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The pandemic has uncovered a broad lack of understanding of the role of the Medical Director in Canadian Long-Term Care (LTC) Homes. Our objectives were to identify the current demographics and practices of LTC Medical Directors, discover how the pandemic affected their practice habits, and inform the content of the Ontario Long-Term Care Clinicians Medical Director Course, to ensure that Medical Directors have the requisite knowledge of the responsibilities of their role.Email survey.Medical directors in Ontario long-term care homes.Responses to open-ended, close-ended, multiple-choice, and free-text questions.A total of 156 medical directors (approximately 24%) completed the survey. Ninety-four percent were family physicians. Approximately 40% of participants had been a medical director for fewer than 5 years, whereas more than 11% have been in the role for greater than 30 years. More than 60% spend fewer than 2 hours per week in their administrative role, with fewer than 23% completing formal evaluations of the attending clinicians. Greater than 75% are either satisfied or extremely satisfied in their medical director role, citing excellent engagement and collaboration with team members. Feelings of dissatisfaction were associated with pandemic stress, increased hours and responsibility, inadequate remuneration, lack of ability to make decisions and lack of acknowledgement that physicians add value to the interdisciplinary team.It is clear that medical directors are in a unique position to impact the care of residents within LTC. It is imperative to engage medical directors as integral members of the LTC health care team. This can be achieved by acknowledging their medical expertise for improving outcomes, providing them with the authority for decision making, compensating them appropriately, and clearly defining the role. By making these changes, we can ensure that there is a higher likelihood to sustain effective medical leadership in LTC.

Conservation and management of Pacific Lamprey Entosphenus tridentatus and other imperiled lamprey species could include the use of chemosensory cues to attract or repel migrating adults. For restoration programs, using cues to help guide lamprey through fishway entrances might improve passage of adult lamprey at dams. In contrast, odors might repel unwanted invasive Sea Lamprey Petromyzon marinus in the Laurentian Great Lakes from spawning habitats or improve trapping efficiency. We conducted bioassays with Pacific Lamprey in a two-choice maze to evaluate the behavioral response of preovulatory adult females to introduced chemical cues and changes in flow. During overnight tests, for each female we measured the number of entries into each arm of the maze and the amount of time spent in each arm after application of natural odors from prespawning conspecifics (males and females) in one of the arms. Using the same methods, we also tested whether adult females were attracted to natural odor from spermiating males, to a synthesized (artificially produced) component of a Sea Lamprey sex pheromone (3-keto petromyzonol sulfate), or to an attraction flow (12 L/min as reference). In all tests, the lamprey showed consistent nocturnal activity, typically moving from sunset until sunrise and remaining inactive during daylight hours. For natural odors, the number of entries and the amount of time females spent in the treatment arm were not significantly different between control and treatment periods. However, females spent significantly less time in the treatment arm with the synthesized 3-keto petromyzonol sulfate than when we delivered no odor. Females showed strong, positive responses to the attraction flow and with our assay, we could identify significant behavioral responses when the differences between the control and experimental means were greater than 15–20%. The response of lampreys to sex pheromones may be species-specific, with Pacific Lamprey less likely to respond to conspecific odors than Sea Lamprey.

Earth scientists are increasingly employing time series data with multiple dimensions and high temporal resolution to study the impacts of climate and environmental changes on Earth's atmosphere, biosphere, hydrosphere, and lithosphere. However, the large number of variables and varying time scales of antecedent conditions contributing to natural phenomena hinder scientists from completing more than the most basic analyses. In this paper, we present EVis (Environmental Visualization), a new visual analytics prototype to help scientists analyze and explore recurring environmental events (e.g. rock fracture, landslides, heat waves, floods) and their relationships with high dimensional time series of continuous numeric environmental variables, such as ambient temperature and precipitation. EVis provides coordinated scatterplots, heatmaps, histograms, and RadViz for foundational analyses. These features allow users to interactively examine relationships between events and one, two, three, or more environmental variables. EVis also provides a novel visual analytics approach to allowing users to discover temporally lagging relationships related to antecedent conditions between events and multiple variables, a critical task in Earth sciences. In particular, this latter approach projects multivariate time series onto trajectories in a 2D space using RadViz, and clusters the trajectories for temporal pattern discovery. Our case studies with rock cracking data and interviews with domain experts from a range of sub-disciplines within Earth sciences illustrate the extensive applicability and usefulness of EVis.

