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The use of debriefing by 6 elite coaches (9–16 years’ experience coaching professional boxers) and 6 professional boxers (minimum 3 professional bouts) was explored via interviews (25–40 minutes). Boxers represented the featherweight, welterweight, and heavyweight divisions. Interview questions were framed around, 1) the use of video and data analysis, 2) coach-athlete interaction, and 3) learning and development. The importance of data, video, and the effective integration of performance analysis to facilitate comprehensive feedback to maximise learning opportunities was identified. The coach-athlete relationship, and engagement of the athlete within the debriefing process emerged as an aspect needing continual micro-management to ensure ongoing effectiveness. The development of an “open and honest” relationship and a “safe space” to air thoughts and opinions was greatly encouraged. The length of debriefing session did not appear to impact overall engagement. The use of video debriefing to facilitate a coach’s ability to develop the athletes mentally, in addition to their physical boxing capabilities, was a key and standout aspect that should be appropriately considered. The findings add to the limited investigation within boxing, providing insight into the debriefing processes within professional boxing by those on both sides, i.e. the coach and the athlete.

Checkpoint inhibitors offer a promising immunotherapy strategy for cancer treatment; however, due to primary or acquired resistance, many patients do not achieve lasting clinical responses. Recently, the transforming growth factor-β (TGFβ) signaling pathway has been identified as a potential target to overcome primary resistance, although the nonselective inhibition of multiple TGFβ isoforms has led to dose-limiting cardiotoxicities. SRK-181 is a high-affinity, fully human antibody that selectively binds to latent TGFβ1 and inhibits its activation. To support SRK-181 clinical development, we present here a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies showed that SRK-181 has no effect on human platelet function and does not induce cytokine release in human peripheral blood. Four-week toxicology studies with SRK-181 showed that weekly intravenous administration achieved sustained serum exposure and was well tolerated in rats and monkeys, with no treatment-related adverse findings. The no-observed-adverse-effect levels levels were 200 mg/kg in rats and 300 mg/kg in monkeys, the highest doses tested, and provide a nonclinical safety factor of up to 813-fold (based on Cmax) above the phase 1 starting dose of 80 mg every 3 weeks. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that SRK-181 is a selective inhibitor of latent TGFβ1 that does not produce the nonclinical toxicities associated with nonselective TGFβ inhibition. These data support the initiation and safe conduct of a phase 1 trial with SRK-181 in patients with advanced cancer.

Concordance between 18 coaches (mean performance analysis experience: 8.3 ± 4.8 years) and 23 performance analysts (mean: 6.4 ± 4.1 years) regarding their performance analysis delivery within applied Olympic and Paralympic environments was investigated using survey-based methods. There was clear agreement on the provision, importance and need for full video. The majority of analysts (73.9%) provided profiling often or all of the time, whereas only one third of coaches felt that this was the required amount. Coaches not only agreed that coaching philosophy was the main factor directing analysis but also emphasised that training goals, level or age of athlete and discussions with athletes were influencers, far more than the analysts realised. A potential barrier for better communication was time, highlighted by all analysts as a major factor impacting their role. The majority of analysts (87%) attempted to provide feedback to athletes within one hour of performance, often or all the time. Coaches expressed a similar philosophy but were far more likely to want to provide feedback at later times. These findings should be utilised by analysts and coaches to review practice, identify gaps within practice and highlight areas for development.

Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 A resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen-antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.

We catalog the 443 bright supernovae discovered by the All-Sky Automated Survey for Supernovae (ASAS-SN) in $2018-2020$ along with the 519 supernovae recovered by ASAS-SN and 516 additional $m_{peak}\leq18$ mag supernovae missed by ASAS-SN. Our statistical analysis focuses primarily on the 984 supernovae discovered or recovered in ASAS-SN $g$-band observations. The complete sample of 2427 ASAS-SN supernovae includes earlier $V$-band samples and unrecovered supernovae. For each supernova, we identify the host galaxy, its UV to mid-IR photometry, and the offset of the supernova from the center of the host. Updated light curves, redshifts, classifications, and host galaxy identifications supersede earlier results. With the increase of the limiting magnitude to $g\leq18$ mag, the ASAS-SN sample is roughly complete up to $m_{peak}=16.7$ mag and is $90\%$ complete for $m_{peak}\leq17.0$ mag. This is an increase from the $V$-band sample where it was roughly complete up to $m_{peak}=16.2$ mag and $70\%$ complete for $m_{peak}\leq17.0$ mag., Comment: 14 pages, 7 figures, 4 tables. Updated to reflect changes made in the published version. Tables containing the catalog data presented in this submission are included in machine-readable format as ancillary files

Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application. © 2022, Springer Nature Limited.

