiversity of soil is routinely assessed with environmental DNA—most often by massive parallel sequencing of marker genes (eDNA metabarcoding). Soil biodiversity may be investigated in relation to biodiversity research or as a tool in forensic investigations. After sampling, the taxonomic composition of soil biotic communities may change. In order to minimize community changes, it is desirable to reduce biological activity, e.g., by freezing immediately after sampling. However, this may be impossible due to remoteness of study sites or, in forensic cases, where soil has been attached to an item of interest for protracted periods of time. Here, we investigated the effect of storage duration and conditions on the assessment of the soil biota with eDNA metabarcoding. We extracted eDNA from freshly collected soil samples and again from the same samples after storage under contrasting temperature conditions and contrasting exposure (open/closed tubes). We used four different primer sets targeting bacteria, fungi, protists (cercozoans), and general eukaryotes. We quantified differences in richness, evenness, and community composition. Subsequently, we tested whether we could correctly infer habitat type and original sample identity after storage using a large reference dataset. We found stronger community composition differences with extended storage time and with higher storage temperature, and differences between open and closed tubes. However, for samples stored

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a technique to aid in resuscitative eff orts for hemorrhagic shock. The use of REBOA is not yet commonplace and there is little understanding of real-world practice patterns. The Endovascular and Hybrid Trauma and Bleeding Management Symposium is a large international conference specifically developed to discuss multidisciplinary, endovascular and hybrid approaches to hemorrhage management. We sought to evaluate provider opinions and practice patterns using REBOA for traumatic vascular injury before and after attending this conference. Methods: A detailed survey was completed by a variety of providers before and after the conference. The survey was composed of demographic information, and focused on practice patterns and opinions regarding the implementation of REBOA. Results: We received 186 survey responses (99 pre, 87 post). There was increased perception of feasibility for REBOA in all settings, with the largest increase for pre-hospital and austere military environments (53.5% pre, 67.8% post and 59.6% pre, 73.6% post respectively). While there was no consensus on tolerable occlusion times and indications for utilization, most participants felt that partial REBOA was the most viable technique for prolonging the benefi ts of REBOA, and more participants came to this conclusion after attending the conference (62.2% pre, 81.6% post, p = 0.006). Conclusions: REBOA is an exciting and important advancement in the management of life threatening hemorrhage; however, its implementation has not been codifi ed and there is much variation in practitioners’ understanding of its use. Continued investigation is needed to determine the appropriate indications, methods, and practical limitations of REBOA as a new hemorrhage management paradigm.

Abstract Background Janus Kinase (JAK) inhibition has recently demonstrated therapeutic efficacy in both restoring hair growth and resolving inflammation in Alopecia Areata (AA). These effects are dose dependent and mainly efficacious at ranges close to a questionable risk profile. Objectives We explored the possibility to separate the beneficial and adverse effects of JAK inhibition by selectively inhibiting JAK1 and thereby avoiding side effects associated with JAK2 blockade. Methods The C3H/HeJ mouse model of AA was used to demonstrate therapeutic efficacy in vivo with different regimens of a selection of JAK inhibitors in regards to systemic versus local drug exposure. Human peripheral blood lymphocytes were stimulated in vitro to demonstrate translation to the human situation. Results We demonstrate that selective inhibition of JAK1 produces fast resolution of inflammation and complete restoration of hair growth in the C3H/HeJ mouse model of AA. Furthermore, we show that topical treatment does not restore hair growth and that treatment needs to be extended well beyond that of restored hair growth in order to reach treatment‐free remission. For translatability to human disease, we show that cytokines involved in AA pathogenesis are similarly inhibited by selective JAK1 and pan‐JAK inhibition in stimulated human peripheral lymphocytes and specifically in CD8+ T cells. Conclusion This study demonstrates that systemic exposure is required for efficacy in AA and we propose that a selective JAK1 inhibitor will offer a treatment option with a superior safety profile to pan‐JAK inhibitors for these patients.

Abstract Silver nanoparticles (AgNPs) are presented within mesoporous natural fiber welded (NFW) cellulose and demonstrated as robust catalysts to reduce 4‐nitrophenol using sodium borohydride. Growing AgNPs this way enables their retention within a nonderivatized, mesoporous, all‐cellulose NFW composite. At an AgNP loading of 1.0 wt%, no leaching is observed during rinsing with polar and nonpolar solvents or any of 12 catalyst cycles and the cloth is easily retrievable and reusable. Comparatively, a 1.0 wt% AgNP loading on non‐NFW cotton thread loses ≈95% of the starting Ag under similar conditions. Only at higher loadings is a very slow leaching observed in the NFW composite (

Functional MRI (fMRI) data acquired using echo-planar imaging (EPI) are highly distorted by magnetic field inhomogeneities. Distortion and differences in image contrast between EPI and T1-weighted and T2-weighted (T1w/T2w) images makes their alignment a challenge. Typically, field map data are used to correct EPI distortions. Alignments achieved with field maps can vary greatly and depends on the quality of field map data. However, many public datasets lack field map data entirely. Additionally, reliable field map data is often difficult to acquire in high-motion pediatric or developmental cohorts. To address this, we developed Synth, a software package for distortion correction and cross-modal image registration that does not require field map data. Synth combines information from T1w and T2w anatomical images to construct an idealized undistorted synthetic image with similar contrast properties to EPI data. This synthetic image acts as an effective reference for individual-specific distortion correction. Using pediatric (ABCD: Adolescent Brain Cognitive Development) and adult (MSC: Midnight Scan Club; HCP: Human Connectome Project) data, we demonstrate that Synth performs comparably to field map distortion correction approaches, and often outperforms them. Field map-less distortion correction with Synth allows accurate and precise registration of fMRI data with missing or corrupted field map information.