The 48 described species of parasitic and non-parasitic lamprey within the order Petromyzontiformes span much of the globe. Although the sea lamprey (Petromyzon marinus) is an unwanted invasive in the Laurentian Great Lakes, most lamprey species are of ecological and cultural value, and of conservation concern. Infectious diseases affect fish health, growth, reproduction, and recruitment; yet, the impact of pathogens that cause them in lamprey have not been comprehensively assessed. This review collates existing information to gain a better understanding of pathogen distribution in lamprey populations. At least 46 genera of parasites, seven genera of bacteria, two genera of fungi and oomycetes, and two viruses belonging to two families have been documented to occur in lamprey, most of which have also been identified in other fish species. Many pathogens of lamprey have not been described completely. Moreover, many details of the host-pathogen interactions in lamprey remain unknown, leaving links between pathogens and disease causation unclear. This knowledge gap is extended by the lack of studies on lamprey immune systems, nor have Koch’s or Rivers’ postulates for most lamprey pathogens been fulfilled. Designing future studies aimed at addressing these knowledge shortfalls will not only clarify the effects that infectious diseases have on imperiled lamprey populations, but also contribute to assessments of potential biocontrol for invasive lamprey populations in the future.

Understanding the relationship between a species and its habitats is important for both conservation of imperiled species and control of invasive species. For migratory species, we hypothesize that maintaining connectivity between segregated habitats is more important than improving the quality of each habitat. In the case of anadromous lampreys of conservation concern, we posit that restoring passage routes between spawning, rearing and feeding habitats will result in higher larval abundance upstream from barriers than efforts to improve quality of these freshwater habitats. To explore this hypothesis, we reviewed conservation actions for native anadromous lampreys in freshwater and found that: i) improving passage between habitats results in immediate and quantifiable increases in larval abundance, ii) anadromous lampreys are capable of existing in suboptimal habitats, and iii) small reservoirs of production drive rapid expansion when anadromous lampreys are released from passage constraints. Hence, maintaining habitat connectivity is clearly crucial for conservation of anadromous lampreys. There are fewer examples of improvements to freshwater habitat that increased larval lamprey abundance, perhaps because lampreys are rarely the focus of these efforts. However, habitat limitations such as stream de-watering, chemical pollution, and scour occur and will likely be exacerbated by climate change. Documenting habitat actions that reverse these problems may provide evidence for the merits of lamprey-specific habitat improvement. Our observations are relevant to sea lamprey control in the Great Lakes because barriers and chemical treatment are key instruments of population regulation, and can be strategically deployed to limit production.

Lampreys (order: Petromyzontiformes) represent one of two extant groups of jawless fishes, also called cyclostomes. Lampreys have a variety of unique features that distinguish them from other fishes. Here we review the physiological features of lampreys that have contributed to their evolutionary and ecological success. The term physiology is used broadly to also include traits involving multiple levels of biological organization, like swimming performance, that have a strong but not exclusively physiological basis. We also provide examples of how sea lamprey traits are currently being used or investigated to control invasive populations in the Great Lakes, such as reduced capacity to detoxify lampricides, inability to surmount low barriers or dams, and sensitivity to several lamprey-specific chemosensory pheromones and alarm cues. Specific suggestions are also provided for how an improved knowledge of lamprey physiological traits could be exploited for more effective conservation of native lampreys and lead to the development of next generation sea lamprey control and conservation tools.

In ITER, the metallic first mirrors (FMs) will undergo erosion due to their proximity to the fusion plasma and deposition of materials originated from the first walls (mainly beryllium). In-situ plasma cleaning is a promising technique to conserve the FMs optical properties by means of ion sputtering. In this work, the evolution of the optical properties of single-crystal (Sc) and nanocrystalline (Nc) molybdenum (Mo) and rhodium (Rh) mirrors were investigated up to 100 cycles of consecutive contamination and cleaning. Aluminum oxide (AlO) was used as contaminant to replace the toxic beryllium. The plasma cleaning was carried out using a capacitively coupled argon (Ar) plasma excited by a 60 MHz radio-frequency generator resulting in the formation of a self-bias applied on the mirrors of -280 V. The plasma potential being around 30 V, the Ar ion energy was about 310 eV. The optical properties of the mirrors were assessed using ex-situ reflectivity measurements. Moreover, the surface topography was characterized by means of scanning electron microscopy (SEM), focused ion beam (FIB) and roughness measurements using atomic force microscopy (AFM). ScMo and ScRh mirrors formerly exposed to 80 successful cleaning cycles using aluminum/tungsten (Al/W) deposits and air storage exhibit drastic changes in their optical properties after being subject to cleaning cycles using AlO as contaminant. Additionally, freshly polished ScRh were exposed to identical cleaning cycles. All Sc mirrors exhibited pits induced by the polishing procedure using diamond paste in addition of mounds/wavy patterns. The carbon incorporated during the polishing process was demonstrated to be responsible for the pitting of the surface. The Nc mirrors preserved their initial reflectivities after up to 100 cycles. The surface topography was systematically characterized and an average erosion rate for NcRh mirrors of about 59 nm per cycle has been estimated from FIB cross-sections. The optical properties of the Nc mirrors showed a superiority in the present study in comparison to the Sc materials due to the influence of their polishing