Extant research indicates that professional law enforcement officers (LEOs) are generally no better than untrained novices at detecting deception. Moreover, traditional training methods are often less effective than no training at all at improving successful detection. Compared to the traditional training, interactive digital games can provide an immersive learning environment for deeper internalization of new information through simulated practices. VERITAS—an interactive digital game—was designed and developed to train LEOs to better detect reliable deception cues when questioning suspects and determining the veracity of their answers. The authors hypothesized that reducing players' reactance would mitigate resistance to training, motivate engagement with materials, and result in greater success at deception detection and knowledge. As hypothesized, LEOs playing VERITAS showed significant improvement in deception detection from the first to the second scenario within the game; and the low-reactance version provided the most effective training. The authors also compared various responses to the game between LEOs and a separate undergraduate student sample. Relative to students, findings show LEOs perceived VERITAS to be significantly more intrinsically motivating, engaging, and appealing as a deception detection activity.

Students are regularly confronted with ethical and environmental issues of a global, regional or local nature which require knowledge of the geosciences to solve. Having the skills to engage, explore and evaluate these problems enhances student’s capacity for creative, real-world problem solving. At the Australian Science and Mathematics School, a Challenge Based Learning approach has been used across a range of learning programs including those with a focus on geoscience. Challenge Based Learning in the context of this paper is defined as a method of teaching and learning which allows students to engage in learning goals through meaningful contexts. An unfamiliar ‘ill-structured’ problem is presented to the students by the teacher and the students are required to determine for themselves how they will go about solving the problem. This process occurs through small groups of students working collaboratively and allows sharing their prior knowledge, skills and understandings to identify gaps in their collective understanding as they attempt to offer solutions to the problem. The example chosen is based around a problem requiring significant time in the field where secondary students come to know and understand the problem in greater depth while developing scientific field investigation skills.

The study considered performance analysis and feedback from the perspective of the performance analyst through the investigation of the ‘what’, ‘how’ and ‘when’ of practice within a selection of Olympic sports. Twenty-three performance analysts (experience 6.4 ± 4.1 years) engaged in a structured interview (85 ± 15 min) regarding their processes within applied practice. Likert scales (All the time, Often, Sometimes, Rarely and Never) were used to facilitate cross-sport and environment comparison. The performance analysts highlighted the experience of their coaches as the most prominent feature influencing analysis direction, and time had the greatest impact upon feedback provision. The main analysis techniques used were video, profiling and performance reports. Feedback was delivered primarily either, (1)

Aims: EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares them with patients enrolled in prior HFpEF trials. Methods and results: EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients [left ventricular ejection fraction (LVEF) >40%] with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type. natriuretic peptide (NT-proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalization. Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72 ± 9 years, 45% were women. Almost all patients had New York Heart Association class II or III symptoms (99.6%), and 23% had prior heart failure hospitalization within 12 months. Thirty-three percent of the patients had baseline LVEF of 41–50%. The mean LVEF (54 ± 9%) was slightly lower while the median NT-proBNP [974 (499–1731) pg/mL] was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor–neprilysin inhibitors (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists. Conclusion: When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of comorbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021. © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

We observed enhanced tau spreading in the aging mouse brain and tau misfolding in brain regions vulnerable in Alzheimer’s disease., The incidence of Alzheimer’s disease (AD), which is characterized by progressive cognitive decline that correlates with the spread of tau protein aggregation in the cortical mantle, is strongly age-related. It could be that age predisposes the brain for tau misfolding and supports the propagation of tau pathology. We tested this hypothesis using an experimental setup that allowed for exploration of age-related factors of tau spread and regional vulnerability. We virally expressed human tau locally in entorhinal cortex (EC) neurons of young or old mice and monitored the cell-to-cell tau protein spread by immunolabeling. Old animals showed more tau spreading in the hippocampus and adjacent cortical areas and accumulated more misfolded tau in EC neurons. No misfolding, at any age, was observed in the striatum, a brain region mostly unaffected by tangles. Age and brain region dependent tau spreading and misfolding likely contribute to the profound age-related risk for sporadic AD.