Abstract Background Plastid genomes (plastomes) present great potential in resolving multiscale phylogenetic relationship but few studies have focused on the influence of genetic characteristics of plastid genes, such as genetic variation and phylogenetic discordance, in resolving the phylogeny within a lineage. Here we examine plastome characteristics of Cycas L., the most diverse genus among extant cycads, and investigate the deep phylogenetic relationships within Cycas by sampling 47 plastomes representing all major clades from six sections. Results All Cycas plastomes shared consistent gene content and structure with only one gene loss detected in Philippine species C. wadei. Three novel plastome regions (psbA-matK, trnN-ndhF, chlL-trnN) were identified as containing the highest nucleotide variability. Molecular evolutionary analysis showed most of the plastid protein-coding genes have been under purifying selection except ndhB. Phylogenomic analyses that alternatively included concatenated and coalescent methods, both identified four clades but with conflicting topologies at shallow nodes. Specifically, we found three species-rich Cycas sections, namely Stangerioides, Indosinenses and Cycas, were not or only weakly supported as monophyly based on plastomic phylogeny. Tree space analyses based on different tree-inference methods both revealed three gene clusters, of which the cluster with moderate genetic properties showed the best congruence with the favored phylogeny. Conclusions Our exploration in plastomic data for Cycas supports the idea that plastid protein-coding genes may exhibit discordance in phylogenetic signals. The incongruence between molecular phylogeny and morphological classification reported here may largely be attributed to the uniparental attribute of plastid, which cannot offer sufficient information to resolve the phylogeny. Contrasting to a previous consensus that genes with longer sequences and a higher proportion of variances are superior for phylogeny reconstruction, our result implies that the most effective phylogenetic signals could come from loci that own moderate variation, GC content, sequence length, and underwent modest selection.

IntroductionHealth-related quality of life (HRQoL) is essential for human wellbeing, influenced by a complex interplay of factors, and is reported lower in women than men. We aimed to evaluate which factors were the most important for HRQoL in a middle-aged general population.MethodsThis was a cross-sectional, multi-centre study of 29,212 men (48%) and women (52%) aged 50-64 in the general population in Sweden. Physical and mental HRQoL (0-100) was assessed using the Short Form 12 questionnaire, and association was evaluated for 356 variables including demographics, lifestyle, symptoms, physiological measurements, and health conditions. Using machine learning, each variable´s importance for HRQoL was measured by an importance score, comparable to effect size, and summarised in 54 factors, in men and women separately.ResultsMen and women had similar mean and standard deviation (SD) scores for physical HRQoL (53.4 [SD 8.1] vs 51.4 [9.7]) and mental HRQoL (37.1 [5.0] vs 37.3 [5.4]). The most important factors for physical HRQoL were (importance score) physical activity (40), employment (36), pain (33), sleep (33), and sense of control (26). The most important factors for mental HRQoL were sense of control (18), physical activity (12), depression (12), pain (6), and employment (5).ConclusionsThe factors important for HRQoL identified by this study are likely to be amenable to interventions, and our findings can support prioritising interventions. The identified factors need to be a target even before middle-age to lay the foundation for long and happy lives.

The aim of this study was to investigate the early-life development of the skin microbiome in atopic dermatitis. Nineteen infants with atopic dermatitis and 19 healthy infants were evaluated 3 times, at 3 months intervals, within the first 30 months of life. Tape-strips were collected from volar forearms, cheeks, and eczema lesions, and the skin microbiome was assessed by 16S rRNA sequencing. Both the community structure and richness of the skin microbiome of infants with atopic dermatitis differed significantly from that of healthy infants, with greater richness in healthy infants. For infants with atopic dermatitis, the community composition was not dominated by Staphylococci. For healthy infants, community composition and richness correlated significantly with age, while such a pattern was not revealed in infants with atopic dermatitis. This suggests a slower maturation of the skin microbiome in atopic dermatitis, which precedes the staphylococcal predominance observed in older children and adults.