Infrared dark clouds (IRDCs) are potential hosts of the elusive early phases of high-mass star formation (HMSF). Here we conduct an in-depth analysis of the fragmentation properties of a sample of 10 IRDCs, which have been highlighted as some of the best candidates to study HMSF within the Milky Way. To do so, we have obtained a set of large mosaics covering these IRDCs with ALMA at band 3 (or 3mm). These observations have a high angular resolution (~3arcsec or ~0.05pc), and high continuum and spectral line sensitivity (~0.15mJy/beam and ~0.2K per 0.1km/s channel at the N2H+(1-0) transition). From the dust continuum emission, we identify 96 cores ranging from low- to high-mass (M = 3.4 to 50.9Msun) that are gravitationally bound (alpha_vir = 0.3 to 1.3) and which would require magnetic field strengths of B = 0.3 to 1.0mG to be in virial equilibrium. We combine these results with a homogenised catalogue of literature cores to recover the hierarchical structure within these clouds over four orders of magnitude in spatial scale (0.01pc to 10pc). Using supplementary observations at an even higher angular resolution, we find that the smallest fragments (16Msun without further fragmentation. These high-mass cores contain trans-sonic non-thermal motions, are kinematically sub-virial, and require moderate magnetic field strengths for support against collapse. The identification of these potential sites of high-mass star formation represents a key step in allowing us to test the predictions from high-mass star and cluster formation theories., 21(+6 in appendix) pages, 12(+3) figures, 3(+3) tables. Machine-readable versions of Table A1, A2 and A3 are available online. Accepted for publication in MNRAS

The objective of this experiment was to evaluate the effects of a multi-strain Bacillus subtilis-based direct-fed microbial (DFM) on nursery pig health as indicated by intestinal mucosal and blood plasma immunological markers and intestinal morphology. Eighty pigs, of equal number of barrows and gilts (initial BW: 7.0 ± 0.60 kg), weaned at 21 ± 1 d of age were randomly allotted to sixteen pens, with five pigs per pen. Two dietary treatments were implemented, a basal control (CON) and a basal control plus DFM (CDFM). Both diets were corn, soybean meal, and distillers dried grains based and were formulated to meet or exceed all nutritional requirements (NRC, 2012) and manufactured on site. Diets were fed for 42 d. On d 21 and 42 of the experiment, one pig per pen was randomly selected and euthanized, with equal number of males and females represented. Blood samples were collected prior to euthanasia for assessment of plasma concentrations of immunoglobulin A (IgA) and intestinal fatty acid binding protein. Segments of the gastrointestinal tract including duodenum, jejunum, ileum, ascending and distal colon were removed for analysis of intestinal morphology, and levels of interleukin 6, interleukin 10 (IL-10), and tumor necrosis factor alpha. Jejunal villus height was greater in the CDFM pigs as compared with CON pigs (P = 0.02) and ascending colon crypt depth tended to be greater on d 21 (P = 0.10). Compared to CON, CDFM significantly increased overall plasma IgA (P = 0.03) (0.58 vs. 0.73 0.05 mg/mL, respectively), while it tended to increase plasma IgA (P = 0.06) on d 21 (0.34 vs. 0.54 ± 0.07 mg/mL, respectively) and tended to increase overall IL-10 (P = 0.10) in the jejunum (113 vs. 195 ± 35 pg/mL, respectively). Addition of a multi-strain Bacillus subtilis-based DFM may have an early benefit to nursery pig health status, observed through specific changes in morphology and both systemic and localized immunological markers.

The COVID-19 pandemic has presented a formidable challenge to care continuity for community mental health clients with serious mental illness and for providers who have had to quickly pivot the modes of delivering critical services. Despite these challenges, many of the changes implemented during the pandemic can and should be maintained. These include offering a spectrum of options for remote and in-person care, greater integration of behavioral and physical healthcare, prevention of viral exposure, increased collaborative decision-making related to long-acting injectable and clozapine use, modifying safety plans and psychiatric advance directives to include new technologies and broader support systems, leveraging natural supports, and integration of digital health interventions. This paper represents the authors' collaborative attempt to both reflect the changes to clinical practice we have observed in CMHCs across the US during this pandemic and to suggest how these changes can align with best practices identified in the empirical literature.