Several theories have sought to address responses to normatively deviant behavior, but have done so with a focus either on group-level or on individual-level behavior. Yet, due to some characteristics of online contexts, identities can be salient at both a group and/or individual level, creating a more complex set of influences on responding to deviance. We explore responses to online communicative deviance by integrating social identity approaches (a group-level perspective) and expectancy violations theory (an individual-level perspective). Social identity emphasizes the role of group identification in responding to deviance, especially relevant in anonymous online contexts, while expectancy violations theory notes how individuals respond to ambiguous deviance through assessing the reward value of the deviant.

The study investigated the observational capabilities of experienced elite coaches whilst focusing upon soccer specific actions and playing positions within elite youth soccer. Six soccer coaches assessed the performances of 10 youth soccer players (across 8 matches) on their short/long passing, tackling, shooting, heading and dribbling. Analysis was undertaken on an overall, quality and positional grouping basis. Mean observational accuracy was 38.8%, with successful shooting (78.6%) and passing (29.9%) illustrating the range. The limited effective observation of dribbling (37.2%), often considered a separating factor within talent identification, highlights the need for objective measures to aid such processes. Positional grouping analysis elicited ∼20% more effective observation for unsuccessful compared with successful actions. The poor level of observational accuracy identified herein has significant implications on talent identification assessments devoid of post-performance analyses. The findings reinforce the importance of performance analysis in the provision of highly accurate and comprehensive augmented feedback within the coaching process.

Proteases are one of the most important and historically utilized classes of drug targets. To effectively interrogate this class of proteins, which encodes nearly 2% of the human proteome, it is necessary to develop effective and cost-efficient methods that report on their activity both in vitro and in vivo. We have developed a robust reporter of caspase proteolytic activity, called caspase-activatable green fluorescent protein (CA-GFP). The caspases play central roles in homeostatic regulation, as they execute programmed cell death, and in drug design, as caspases are involved in diseases ranging from cancer to neurodegeneration. CA-GFP is a genetically encoded dark-to-bright fluorescent reporter of caspase activity in in vitro, cell-based, and animal systems. Based on the CA-GFP platform, we developed reporters that can discriminate the activities of caspase-6 and -7, two highly related proteases. A second series of reporters, activated by human rhinovirus 3C protease, demonstrated that we could alter the specificity of the reporter by reengineering the protease recognition sequence. Finally, we took advantage of the spectrum of known fluorescent proteins to generate green, yellow, cyan, and red reporters, paving the way for multiplex protease monitoring.

Apoptosis is critical for organismal homeostasis and a wide variety of diseases. Caspases are the ultimate executors of the apoptotic programmed cell death pathway. As caspases play such a central role in apoptosis, there is significant demand for technologies to monitor caspase function. We recently developed a caspase activatable-GFP (CA-GFP) reporter. CA-GFP is unique due to its “dark” state, where chromophore maturation of the GFP is inhibited by the presence of a C-terminal peptide. Here we show that chromophore maturation is prevented because CA-GFP does not fold into the robust β-barrel of GFP until the peptide has been cleaved by active caspase. Both CA-GFP and GFP1-10, a split form of GFP lacking the 11th strand, have similar secondary structure, different from mature GFP. A similar susceptibility to proteolytic digestion indicates that this shared structure is not the robust, fully formed GFP β-barrel. We have developed a model that suggests that as CA-GFP is translated in vivo it follows the same folding path as wild-type GFP; however, the presence of the appended peptide does not allow CA-GFP to form the barrel of the fully matured GFP. CA-GFP is therefore held in a “pro-folding” intermediate state until the peptide is released, allowing it to continue folding into the mature barrel geometry. This new understanding of the structural basis of the dark state of the CA-GFP reporter will enable manipulation of this mechanism in the development of reporter systems for any number of cellular processes involving proteases and potentially other enzymes.