The Brain Imaging Data Structure (BIDS) is a specification accompanied by a software ecosystem that was designed to create reproducible and automated workflows for processing neuroimaging data. BIDS Apps flexibly build workflows based on the metadata detected in a dataset. However, even BIDS valid metadata can include incorrect values or omissions that result in inconsistent processing across sessions. Additionally, in large-scale, heterogeneous neuroimaging datasets, hidden variability in metadata is difficult to detect and classify. To address these challenges, we created a Python-based software package titled “Curation of BIDS” (CuBIDS), which provides an intuitive workflow that helps users validate and manage the curation of their neuroimaging datasets. CuBIDS includes a robust implementation of BIDS validation that scales to large samples and incorporates DataLad––a version control software package for data––as an optional dependency to ensure reproducibility and provenance tracking throughout the entire curation process. CuBIDS provides tools to help users perform quality control on their images’ metadata and identify unique combinations of imaging parameters. Users can then execute BIDS Apps on a subset of participants that represent the full range of acquisition parameters that are present, accelerating pipeline testing on large datasets.

Abstract As continued growth in gut microbiota studies in captive and model animals elucidates the importance of their role in host biology, further pursuit of how to retain a wild‐like microbial community is becoming increasingly important to obtain representative results from captive animals. In this study, we assessed how the gut microbiota of two wild‐caught small mammals, namely Crocidura russula (Eulipotyphla, insectivore) and Apodemus sylvaticus (Rodentia, omnivore), changed when bringing them into captivity. We analyzed fecal samples of 15 A. sylvaticus and 21 C. russula, immediately after bringing them into captivity and 5 weeks later, spread over two housing treatments: a “natural” setup enriched with elements freshly collected from nature and a “laboratory” setup with sterile artificial elements. Through sequencing of the V3–V4 region of the 16S recombinant RNA gene, we found that the initial microbial diversity dropped during captivity in both species, regardless of treatment. Community composition underwent a change of similar magnitude in both species and under both treatments. However, we did observe that the temporal development of the gut microbiome took different trajectories (i.e., changed in different directions) under different treatments, particularly in C. russula, suggesting that C. russula may be more susceptible to environmental change. The results of this experiment do not support the use of microbially enriched environments to retain wild‐like microbial diversities and compositions, yet show that specific housing conditions can significantly affect the drift of microbial communities under captivity.

Neurological disorders and type 2 diabetes mellitus (T2DM) are deeply intertwined. For example, autonomic neuropathy contributes to the development of T2DM and continued unmanaged T2DM causes further progression of nerve damage. Increasing glycemic control has been shown to prevent the onset and progression of diabetic autonomic neuropathies. Neuromodulation consisting of combined stimulation of celiac vagal fibers innervating the pancreas with concurrent electrical blockade of neuronal hepatic vagal fibers innervating the liver has been shown to increase glycemic control in animal models of T2DM. The present study demonstrated that the neuromodulation reversed glucose intolerance in alloxan-treated swine in both pre- and overt stages of T2DM. This was demonstrated by improved performance on oral glucose tolerance tests (OGTTs), as assessed by area under the curve (AUC). In prediabetic swine (fasting plasma glucose (FPG) range: 101–119 mg/dL) the median AUC decreased from 31.9 AUs (IQR = 28.6, 35.5) to 15.9 AUs (IQR = 15.1, 18.3) p = 0.004. In diabetic swine (FPG range: 133–207 mg/dL) the median AUC decreased from 54.2 AUs (IQR = 41.5, 56.6) to 16.0 AUs (IQR = 15.4, 21.5) p = 0.003. This neuromodulation technique may offer a new treatment for T2DM and reverse glycemic dysregulation at multiple states of T2DM involved in diabetic neuropathy including at its development and during progression.

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor–mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.

Senescence-associated secretory phenotype (SASP) involves secretion of factors such as pro-inflammatory cytokines. Here the authors show that MIR31HG regulates the expression and secretion of a subset of SASP components that induce paracrine invasion, through interaction with YBX1 and induction of IL1A translation.

Circulating tumour DNA (ctDNA) represents a non-invasive option to monitor cancer progression. Here, the authors perform deep sequencing of plasma cell-free DNA, and find that nucleosome-dependent cfDNA degradation at 6 specific regulatory regions is predictive of ctDNA burden.

Abstract The Lund collection is one of the oldest subfossil collections in the world. The vast assemblage of subfossils was collected in the 1830s and 1840s by Peter Wilhelm Lund in Lagoa Santa, Brazil, and was shipped to Copenhagen in 1848, where it was stored in various locations around the city with little attention for the future preservation of the collection. So far, successful genetic research on the material collected by Lund has been limited to two samples of human petrous bone. However, less is known about the preservation conditions of the vast amounts of small and fragmentary bones stored in the collection. To address this, we studied ancient DNA from bulk bone samples of approximately 100 bone fragments from the P.W. Lund collection from boxes with varying degrees of physical preservation conditions. Using bulk bone metabarcoding, we found a high species diversity in all samples. In total, we identified 17 species, representing 11 mammals, two birds, one fish, and three frogs. Of these, two species are new to the collection. Collectively, these results exhibit the potential of future genetic studies on the famous P.W. Lund collection and suggest that the effects of poor storage conditions are probably negligible compared with the long‐term in situ degradation that specimens undergo before excavation.