Rotator cuff supraspinatus tendon injuries are common with high rates of anatomic failure after surgical repair. The purpose of the study was to define clinically relevant features of a mouse model of supraspinatus tendon injury to determine painful, functional, and structural outcomes; we further investigated two cell populations mediating healing using genetic lineage tracing after full detachment and repair of the supraspinatus tendon in mice. Pain was assessed using the mouse grimace scale and function by gait analysis and tensile testing. Histological and microCT analyses were used to determine enthesis/tendon and bone structure, respectively. Lineage tracing was carried out using inducible Cre lines for ScxCreERT2 (tendon cells) and αSMACreERT2 (myofibroblasts and mesenchymal progenitors). Mice only expressed pain transiently after surgery despite long-term impairment of functional and structural properties. Gait, tensile mechanical properties, and bone properties were significantly reduced after injury and repair. Lineage tracing showed relatively few Scx(lin) tendon cells while αSMA(lin) cells contributed strongly to scar formation. Despite surgical reattachment of healthy tendon, lineage tracing revealed poor preservation of supraspinatus tendon after acute injury and loss of tendon structure, suggesting that tendon degeneration is also a key impediment of successful rotator cuff repair. Scar formation after surgery is mediated largely by αSMA(lin) cells and results in permanently reduced functional and structural properties.

A psychiatric advance directive (PAD) is designed to prevent involuntary mental health interventions by enabling people with serious mental illnesses to plan ahead for their own treatment during a future incapacitating crisis. This study implemented PAD facilitation in assertive community treatment (ACT) teams.We examined ACT clients' attitudes toward PAD facilitators, satisfaction with PAD facilitation, the short-term impact of PAD completion on subjective sense of empowerment and attitudes toward treatment, and whether the type of PAD facilitator made a difference.Participants were randomly assigned to be offered PAD facilitation by a peer support specialist or non-peer ACT team clinician, and interviewed at baseline (There was no evidence of bias against peer-facilitators. There was a modest positive impact of PAD facilitation on treatment attitudes and empowerment.PAD facilitation by peer support specialists and others working in community mental health settings supports recovery.

Alternative fuels play a critical role in strategies aiming at the decarbonization of civil aviation. In this context, Power-to-Liquid fuels produced from renewable electricity, water and carbon dioxide represent a scalable and sustainable option [1]. An in-depth understanding of the entire process chain is key to identify the levers in future scale-up scenarios for PtL capacity deployment. This is not only true for the conversion and upgrading steps, but also extends to the green hydrogen and carbon dioxide feedstocks required. Direct capture from air (DAC) is a potential solution for sustainable CO2 provision at scale. It effectively closes the carbon cycle and enables decoupling the carbon source from fossil infrastructures and biomass. On the other hand, data availability is comparatively low, as DAC is a novel technology and only a small number of operational plants with a total annual output of around 10 t have been realized [2] orders of magnitude lower than what would be required in a net-zero emission scenario. Consequently, DAC, while representing a corner stone in the Power-to-Liquids process chain, is associated with considerable uncertainties when it comes to its potential for future widespread application. Several technology options based on solid or liquid sorbents exist, employing different temperature ranges and typically demanding both thermal and electrical energy. To deepen the understanding and illustrate the associated trade-offs, we employ future technology analysis and consolidate the results in a comparative multi-criteria assessment, taking into account energy demand, scalability, integrability, land requirements and future cost estimations, among other metrics. Further, we apply the learnings as an input to a thorough sensitivity study of the Power-to-Liquids production and supply chain, shedding light onto possible levers and bottlenecks. Finally, we draw a brief comparison to other fuel choices. References [1] Batteiger, V.; Ebner, K.; Habersetzer, A.; Moser, L.; Schmidt, P.; Weindorf, W.; Rakscha, T., Power-to-Liquids - A scalable and sustainable fuel supply perspective for aviation., German Environment Agency. (2022), available at: https://www.umweltbundesamt.de/en/publications [2] IEA, Direct Air Capture (2021), available at: https://www.iea.org/reports/direct-air-capture

The EU Horizon 2020 project HyFlexFuel successfully demonstrated hydrothermal liquefaction (HTL) fuel production chains from different feedstock types to upgraded kerosene products. Now the question arises which commercial scale HTL system design is associated with the lowest environmental impact and production costs. The contribution addresses this research question by establishing a comprehensive process model for different feedstock types (sewage sludge, straw, miscanthus and microalgae) based on experimental biocrude production and upgrading campaigns in pilot and laboratory scale. This model enables evaluating different process configurations and serves as basis for subsequent system analyses by applying techno-economic and life cycle analyses (TEA and LCA). Upgraded biocrude using sewage sludge, representing a waste stream in wastewater management, can be produced at near-competitive price levels. Compared to conventional jet fuel production, greenhouse gases are reduced significantly. However, sewage sludge is a limited resource and only limited amounts of jet fuel could be substituted. Lignocellulosic feedstock such as straw or miscanthus are available in larger quantities and provide the opportunity to produce large amounts of sustainable aviation fuels at moderate costs.