In Alzheimer's disease and other tauopathies, tau displays several abnormal post-translation modifications such as hyperphosphorylation, truncation, conformation, and oligomerization. Mouse monoclonal antibodies have been raised against such tau modifications for research, diagnostic, and therapeutic purposes. However, many of these primary antibodies are at risk of giving nonspecific signals in common Western blotting procedures. Not because they are unspecific, but because the secondary antibodies used to detect them will also detect the heavy chain of endogenous mouse immunoglobulins (Igs), and give a nonspecific signal at the same molecular weight than tau protein (around 50 kDa). Here, we propose the use of anti-light chain secondary antibodies as a simple and efficient technique to prevent nonspecific Igs signals at around 50 kDa. We demonstrate the efficacy of this method by removing artifactual signals when using monoclonal antibodies directed at tau phosphorylation (AT100, 12E8, AT270), tau truncation (TauC3), tau oligomerization (TOMA), or tau abnormal conformation (Alz50), in wild-type, 3×Tg-AD, and tau knockout mice.

In Alzheimer's disease and other tauopathies, tau displays several abnormal post-translation modifications such as hyperphosphorylation, truncation, conformation, and oligomerization. Mouse monoclonal antibodies have been raised against such tau modifications for research, diagnostic, and therapeutic purposes. However, many of these primary antibodies are at risk of giving nonspecific signals in common Western blotting procedures. Not because they are unspecific, but because the secondary antibodies used to detect them will also detect the heavy chain of endogenous mouse immunoglobulins (Igs), and give a nonspecific signal at the same molecular weight than tau protein (around 50 kDa). Here, we propose the use of anti-light chain secondary antibodies as a simple and efficient technique to prevent nonspecific Igs signals at around 50 kDa. We demonstrate the efficacy of this method by removing artifactual signals when using monoclonal antibodies directed at tau phosphorylation (AT100, 12E8, AT270), tau truncation (TauC3), tau oligomerization (TOMA), or tau abnormal conformation (Alz50), in wild-type, 3×Tg-AD, and tau knockout mice.

SN 2016gkg is a nearby Type IIb supernova discovered shortly after explosion. Like several other Type IIb events with early-time data, SN 2016gkg displays a double-peaked light curve, with the first peak associated with the cooling of a low-mass extended progenitor envelope. We present unprecedented intranight-cadence multi-band photometric coverage of the first light-curve peak of SN 2016gkg obtained from the Las Cumbres Observatory Global Telescope network, the Asteroid Terrestrial-impact Last Alert System, the Swift satellite and various amateur-operated telescopes. Fitting these data to analytical shock-cooling models gives a progenitor radius of ~25-140 solar radii with ~2-30 x 10^-2 solar masses of material in the extended envelope (depending on the model and the assumed host-galaxy extinction). Our radius estimates are broadly consistent with values derived independently (in other works) from HST imaging of the progenitor star. However, the shock-cooling model radii are on the lower end of the values indicated by pre-explosion imaging. Hydrodynamical simulations could refine the progenitor parameters deduced from the shock-cooling emission and test the analytical models., Accepted by ApJL

This manuscript presents information for all supernovae discovered by the All-Sky Automated Survey for SuperNovae (ASAS-SN) during 2015, its second full year of operations. The same information is presented for bright ($m_V\leq17$), spectroscopically confirmed supernovae discovered by other sources in 2015. As with the first ASAS-SN bright supernova catalog, we also present redshifts and near-UV through IR magnitudes for all supernova host galaxies in both samples. Combined with our previous catalog, this work comprises a complete catalog of 455 supernovae from multiple professional and amateur sources, allowing for population studies that were previously impossible. This is the second of a series of yearly papers on bright supernovae and their hosts from the ASAS-SN team., 16 pages, 6 figures, 4 tables. Submitted to MNRAS. Tables containing the catalog data presented in this submission are included in machine-readable format as ancillary files. Manuscript updated to reflect changes made in the published version and to correct an error in the host galaxy magnitudes presented in Tables 3 and 4. For a brief video explaining this paper, see https://youtu.be/iqYJp1AmyMw

Tau is a neuronal microtubule binding protein that, in Alzheimer’s disease and other neurodegenerative diseases, can form oligomeric and large fibrillar aggregates, which deposit in neurofibrillary tangles. Tau’s physiological state of multimerization appears to vary across conditions, and a stable dimeric form of soluble tau has been suggested from experiments using recombinant tau in vitro. We tested if tau dimerization, or oligomerization, also occurs in cells, and if soluble tau oligomers are relevant for the release and internalization of tau. We developed a sensitive tau split-luciferase assay to show the rapid intracellular formation of stable tau dimers that are released and taken up by cells. Our data further suggest that tau dimerization can be accelerated slightly by aggregation catalysts. We conclude that tau oligomers are a stable physiological form of tau, and that tau oligomerization does not necessarily lead to tau aggregation.