IoT networks are getting overcrowded following the vast increase in number of Internet-of-Things (IoT) devices and connections. Networks can be extended with more gateways, increasing the number of supported devices. However, as investigated in this work, massive MIMO has the potential to increase the number of simultaneous connections and moreover lower the energy expenditure of these devices. We present a study of the channel characteristics of massive MIMO in the narrowband unlicensed sub-GHz band. The goal is to support IoT applications with strict requirements in terms of number of devices, power consumption, and reliability. The assessment is based on experimental measurements using both a uniform linear and a rectangular array. Our study demonstrates and validates the advantages of deploying massive MIMO gateways to serve IoT nodes. While the results are general, here we specifically focus on static nodes. The array gain and channel hardening effect yield opportunities to lower the transmit power of IoT nodes while also increasing reliability. The exploration confirms that exploiting large arrays brings great opportunities to connect a massive number of IoT devices by separating the nodes in the spatial domain. In addition, we give an outlook on how static IoT nodes could be scheduled based on partial channel state information.

In this study, imidazolium-based polymerizable ionic liquids (Poly-ILs) were used to prepare novel polyionic biocomposites through Natural Fiber Welding. Two new Poly-ILs containing a 1-alkyl-3-vinylimidazolium cation and an alkylphosphonate anion were synthesized and evaluated for their ability to (i) solubilize a biopolymer (cellulose) matrix and (ii) polymerize with and without dissolved cellulose. Raman spectroscopy and scanning electron microscopy (SEM) were used to characterize the fiber-welded composites. Optimized fiber-welding parameters yielded polyionic biocomposite materials whose physicochemical properties were evaluated using SEM, energy dispersive X-ray spectroscopy (EDS) and water sorption testing in a controlled relative humidity chamber. SEM/EDS revealed polymerized Poly-IL integrated throughout a fiber-welded, polyionic biocomposite matrix; the materials absorbed ca. 38-40 % of their mass in water when exposed to a controlled (70%) relative humidity environment. To reduce the hygroscopic nature of the fiber-welded composites, the methylphosphonate anion was partially exchanged for a more hydrophobic anion (bis-trifluorosufonylimide, TFSI) through a single-pass anion exchange. SEM/EDS of sample cross sections before and after treatment show that this simple anion exchange and rinse procedure delivers up to ca. 5% exchange from methylphosphonate to TFSI. In spite of this low exchange, the water sorption properties of the exchanged polyionic biocomposites were successfully reduced by 14% and could be easily returned to their original dry state at low temperature under vacuum.

The influences of indole-3-butyric acid (IBA) concentrations of 0–30 mg·g−1 on the success and speed of adventitious root development of Zamia furfuracea L.f. and Zamia integrifolia L.f. stem cuttings were determined. Root formation success for both species was greater than 95%. The IBA concentrations did not influence the speed of root development for Z. furfuracea, but the Z. integrifolia cuttings that received IBA concentration of 3 mg·g−1 generated adventitious roots more slowly than the cuttings in the control group. The ending dry weights of the stems, leaves, and roots were not influenced by IBA concentration for either species. Our results indicated that adventitious root formation on stem cuttings of these two Zamia species is successful without horticultural application of IBA. Additional IBA studies are needed on the other 300+ cycad species, especially those that are in a threatened category.

The impact of late Pleistocene climate change on ecosystems has been hard to assess. Here, the authors sequence ancient DNA from Hall’s Cave, Texas and find that both plant and vertebrate diversity decreased with cooling, and though plant diversity recovered with rewarming, megafauna went extinct.

Abstract Background The archaeological incidence of ancient human faecal material provides a rare opportunity to explore the taxonomic composition and metabolic capacity of the ancestral human intestinal microbiome (IM). Here, we report the results of the shotgun metagenomic analyses of an ancient South African palaeo-faecal specimen. Methods Following the recovery of a single desiccated palaeo-faecal specimen from Bushman Rock Shelter in Limpopo Province, South Africa, we applied a multi-proxy analytical protocol to the sample. The extraction of ancient DNA from the specimen and its subsequent shotgun metagenomic sequencing facilitated the taxonomic and metabolic characterisation of this ancient human IM. Results Our results indicate that the distal IM of the Neolithic ‘Middle Iron Age’ (c. AD 1460) Bantu-speaking individual exhibits features indicative of a largely mixed forager-agro-pastoralist diet. Subsequent comparison with the IMs of the Tyrolean Iceman (Ötzi) and contemporary Hadza hunter-gatherers, Malawian agro-pastoralists and Italians reveals that this IM precedes recent adaptation to ‘Western’ diets, including the consumption of coffee, tea, chocolate, citrus and soy, and the use of antibiotics, analgesics and also exposure to various toxic environmental pollutants. Conclusions Our analyses reveal some of the causes and means by which current human IMs are likely to have responded to recent dietary changes, prescription medications and environmental pollutants, providing rare insight into human IM evolution following the advent of the Neolithic c. 12,000 years ago. Video Abtract.