In this work, we present methods allowing parallel, hybrid, and serial manipulators to be analyzed, calibrated, and controlled with the same analytical tools. We introduce a general approach to describe any robotic manipulator using established serial-link representations. We use this framework to generate analytical kinematic and calibration Jacobians for general manipulator constructions using null space constraints and extend the methods to hybrid manipulator types with complex geometry. We leverage the analytical Jacobians to develop detailed expressions for post-calibration pose uncertainties that are applied to describe the relationship between data set size and post-calibration uncertainty. We demonstrate the calibration of a hybrid manipulator assembled from high precision calibrated industrial components resulting in 91.1 μm RMS position error and 71.2 μrad RMS rotation error, representing a 46.7% reduction compared to the baseline calibration of assembly offsets.

While MacNeish was excavating at Purron Cave in the Tehuacan Valley, he was frequently asked what he was finding. “Well,” ran his favorite reply, “at least the botanist had a good day.” This response reflected the fact that Purron Cave had superb plant preservation but not many highly diagnostic artifacts per square meter. The month of March was spent in testing other caves and extending our survey. Finally the authors returned to Guila Naquitz on April 14 with a larger crew and excavated there until May 10, 1966. Digging at Guila Naquitz was so soft that it was never necessary to use a tool larger than a trowel. In addition to a trowel, however, each excavator was provided with a screwdriver. The excavation of a typical square would begin with an examination of the profile and a discussion of exactly how deep the trowel would have to go to loosen the first living floor.

Pacific lamprey (Entosphenus tridentatus) is a First Food of Native Americans. Declines in lamprey abundance due to dam construction and habitat loss have curtailed traditional harvest opportunities. Artificial propagation is an emerging recovery tool for this imperiled species, and other lamprey species in Finland and Japan. To manage disease risk at prospective lamprey hatcheries, it is critical to understand the pathogens and parasites most likely to affect lamprey and other fish, both in culture and in the wild. We assembled data from regional fish health laboratories to assess pathogen prevalence in Pacific lamprey sampled from various sources (518 adults, 275 larvae, and one juvenile). In adults, Aeromonas salmonicida was identified using standard health screening methods in 0–69% of dead lamprey samples submitted, but no other pathogens were typically observed. All larvae were negative for bacterial and viral infections, and larvae experimentally exposed to A. salmonicida showed no infection or mortality. Conspicuously absent were detailed health assessments for metamorphosed larvae (juveniles). However, external examinations of over 20,000 juveniles captured at dams on the lower Columbia River indicated that they are susceptible to fungal infection in warm water conditions (> 12 °C), which can lead to mortality. To fully evaluate the disease risk associated with lamprey culture, directed research is needed along with standardized health screenings of lamprey at all life stages. Control of A. salmonicida, the etiological agent for furunculosis, will be a top priority for Pacific lamprey use, as this was the only pathogen regularly identified in this species.