A 74-year-old woman received thrombolysis for pericarditis. She subsequently developed shock and cardiac arrest. The case report describes the events of how a simple immediate bedside focused echo proved to be a life saving assessment. Current availability and training issues in focused transthoracic echo are discussed.

Australia has an abundance of native Sapindaceae, with a few species that are considered to have an edible aril. A number of these have minor 'bush food' status but have limited commercial potential. Longan, lychee and rambutan were introduced into Australia from the mid 1800s. Serious commercialization of these crops began from the 1970s when farmers in sub-tropical and tropical regions of Australia were seeking new commercial horticultural opportunities. Currently the value of these industries is in the vicinity of $35 M with lychee the predominate crop followed by longan and rambutan respectively. Despite Australia being a minor producer on the world scale it has contributed significantly to the scientific and production developments through the combined efforts of researchers and innovative growers. This paper details the development and status of the commercial Sapindaceae in Australia and highlights production and research activities.

Tree dwelling bats select cavities in large, old, dying or dead trees. This inevitably brings them into direct conflict with the interests of forest managers, who are trained to fell such trees. Therefore the identification of forest stands providing optimal roosting opportunities for bats is crucial, in order to provide appropriate guidelines for forest management. It is also important to identify the extent to which the roosting ecology of bats changes in response to habitat modification. Bialowieza Forest (BF) offers a unique opportunity, in the temperate zone, to observe differences between areas with no direct human intervention and managed areas and in particular to reveal the effect of forest management on the roosting ecology of forest dwelling bat species. We used GIS techniques to evaluate bats' spatial response to changes in forest structure and to test the hypotheses that the forest dwelling bats Nyctalus noctula and Nyctalus leisleri prefer roost sites within old deciduous or wet woodlands over young and coniferous ones and that roost site preferences reflect the extent to which dead and dying trees are removed. There was a significant difference in the selection of roosting habitat between the managed and pristine areas of the forest. Within the pristine forest, both species displayed a strong preference for roost trees located within old deciduous stands (>100 years), whereas in the managed part of the forest old wet woodland was preferred while all medium and young forest stands were avoided. Our data reveal a high degree of lability in the selection of roosting habitat by bats. It appears that bats are able to respond to changes in their environment by changing their roost site preferences and could therefore occupy habitat previously considered less suitable.

We report the discovery of ASASSN-15lh (SN 2015L), which we interpret as the most luminous supernova yet found. At redshift z = 0.2326, ASASSN-15lh reached an absolute magnitude of Mu ,AB = -23.5 ± 0.1 and bolometric luminosity Lbol = (2.2 ± 0.2) × 10(45) ergs s(-1), which is more than twice as luminous as any previously known supernova. It has several major features characteristic of the hydrogen-poor super-luminous supernovae (SLSNe-I), whose energy sources and progenitors are currently poorly understood. In contrast to most previously known SLSNe-I that reside in star-forming dwarf galaxies, ASASSN-15lh appears to be hosted by a luminous galaxy (MK ≈ -25.5) with little star formation. In the 4 months since first detection, ASASSN-15lh radiated (1.1 ± 0.2) × 10(52) ergs, challenging the magnetar model for its engine.

Objective Cerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimer's disease (AD) patients. However, whether the elevated tau in AD CSF is just a marker of neurodegeneration or, in fact, a part of the disease process is uncertain. Moreover, it is unknown how CSF tau relates to the recently described soluble high-molecular-weight (HMW) species that is found in the postmortem AD brain and can be taken up by neurons and seed aggregates. Methods We have examined seeding and uptake properties of brain extracellular tau from various sources, including interstitial fluid (ISF) and CSF from an AD transgenic mouse model and postmortem ventricular and antemortem lumbar CSF from AD patients. Results We found that brain ISF and CSF tau from the AD mouse model can be taken up by cells and induce intracellular aggregates. Ventricular CSF from AD patients contained a rare HMW tau species that exerted a higher seeding activity. Notably, the HMW tau species was also detected in lumbar CSF from AD patients, and its levels were significantly elevated compared to control subjects. HMW tau derived from CSF of AD patients was seed competent in vitro. Interpretation These findings suggest that CSF from an AD brain contains potentially bioactive HMW tau species, giving new insights into the role of CSF tau and biomarker development for AD. Ann Neurol 2016;80:355–367