During sub-sea oil spills to the marine environment, oil droplets will rise towards the sea surface at a rate determined by their density and diameter as well as the vertical turbulence in the water. Micro-droplets (< 50 µm) are expected to have prolonged residence times in the water column. If present, pelagic fish eggs may thus be exposed to dispersed oil from subsurface oil spills for days, and the contribution of these micro-droplets to toxicity is not well known. The purpose of this work was to investigate to what extent timing of exposure and the presence of oil micro droplets affects PAH uptake and survival of pelagic Atlantic cod eggs. A single batch of eggs was separated in two groups and exposed to dispersions and corresponding water-soluble fraction at 3–7 days (Early exposure) and 9–13 days (Late exposure) post fertilization. Partitioning of PAHs between crude oil microdroplets, water and eggs was estimated as well as the contribution of oil droplets to PAH body residue and acute and delayed mortality. Timing of oil exposure clearly affects both the mortality rate and the timing of mortality. Even though the body residue of PAHs were lower when embryos were exposed in the later embryonic stage, mortality rate increased relative to the early exposure indicating that critical body residue threshold is stage specific. Although our results suggest that the dissolved fraction is the dominating driver for toxicity in cod embryos exposed to oil dispersions, crude oil micro droplets contribute to increased mortality as well.

Background. Endothelial dysfunction is an early and potentially reversible stage in the atherosclerotic process. We assessed endothelial dysfunction noninvasively in kidney transplant recipients (KTRs) and evaluated the association with mortality and graft outcomes. Methods. Flow-mediated dilation (FMD) was measured in arteria brachialis by ultrasound, with baseline diameters obtained at rest and maximal diameters obtained during reactive hyperemia occurring after 5 min of forearm occlusion. FMD% is the percentage difference of flow-mediated dilation relative to baseline. Endpoints on mortality and graft outcomes were collected from The Norwegian Renal Registry. The distribution of risk according to FMD levels was assessed in Cox regression using a restricted cubic spline function. FMD was dichotomized using receiver operating characteristic analysis to identify optimal cut points at maximal sensitivity and specificity. Results. From a total of 269 KTRs in 2012, 152 (56.5%) were eligible and examined 10 wk after transplantation, and 145 had successful FMD measurements. During a mean follow-up of 6.5 y, 26 patients died, 11 lost their graft, and 34 experienced either graft loss or death. Mortality increased with lower FMD levels until about 5% dilation and did not change with further reduction in FMD% (P for nonlinearity

Background: Generally, food intake occurs in a three-meal per 24 h fashion with in-between meal snacking. As such, most humans spend more than ∼ 12–16 h per day in the postprandial state. It may be reasoned from an evolutionary point of view, that the human body is physiologically habituated to less frequent meals. Metabolic flexibility (i.e., reciprocal changes in carbohydrate and fatty acid oxidation) is a characteristic of metabolic health and is reduced by semi-continuous feeding. The effects of time-restricted feeding (TRF) on metabolic parameters and physical performance in humans are equivocal.Methods: To investigate the effect of TRF on metabolism and physical performance in free-living healthy lean individuals, we compared the effects of eucaloric feeding provided by a single meal (22/2) vs. three meals per day in a randomized crossover study. We included 13 participants of which 11 (5 males/6 females) completed the study: age 31.0 ± 1.7 years, BMI 24.0 ± 0.6 kg/m2 and fat mass (%) 24.0 ± 0.6 (mean ± SEM). Participants consumed all the calories needed for a stable weight in either three meals (breakfast, lunch and dinner) or one meal per day between 17:00 and 19:00 for 11 days per study period.Results: Eucaloric meal reduction to a single meal per day lowered total body mass (3 meals/day –0.5 ± 0.3 vs. 1 meal/day –1.4 ± 0.3 kg, p = 0.03), fat mass (3 meals/day –0.1 ± 0.2 vs. 1 meal/day –0.7 ± 0.2, p = 0.049) and increased exercise fatty acid oxidation (p < 0.001) without impairment of aerobic capacity or strength (p > 0.05). Furthermore, we found lower plasma glucose concentrations during the second half of the day during the one meal per day intervention (p < 0.05).Conclusion: A single meal per day in the evening lowers body weight and adapts metabolic flexibility during exercise via increased fat oxidation whereas physical performance was not affected.

A 16-year-old boy presented to a level I trauma center after multiple gun shot wounds and a motorcycle crash. He was in profound hemorrhagic shock and had multiple traumatic injuries, including a right common iliac arterial injury. The vessel was shunted for damage control and subsequently repaired primarily. On hospital day 18, he experienced dehiscence of the anastomosis requiring urgent surgery. The artery was ultimately repaired with an expandable polytetrafluoroethylene stent graft deployed in an open fashion through the site of injury. We discuss the use of stent grafts as an interesting alternative to suture repair after anastomotic disruption. Keywords: Direct site endovascular repair, DSER, Stent graft, Vascular trauma