The aim was to investigate the correlation of bone tracer uptake (BTU) in SPECT/CT and changes in coronal knee alignment after total knee arthroplasty (TKA). We questioned if undercorrection of preoperative varus alignment leads to a difference in BTU compared to neutral alignment.Consecutive 66 patients who received SPECT/CT before and after TKA were retrospectively included. Adjusted mechanical alignment was the alignment target. The alignment of the knee was measured on 3D-CT by selecting standardized landmarks. Maximum (mean ± SD) and relative BTU (ratio to the reference) were recorded using a previously validated localization scheme (p 0.05).In the native group, 20 knees were aligned (30.3%) in valgus (HKA 181.5°), 12 (18.2%) in neutral (178.5°-181.5°) and 34 (51.5%) in varus (HKA 178°). Overall TKA changed the alignment towards neutral. 48.5% remained in the same groups, whereas 50% of native valgus and 33% of varus knees changed to neutral after TKA. In native varus alignment mean BTU was significantly higher in some medial tibial and femoral regions (fem1ia (p = 0.010), fem1ip (p = 0.002), tib1a.mid (p = 0.005), tib1a.tray (p = 0.000), tib1p.tray (p = 0.000)); in native valgus alignment mean BTU was higher in the corresponding lateral tibial and femoral regions (fem2ip (p = 0.001), tib2a.tray (p = 0.011), tib2p.tray (p = 0.002)). After TKA, a significant decrease in femoral and tibial BTU (femoral preoperative BTU 1.64 +/-0.69; femoral postoperative BTU 0.95 +/-0.42; p = 0.000// tibial preoperative BTU 1.65 +/- 0.93; tibial postoperative BTU 1.16 +/- 0.48; p = 0.000) and an increase in patellar BTU was observed (p = 0.025). Native varus alignment correlated with a higher medial BTU decrease medially. Undercorrection of preoperative varus alignment showed no higher BTU after TKA.Preoperative varus alignment correlated with a higher decrease in BTU in specific femoral and tibial medial regions. Preoperative valgus alignment correlated with a higher decrease in the corresponding lateral regions. Undercorrection of preoperative varus alignment did not lead to higher bone loading reflected by BTU after TKA.

A study was conducted to evaluate the effects of a multi-strain Bacillus subtilis-based direct-fed microbial (DFM) on growth performance and apparent nutrient digestibility of nursery pigs. Eighty pigs, of equal number of barrows and gilts (initial body weight: 7.0 ± 0.60 kg), were weaned at 21 ± 1 d and randomly allotted to 1 of the 16 pens, with 5 pigs per pen. Two dietary treatments were implemented, a basal control (CON) and a control plus DFM (CDFM). Both diets were corn, soybean meal, and distillers dried grains based. Diets were fed for 42 d and growth performance measures were recorded weekly. On days 21 and 42 of the experiment, one pig per pen, with equal number of males and females, was randomly selected and euthanized. Digestibility of nitrogen (N), amino acids (AA), and energy were evaluated within the duodenum, jejunum, ileum, and ascending and distal colon. Relative to CON, CDFM tended to increase ADG during week 2 (P = 0.08) and significantly increased ADFI during week 2 (P = 0.04) and week 3 (P = 0.02). In addition, CDFM decreased the gain to feed ratio (G:F) during week 6 relative to CON (P = 0.04). Within the jejunum, pigs fed the DFM had greater digestibility of tryptophan (P = 0.04) and cysteine (P = 0.04) and tended to have greater digestibility of lysine (P = 0.07), methionine (P = 0.06), and threonine (P = 0.08), relative to CON. The content pH in the ascending colon did not differ between CDFM and CON. Compared with CON, apparent total tract digestibility (ATTD) of energy did not differ from CDFM, whereas ATTD of nitrogen of CDFM was lower (P = 0.05). The addition of a multi-strain B. subtilis-based DFM appears to impact growth performance, AA, and N digestibility depending upon the location in the gastrointestinal tract, with primary AA differences occurring within the mid-jejunum.

The proliferation of hyperscale data centers, as well as edge and 5G infrastructure build-outs, requires SerDes running at different rates, over different insertion losses, and in different environments. This work presents a scalable ADC/DSP-based transceiver architecture that runs from 1.25Gb/s NRZ to 56Gb/s PAM-4 in 16nm, supporting channels from very short reach (VSR) at 10dB to long reach (LR) above 35dB. A follow-on design supports 1.25Gb/s NRZ to 112Gb/s PAM-4 in 7nm, and its measured results are also presented in this paper. Some of the key architectural features and innovations that will be described in the paper are: a single decision-feedback equalizer (DFE) with minimum mean square error (MMSE) criteria to drive all feedback control loops, including (i) decision-directed MMSE (DD-MMSE) clock and data recovery (CDR), (ii) feed-forward equalization/decision-feedback equalization (FFE/DFE) bit-error rate (BER) optimization, and (iii) time-interleaved ADC (TI-ADC) clock skew correction.