We report the discovery of ASASSN-15lh (SN 2015L), which we interpret as the most luminous supernova yet found. At redshift z = 0.2326, ASASSN-15lh reached an absolute magnitude of M_{u,AB} = -23.5+/-0.1 and bolometric luminosity L_bol = (2.2+/-0.2)x 10^45 ergs s^-1, which is more than twice as luminous as any previously known supernova. It has several major features characteristic of the hydrogen-poor super-luminous supernovae (SLSNe-I), whose energy sources and progenitors are currently poorly understood. In contrast to most previously known SLSNe-I that reside in star-forming dwarf galaxies, ASASSN-15lh appears to be hosted by a luminous galaxy (M_K ~ -25.5) with little star formation. In the 4 months since first detection, ASASSN-15lh radiated (1.1+/- 0.2)x10^52 ergs, challenging the magnetar model for its engine., Comment: Published in the January 15, 2016 Issue of Science Magazine

In Alzheimer's disease and tauopathies, tau protein aggregates into neurofibrillary tangles that progressively spread to synaptically connected brain regions. A prion-like mechanism has been suggested: misfolded tau propagating through the brain seeds neurotoxic aggregation of soluble tau in recipient neurons. We use transgenic mice and viral tau expression to test the hypotheses that trans-synaptic tau propagation, aggregation, and toxicity rely on the presence of endogenous soluble tau. Surprisingly, mice expressing human P301Ltau in the entorhinal cortex showed equivalent tau propagation and accumulation in recipient neurons even in the absence of endogenous tau. We then tested whether the lack of endogenous tau protects against misfolded tau aggregation and toxicity, a second prion model paradigm for tau, using P301Ltau-overexpressing mice with severe tangle pathology and neurodegeneration. Crossed onto tau-null background, these mice had similar tangle numbers but were protected against neurotoxicity. Therefore, misfolded tau can propagate across neural systems without requisite templated misfolding, but the absence of endogenous tau markedly blunts toxicity. These results show that tau does not strictly classify as a prion protein.

Tau pathology is known to spread in a hierarchical pattern in Alzheimer’s disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.

Multiple antenna transceivers combined with MIMO signal processing offer the potential for increased data rates and/or range in wireless systems. This paper presents a fully integrated 5-GHz 2times2 MIMO WLAN transceiver RFIC implemented in 90-nm CMOS. The paper identifies the key MIMO integration issues and proposes techniques to optimize MIMO performance. It is shown that crosstalk between the multiple transceivers residing on the same die can degrade MIMO performance and has to be carefully minimized, especially when power amplifiers are integrated on-die. A shared LO generation and distribution network is designed to maximize MIMO phase noise immunity without introducing undesired crosstalk. The fabricated MIMO receiver achieves a sensitivity of -63 dBm while receiving 108Mb/s in MIMO spatial multiplexing mode in the presence of a 25-ns Rayleigh fading channel. The sensitivity of a single receiver in the presence of AWGN noise is -76 dBm. Linearized 3.3-V 5-GHz power amplifiers with P1dB=20.5 \ dBm deliver an average power of +13/+16 dBm each, in MIMO/SISO modes respectively (EVM=-27/-25 dB). The measured performance demonstrates the effectiveness of the isolation techniques employed. The system in a package includes an 18 mm2 die and microstrip front-end matching networks implemented on a flip-chip package

The extent of spatial partitioning in insectivorous bats, whose prey is patchily distributed and transient in nature, remains a contentious issue. The recent separation of a common Palaearctic bat, the pipistrelle, into Pipistrellus pipistrellus and Pipistrellus pygmaeus, which are morphologically similar and sympatric, provides an opportunity to examine this question. The present study used radio telemetry to address the spatial distribution and foraging characteristics of P. pipistrellus and P. pygmaeus in northeast Scotland, to test the hypothesis that coexistence between these species is facilitated through spatial segregation. We reveal large and significant differences in the spatial distribution and foraging characteristics of these two cryptic species. Individual P. pipistrellus home ranges were on average three times as large as that of P. pygmaeus, and they foraged for approximately an hour longer each night. Inter-specific spatial overlap was minimal (

Caspases are a family of integral proteases playing a role in apoptosis. The importance of apoptosis in disease has made these proteases not only an attractive drug target but also a focal point for measuring apoptosis in vivo. The critical role caspases play in determining cell death has led to the development of a wide array of technologies to measure caspase activity in vivo, ranging from small molecule PET imaging reagents to fluorescent and luminescent protein-based reporters used in whole animal and cell-based applications. This chapter reviews this wide range of technologies available as well as the most appropriate applications for each reagent and the mechanism of how it measures caspase activity in vivo.