Objectives: To study Epstein-Barr virus (EBV) antibody patterns in twin individuals with rheumatoid arthritis (RA) and their healthy co-twins, and to determine the heritability of antibody responses against the EBV encoded EBNA1 protein.Methods: Isotypes of EBNA1 antibodies were measured in 137 RA affected- and 150 healthy twin pairs. We estimated the effect of RA and RA predisposition, anti-citrullinated antibodies (ACPA), IgM rheumatoid factor (RF), the shared epitope (SE) and the PTPN22-T allele (PTPN22) on the level of EBNA1 antibodies. We also determined the heritability of EBNA1 antibody levels.Results: IgA-EBNA1 antibody levels were increased in twins from RA discordant twin pairs irrespective of RA, ACPA or IgM-RF status. The IgG-EBNA1 antibody level was elevated in healthy co-twins from RA discordant twin pairs but not in RA affected twins. The IgM-EBNA1 antibody level was elevated in both RA twins and their healthy co-twins. The effect of RA on the IgA-EBNA1 antibody level was reversed when SE was present and with no effect of PTPN22. The heritability of IgA-, IgG- and IgM-EBNA1 antibody level was 40.6, 65.5, and 54.3%, with no effect of environment shared by the twins.Conclusion: EBNA1 antibody levels are distinctively different between patients with RA and healthy subjects but also between relatives of RA strongly predisposed to RA and healthy subjects. The high level of IgA EBNA1 antibodies associated with RA and a family predisposition to RA is attributable to both genetics incl. the shared epitope and environmental variation.

The study of South American camelids and their domestication is a highly debated topic in zooarchaeology. Identifying the domestic species (alpaca and llama) in archaeological sites based solely on morphological data is challenging due to their similarity with respect to their wild ancestors. Using genetic methods also presents challenges due to the hybridization history of the domestic species, which are thought to have extensively hybridized following the Spanish conquest of South America that resulted in camelids slaughtered en masse. In this study, we generated mitochondrial genomes for 61 ancient South American camelids dated between 3,500 and 2,400 years before the present (Early Formative period) from two archaeological sites in Northern Chile (Tulán-54 and Tulán-85), as well as 66 modern camelid mitogenomes and 815 modern mitochondrial control region sequences from across South America. In addition, we performed osteometric analyses to differentiate big and small body size camelids. A comparative analysis of these data suggests that a substantial proportion of the ancient vicuña genetic variation has been lost since the Early Formative period, as it is not present in modern specimens. Moreover, we propose a domestication hypothesis that includes an ancient guanaco population that no longer exists. Finally, we find evidence that interbreeding practices were widespread during the domestication process by the early camelid herders in the Atacama during the Early Formative period and predating the Spanish conquest.

Modern techniques for estimating basal levels of electroactive neurotransmitters rely on the measurement of oxidative charges. This requires time integration of oxidation currents at certain intervals. Unfortunately, the selection of integration intervals relies on ad-hoc visual identification of peaks on the oxidation currents, which introduces sources of error and precludes the development of automated procedures necessary for analysis and quantification of neurotransmitter levels in large data sets. In an effort to improve charge quantification techniques, here we present novel methods for automatic selection of integration boundaries. Our results show that these methods allow quantification of oxidation reactions both in vitro and in vivo and of multiple analytes in vitro.

Background: Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in the management of pediatric abdomino-pelvic hemorrhage from trauma or iatrogenic injury is limited by a lack of appropriately sized balloon catheters that can be delivered through a less than 7-Fr sheath. Methods: We bench tested the occlusion capability of eight commercially available balloon catheters deliverable through 4-Fr, 5-Fr, and 6-Fr sheaths in an anatomic pulsatile flow model of the pediatric aorta with variable luminal diameters (5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, and 12 mm). Inflated balloon migration and the deflated balloon’s effect on aortic flow were recorded. The flow chamber was calibrated to an approximate size-appropriate physiologic aortic blood flow. Results: Seven of the eight devices were able to occlude the test lumen diameter corresponding to their manufactured specifications. Deflated luminal flow restriction in the smallest test lumen was lowest in the Fogarty devices (0–3%) followed by Cordis (8–10%) and Numed (14–26%) devices. The Fogarty devices demonstrated the most distal migration (10–15 mm) followed by Numed (1–5 mm). Device migration was undetectable in the Cordis devices. Conclusion: There are commercially available balloon catheters, deliverable through smaller than 7-Fr sheaths, which can occlude pediatric sized aortic test lumens in the setting of physiologic pulsatile flow. While the use of these catheters for occlusion represents off-label use, these results will help inform future research, device development, and practice in the field of pediatric REBOA.

Introduction: A clean and functional microscope is necessary for accurate diagnosis of infectious diseases. In tropical climates, high humidity levels and improper storage conditions allow for the accumulation of debris and fungus on the optical components of diagnostic equipment, such as microscopes. Objective: Our objective was to develop and implement a low-cost, sustainable, easy to manage, low-maintenance, passive humidity control chamber to both reduce debris accumulation and microbial growth onto the optical components of microscopes. Methods: Constructed from easily-sourced and locally available materials, the cost of each humidity control chamber is approximately $2.35 USD. Relative humidity levels were recorded every 30 minutes over a period of 10 weeks from two chambers deployed at the Belize Vector and Ecology Center and the University of Belize. Results: The humidity control chamber deployed at the University of Belize maintained internal relative humidity at an average of 35.3% (SD = 4.2%) over 10 weeks, while the average external relative humidity was 86.4% (SD = 12.4%). The humidity control chamber deployed at the Belize Vector and Ecology Center effectively maintained internal relative humidity to an average of 54.5% (SD = 9.4%) over 10 weeks, while the average external relative humidity was 86.9% (SD = 12.9%). Conclusions: Control of relative humidity is paramount for the sustainability of medical equipment in tropical climates. The humidity control chambers reduced relative humidity to levels that were not conducive for fungal growth while reducing microscope contamination from external sources. This will likely extend the service life of the microscopes while taking advantage of low-cost, locally sourced components.