BackgroundSmall molecule inhibitors targeting members of the bromodomain and extra-terminal (BET) protein family (BRD2, BRD3, BRD4) have anti-inflammatory properties in rheumatoid arthritis (RA). BET proteins are readers of acetylated histone side chains and activators of transcription. BRD3 is an understudied member of BET proteins.ObjectivesTo analyse individual functions of BET proteins and mechanisms underlying BET inhibition in RA synovial fibroblasts (SF).MethodsThe expression of BRD2, BRD3, and BRD4 was silenced by lenti-viral transduction followed by TNF stimulation (10 ng/µl, 24h). Silencing was confirmed by Western blotting. Transcriptomes were determined by RNA-seq (Illumina NovaSeq 6000, n=3). Pathway enrichment analysis for KEGG and Reactome databases was conducted with significantly affected genes (± fold change > 1.5, FDR < 0.05). SF were treated with I-BET (1 µM) and TNF (10 ng/µl, 24h). Autophagy was evaluated by Western blotting using the conversion of LC3B as a marker (n=9). I-BET-induced global changes on post-translational histone modifications were analysed by mass spectrometry (Mod Spec, Active Motif; n=2; 120h protocol) and Western blotting (H3K27ac, H3K18ac, total acH3; n=7; 24h and 120h protocol). For this purpose, SF were stimulated with I-BET (1 µM) for 24h, and either co-stimulated with TNF (24h protocol), or washed with PBS, followed by a 24h stimulation with TNF 120h after the I-BET treatment (120h protocol).ResultsSilencing of BRD2 and BRD4 in SF was, in contrast to silencing of BRD3, associated with high levels of cell death, and therefore not analyzed further. We detected 257 and 324 differentially expressed genes (DEG) that were affected by BRD3 silencing in unstimulated and TNF-stimulated SF, respectively. 105 DEG overlapped between the two groups. DEG were enriched in inflammatory pathways such as “TNF signaling pathway”, “rheumatoid arthritis”, “Toll-like receptor cascades”, “MAPK signaling pathway”, “IL-17 signaling pathway” and “signaling by interleukins”. Furthermore, pathway enrichment analysis suggested a role for BRD3 in different stress-associated pathways, including “DNA repair”, “chaperone mediated autophagy”, “cellular responses to stress”, and “autophagy”. In line with the pathway enrichment analysis, I-BET induced levels of LC3B-II in unstimulated (4.3 fold, p=0.07) and TNF-stimulated (2.9 fold, p=0.07) SF, indicating a role of BET proteins in the regulation of autophagy. To further study the mechanisms underlying I-BET-mediated suppression of gene expression, we analyzed potential effects of I-BET on histone modifications. Mod Spec analysis indicated that I-BET induced profound changes in chromatin modifications, with a global reduction of acetylation on different histone side chains. We confirmed some of these differences in independent samples. I-BET treatment reduced mean TNF-induced levels of total acH3 by 25.2% (120h; p=0.0303), of H3K18ac by 35.3% (24h; p=0.0288) and by 29.3% (120h; p=0.0373) and of H3K27ac by 41.7% (120h; p=0.0587).ConclusionBRD3 acts as an upstream regulatory factor that integrates the response to inflammatory stimuli and stress conditions in SF. Our data suggest that BET inhibitors do not only prevent the reading of acetylated histone side chains, but also directly affect the chromatin structure, in particular by downregulating global levels of histone acetylation.Disclosure of InterestsMalgorzata Maciukiewicz: None declared, Larissa Moser: None declared, Monika Krosel: None declared, Tanja Seifritz: None declared, Matija Tomsic: None declared, Britta Maurer Speakers bureau: Boehringer-Ingelheim, Consultant of: Novartis, Boehringer Ingelheim, Janssen-Cilag, Grant/research support from: AbbVie, Protagen, Novartis Biomedical Research, Oliver Distler Consultant of: Abbvie, Caroline Ospelt: None declared, Kerstin Klein Grant/research support from: Novartis Foundation for biomedical research (2019)