Caspases are a family of integral proteases playing a role in apoptosis. The importance of apoptosis in disease has made these proteases not only an attractive drug target but also a focal point for measuring apoptosis in vivo. The critical role caspases play in determining cell death has led to the development of a wide array of technologies to measure caspase activity in vivo, ranging from small molecule PET imaging reagents to fluorescent and luminescent protein-based reporters used in whole animal and cell-based applications. This chapter reviews this wide range of technologies available as well as the most appropriate applications for each reagent and the mechanism of how it measures caspase activity in vivo.

Laboratory-scale upflow anaerobic sludge blanket (UASB) digesters containing granular sludge adapted to brewery effluent were fed increasing concentrations of artificial coal gasification (CG) waste water in brewery effluent and were effective at purifying this combined waste water up to a CG effluent concentration of 15%. At higher CG waste water concentrations and flow rates, performance declined rapidly.

Neurofibrillary tangles (NFTs), a marker of neuronal alterations in Alzheimer's disease (AD) and other tauopathies, are comprised of aggregates of hyperphosphorylated tau protein. We recently studied the formation of NFTs in the entorhinal cortex (EC) and their subsequent propagation through neural circuits in the rTgTauEC mouse model (de Calignon et al., 2012). We now examine the consequences of suppressing transgene expression with doxycycline on the NFT-associated pathological features of neuronal system deafferentation, NFT progression and propagation, and neuronal loss. At 21 months of age we observe that EC axonal lesions are associated with an abnormal sprouting response of acetylcholinesterase (AChE)-positive fibers, a phenotype reminiscent of human AD. At 24 months, NFTs progress, tau inclusions propagate to the dentate gyrus, and neuronal loss is evident. Suppression of the transgene expression from 18 to 24 months led to reversal of AChE sprouting, resolution of Gallyas-positive and Alz50-positive NFTs, and abrogation of progressive neuronal loss. These data suggest that propagation of NFTs, as well as some of the neural system consequences of NFTs, can be reversed in an animal model of NFT-associated toxicity, providing proof in principle that these lesions can be halted, even in established disease.

Neurofibrillary tangles (NFTs), a hallmark of Alzheimer’s disease (AD), are intracellular silver and thioflavin S-staining aggregates that emerge from earlier accumulation of phospho-tau in the soma. Whether soluble misfolded but nonfibrillar tau disrupts neuronal function is unclear. Here we investigate if soluble pathological tau, specifically directed to the entorhinal cortex (EC), can cause behavioral or synaptic deficits. We studied rTgTauEC transgenic mice, in which P301L mutant human tau overexpressed primarily in the EC leads to the development of tau pathology, but only rare NFT at 16 months of age. We show that the early tau lesions are associated with nearly normal performance in contextual fear conditioning (CFC), a hippocampal related behavior task, but more robust changes in neuronal system activation as marked by Arc induction and clear electrophysiological defects in perforant pathway synaptic plasticity. Electrophysiological changes were likely due to a presynaptic deficit and changes in probability of neurotransmitter release. The data presented here support the hypothesis that misfolded and hyperphosphorylated tau can impair neuronal function within the entorhinal-hippocampal network, even prior to frank NFT formation and overt neurodegeneration.

We report gas-phase electronic structure calculations on helical peptides that act as scaffolds for imidazole-based hydrogen-bonding networks (proton wires). We have modeled various 21-residue polyalanine peptides substituted at regular intervals with histidines (imidazole-bearing amino acids), using a hybrid approach with a semiempirical method (AM1) for peptide scaffolds and density functional theory (B3LYP) for proton wires. We have computed energy landscapes including barriers for Grotthuss-shuttling-type proton motions though wires supported on 3(10)-, α- and π-helical structures, showing the 3(10)- and α-helices to be attractive targets in terms of high proton affinities, low Grotthuss shuttling barriers, and high stabilities. Moreover, bias forces provided by the helical dipole moments were found to promote unidirectional proton translocation.