The blacklegged tick, Ixodes scapularis, is established in several regions of Ontario, Canada, and continues to spread into new geographic areas across the province at a rapid rate. This poses a significant public health risk since I. scapularis transmits the Lyme disease-causing bacterium, Borrelia burgdorferi, and other pathogens of potential public health concern. The objective of this study was to develop species distribution models for I. scapularis and B. burgdorferi to predict and compare the potential distributions of the tick vector and the Lyme disease pathogen as well as the ecological factors most important for species establishment. Ticks were collected via tick dragging at 120 sites across southern, central, and eastern Ontario between 2015 and 2018 and tested for tick-borne pathogens. A maximum entropy (Maxent) approach was used to model the potential distributions of I. scapularis and B. burgdorferi. Two independent datasets derived from tick dragging at 25 new sites in 2019 and ticks submitted by the public to local health units between 2015 and 2017 were used to validate the predictive accuracy of the models. The model for I. scapularis showed high suitability for blacklegged ticks in eastern Ontario and some regions along the shorelines of the Great Lakes, and moderate suitability near Algonquin Provincial Park and the Georgian Bay with good predictive accuracy (tick dragging 2019: AUC = 0.898; ticks from public: AUC = 0.727). The model for B. burgdorferi showed a similar predicted distribution but was more constrained to eastern Ontario, particularly between Ottawa and Kingston, and along Lake Ontario, with similarly good predictive accuracy (tick dragging 2019: AUC = 0.958; ticks from public: AUC = 0.863. The ecological variables most important for predicting the distributions of I. scapularis and B. burgdorferi included elevation, distance to deciduous and coniferous forest, proportions of agricultural land, water, and infrastructure, mean summer/spring temperature, and cumulative annual degree days above 0°C. Our study presents a novel application of species distribution modelling for I. scapularis and B. burgdorferi in Ontario, Canada, and provides an up to date projection of their potential distributions for public health knowledge users.

Microcycas calocoma is the monotypic species from the critical endangered and endemic cycad genus Microcycas in Cuba, an important taxon to study the evolution of extant gymnosperms. Here we report the complete chloroplast sequences of M. calocoma and characterize the genome structure of this species. The genome size of M. calocoma is 165,667 bp in length which contains 135 genes, including 88 protein-coding genes, eight ribosomal RNA genes and 39 transfer RNA genes. The GC content of this genome is 39.6%. Phylogenomic study shows M. calocoma is mostly closely related to the cycad genus Zamia, which corresponds to previous studies based on multiple nuclear genes and combined plastid and nuclear evidence. The plastome information of M. calocoma offered by this study can contribute to further comparative chloroplast genome in cycads/gymnosperms as well as conservation genetic studies of M. calocoma.

Mortality attributable to extreme hot weather is a growing concern in many urban environments, and spatial heat vulnerability indexes are often used to identify areas at relatively higher and lower risk. Three indexes were developed for greater Vancouver, Canada using a pool of 20 potentially predictive variables categorized to reflect social vulnerability, population density, temperature exposure, and urban form. One variable was chosen from each category: an existing deprivation index, senior population density, apparent temperature, and road density, respectively. The three indexes were constructed from these variables using (1) unweighted, (2) weighted, and (3) data-driven Heat Exposure Integrated Deprivation Index (HEIDI) approaches. The performance of each index was assessed using mortality data from 1998–2014, and the maps were compared with respect to spatial patterns identified. The population-weighted spatial correlation between the three indexes ranged from 0.68–0.89. The HEIDI approach produced a graduated map of vulnerability, whereas the other approaches primarily identified areas of highest risk. All indexes performed best under extreme temperatures, but HEIDI was more useful at lower thresholds. Each of the indexes in isolation provides valuable information for public health protection, but combining the HEIDI approach with unweighted and weighted methods provides richer information about areas most vulnerable to heat. Keywords: Heat vulnerability index, Hot weather mortality, Case-crossover analysis, Spatial mapping, Index performance, Public health

Metal nanoparticles prepared by exsolution at the surface of perovskite oxides are key species in catalysis and energy fields. Here, the authors develop a chemistry at a point concept by tracking individual nanoparticles with excellent activity and stability throughout various chemical transformations.