BackgroundRheumatoid arthritis synovial fibroblasts (SF) exhibit a prolonged histone 3 lysine 27 acetylation (H3K27ac) after stimulation with TNF, leading to a sustained inflammatory response. Enhancer RNAs (eRNAs) are short-lived non-coding RNAs transcribed from cell type-specific H3K27ac-marked enhancers that facilitate the transcription of their linked coding genes. The interrelation of eRNAs and their linked coding genes in SF has not been studied yet.ObjectivesTo analyze the expression and regulation of inflammatory eRNAs in SF.MethodsThe expression of eRNAs in SF (n=9), stimulated with TNF (24h; 10 ng/µl) or left untreated, was detected by cap analysis of gene expression followed by sequencing (CAGEseq). To further investigate eRNA expression in SF, the expression of selected eRNAs and their linked coding genes (CXCL1, CCL20, IL6, CCL2, CXCL12, IL8) was analyzed by real-time PCR in SF that were stimulated with TNF (1, 3, 6, 24h; 10 ng/µl), IL1 (1, 24h; 1 ng/ml), or the Toll-like receptor agonists Pam3 (1, 24h; 1 ng/ml), pIC (1, 24h; 10 μg/ml) and LPS (1, 24h; 100 ng/µl). Samples containing the untranscribed RNA were measured in parallel. To study eRNA regulation, SF were treated with the bromodomain inhibitor I-BET (1 µM; 24h), or silenced for the histone acetyltransferases CBP and p300 by transfection of antisense LNA gapmeRs (12.5 nM) prior to stimulation with TNF (1, 24h).ResultsWe have selected four potential eRNAs for CCL2 and IL8, three for CXCL12, two for IL6 and CXCL1 and one for CCL20 from CAGEseq analysis. They were located upstream (eCCL2#1, eCCL2#2, eCXCL1#2, eCXL12#3, eIL6#1 + 2, eIL8#1-4), downstream (eCCL2#3, eCCL2#4, eCXCL1#1, eCXL12#1) and intronic (eCCL20, eCXL12#2) at distances between 300 bp to 35.6 kb relative to the transcription start sites of the corresponding coding genes. None of the eRNAs was present in all nine samples in CAGEseq data sets, indicating a patient-dependent variability in eRNA expression. The majority of eRNAs were not detected in unstimulated SF, with the exception of eRNAs for CXCL12. By performing TNF time course experiments (Figure 1), we have detected different patterns of eRNAs: (a) eRNAs, that peaked at 1h (eCCL20, eIL8#2, eCCL2#1), (b) at 6h (eCXCL1#1), (c) or at 24h (eIL8#1, eIL8#3, eIL8#4, eCXCL1#2) after stimulation, (d) eRNAs that were stably expressed over the time points (eCCL2#2, 3, 4), and (e) eRNAs that were down regulated by TNF stimulation (eCXCL12#1, eCXCL12#3). All inflammatory stimuli induced eRNA expression in SF, with LPS and IL1, followed by TNF, being the most potent inducers of eRNAs. I-BET suppressed the TNF-induced expression of all eRNAs tested. The effects on the expression of eRNAs after silencing of p300 but not of CBP mirrored to a large extent those of the respective coding genes.Figure 1.ConclusionIn SF, the expression of some eRNAs is maintained for up to 24h, contradicting previous reports that eRNAs are short-lived. Our data suggest that different eRNAs orchestrate the early and sustained expression of cytokines and chemokines in SF. eRNA expression is controlled by p300 and BET bromodomain proteins.Disclosure of InterestsLarissa Moser: None declared, Miranda Houtman: None declared, Oliver Distler Consultant of: Abbvie, Britta Maurer Speakers bureau: Boehringer-Ingelheim, Consultant of: Novartis, Boehringer Ingelheim, Janssen-Cilag, Grant/research support from: AbbVie, Protagen, Novartis Biomedical Research, Caroline Ospelt: None declared, Kerstin Klein Grant/research support from: Novartis Foundation for biomedical research (2019)

A study was conducted to evaluate the effects of a multi-strain Bacillus subtilis-based direct-fed microbial (DFM) on growth performance and apparent nutrient digestibility of nursery pigs. Eighty pigs, of equal number of barrows and gilts (initial body weight: 7.0 ± 0.60 kg), were weaned at 21 ± 1 d and randomly allotted to 1 of the 16 pens, with 5 pigs per pen. Two dietary treatments were implemented, a basal control (CON) and a control plus DFM (CDFM). Both diets were corn, soybean meal, and distillers dried grains based. Diets were fed for 42 d and growth performance measures were recorded weekly. On days 21 and 42 of the experiment, one pig per pen, with equal number of males and females, was randomly selected and euthanized. Digestibility of nitrogen (N), amino acids (AA), and energy were evaluated within the duodenum, jejunum, ileum, and ascending and distal colon. Relative to CON, CDFM tended to increase ADG during week 2 (P = 0.08) and significantly increased ADFI during week 2 (P = 0.04) and week 3 (P = 0.02). In addition, CDFM decreased the gain to feed ratio (G:F) during week 6 relative to CON (P = 0.04). Within the jejunum, pigs fed the DFM had greater digestibility of tryptophan (P = 0.04) and cysteine (P = 0.04) and tended to have greater digestibility of lysine (P = 0.07), methionine (P = 0.06), and threonine (P = 0.08), relative to CON. The content pH in the ascending colon did not differ between CDFM and CON. Compared with CON, apparent total tract digestibility (ATTD) of energy did not differ from CDFM, whereas ATTD of nitrogen of CDFM was lower (P = 0.05). The addition of a multi-strain B. subtilis-based DFM appears to impact growth performance, AA, and N digestibility depending upon the location in the gastrointestinal tract, with primary AA differences occurring within the mid-jejunum.