Abstract Background An increasing number of studies are addressing the evolutionary genomics of dog domestication, principally through resequencing dog, wolf and related canid genomes. There is, however, only one de novo assembled canid genome currently available against which to map such data - that of a boxer dog (Canis lupus familiaris). We generated the first de novo wolf genome (Canis lupus lupus) as an additional choice of reference, and explored what implications may arise when previously published dog and wolf resequencing data are remapped to this reference. Results Reassuringly, we find that regardless of the reference genome choice, most evolutionary genomic analyses yield qualitatively similar results, including those exploring the structure between the wolves and dogs using admixture and principal component analysis. However, we do observe differences in the genomic coverage of re-mapped samples, the number of variants discovered, and heterozygosity estimates of the samples. Conclusion In conclusion, the choice of reference is dictated by the aims of the study being undertaken; if the study focuses on the differences between the different dog breeds or the fine structure among dogs, then using the boxer reference genome is appropriate, but if the aim of the study is to look at the variation within wolves and their relationships to dogs, then there are clear benefits to using the de novo assembled wolf reference genome.

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be beneficial in the management of traumatic and iatrogenic vascular and solid organ injuries in children, but requires an understanding of vessel diameter at the access site and landing zones. We adapted the Broselow Tape method to estimate aortic and femoral artery diameters for this purpose. Methods: Computed tomography scans from trauma and non-trauma pediatric patients at a level 1 trauma center were reviewed for vascular dimensions at aorta Zone I, Zone III, and the common femoral artery (CFA). Vessel size was measured by two providers using a vascular software suite with a 10% interobserver comparison. Height was used to create linear regression equations for each location and calculate ranges for each Broselow Tape category. Results: We reviewed scans from 110 patients ages 2–14 years with less than 8% interobserver variability. Of these, 64% were male and 46% were trauma patients. Height-based regression equations were closely correlated with vessel diameter: Zone I (mm) = [0.093 ± 0.006 ⋅ height (cm)] + 0.589 ± 0.768; R2 = 0.714, p < 0.001; Zone III (mm) = [0.083 ± 0.005 ⋅ height (cm)] – 0.703 ± 0.660; and R2 = 0.728, p < 0.001; CFA (mm) = [0.043 ± 0.003 ⋅ height (cm)] + 0.644 ± 0.419; R2 = 0.642, p < 0.001. These equations, along with the minimum and maximum length for each Broselow Tape color, were used to define color-coded normal ranges for each REBOA landing zone and access site. Conclusion: Knowledge of the access vessel and occlusion zone diameters in pediatric patients is crucial for future research and application of REBOA in this population. Furthermore, an adapted Broselow Tape including these measurements would assist in appropriate sheath and balloon catheter selection in emergent settings.

Background: Endovascular methods for hemorrhage control, including resuscitative endovascular balloon occlusion of the aorta (REBOA), are evolving and are increasingly being applied clinically. Partial flow strategies to mitigate the consequences of complete aortic occlusion have been demonstrated in pre-clinical models to enhance REBOA and expand its application to various shock states. Initial studies demonstrated that controlled partial flow requires precision beyond the capabilities of manual balloon volume adjustment, therefore automation is required. Our group previously developed a proof-of-concept computer-controlled extracorporeal flow circuit capable of precision aortic flow regulation, but it was not clinically applicable. To bring this concept closer to clinical applicability, we have developed the first endovascular strategy to achieve precision aortic flow regulation, termed endovascular variable aortic control (EVAC). Methods: Following instrumentation, five Yorkshire-cross swine were subjected to controlled 25% hemorrhage, followed by precision low volume aortic flow regulation using a commercially available compliant balloon catheter pre-positioned in the descending thoracic aorta, connected to a custom, wireless syringe pump. Closed-loop feed-back algorithms based on streaming physiologic data were used to determine balloon volume changes. Results: The EVAC syringe pump was highly effective at maintaining precise aortic flow throughout the 45-minute intervention period during steady-state conditions as well as during rapid fluid administration. Aortic flow and distal mean arterial pressure remained stable during EVAC, despite changing proximal hemodynamics. Balloon volume was dynamic, averaging over 500 changes during intervention, with a mean volume change of 6.7 μL and a maximal change of 100 μL. Conclusions: The EVAC syringe pump is capable of achieving aortic flow regulation with high precision, beyond what is achievable with manual control. This serves as a model for future device design, enabling as of yet unachievable clinical therapies for hemorrhage and shock states. Future technological development is required to fully translate this into clinical use.

The literature covering the biology, invasion chronology, host plant responses, and control efforts of the armored scale Aulacaspis yasumatsui Takagi (Hempitera: Diaspididae) is reviewed. The small size of this cycad pest and complex surface morphology of the host cycad organs combine to make visual detection of every cryptic infestation difficult or impossible to achieve. The international movement of Cycas revoluta Thunb. nursery plants and the presence of C. revoluta nursery industries in so many countries have enabled this pest to wreak havoc on the international cycad horticulture trade over the last 25 years. The short pre-oviposition period and considerable female fecundity lead to rapid population expansion on the plants initially infested in newly invaded regions. A depletion of non-structural carbohydrates accompanies long-term infestations and precedes plant death. Enemy escape within the invasive range allows the scale population growth to remain unchecked until anthropogenic efforts establish non-native biological control.