cssi/SciSciGPT-SciSciNet huggingface dataset:
Measuring the Fit of Sequence Data to Phylogenetic Model: Allowing for Missing Data

It is fundamentally important to assess the fit of data to model in phylogenetic and evolutionary studies. Phylogenetic methods using molecular sequences typically start with a multiple alignment. It is possible to measure the fit of data to model expectations of data, for example, via the likelihood-ratio (G) test or the X(2) test, if all sites in all sequences have an unambiguous residue. However, nearly all alignments of interest contain sites (columns of the alignment) with missing data, that is, ambiguous nucleotides, gaps, or unsequenced regions, which must presently be removed before using the above tests. Unfortunately, this is often either undesirable or impractical, as it will discard much of the data. Here, we show how iterative ML estimators may directly estimate the site-pattern probabilities for columns with missing data, given only standard i.i.d. assumptions. The optimization may use an EM or Newton algorithm, or any other hill-climbing approach. The resulting optimal likelihood under the unconstrained or multinomial model may be compared directly with the likelihood of the data coming from the model (a G statistic). Alternatively the modified observed and the expected frequencies of site patterns may be compared using a X(2) test. The distribution of such statistics is best assessed using appropriate simulations. The new method is applicable to models using codons or paired sites. The methods are also useful with Hadamard conjugations (spectral analysis) and are illustrated with these and with ML evolutionary models that allow site-rate variability.
Observations on the superficial sediment temperatures of some lakes in the southeastern United States

Summary Temperatures of the water column and upper 5 cm of sediment were monitored over a yearly cycle in two South Carolina lakes. Occasional supportive data were also obtained for several lakes in north central Florida. Plans are given for a new type of sediment-interface sampler that is useful in obtaining detailed temperature or chemical profiles extending from the sediment surface upward. The sampler was used in the investigation to demonstrate the thermal microstratigraphy near the mud surface. The deep-water (16 m) temperature for the larger of the two South Carolina lakes changes seasonally from 10·5°C in February to 18·0°C in July. The smaller, shallower (11 m) lake follows an almost identical seasonal cycle but is always 4·0°C cooler because the larger lake receives a heated effluent that has a long-term effect on hypolimnetic temperatures. In both lakes the uppermost sediments are warmer than the overlying water by an average of 0·1 to 1·0°C during the warming period. Heat accretion near the bottom continues but is slower after stratification, probably due to the relatively low temperature (density) differential between water layers in these warm lakes. Cooling in deep water begins long before breakdown of stratification and is apparently caused by cold density currents from the shallows. The coldest water is located in a thin layer just over the sediment. There is evidence from one of the South Carolina lakes and from the Florida lakes that when the density flows begin they at first flow over a warmer water layer that is more dense due to a high electrolyte content derived from the sediment. There is a slight deep water warming in all of the lakes when stratification breaks down. After destratification, the deep water is cooled by turbulence rather than density flows. The surface sediments at this time are consistently warmer than the hypolimnion and remain so through the cooling period. There is strong evidence from one Florida lake that turbulence mixes the upper 3 cm of sediment during the isothermal period. It is concluded that the sediment-water interface of a warm lake will in general experience greater heat flux than that of a comparable cold lake during the periods of temperature maximum and minimum. Conversely, there is likely to be less heat flux during the warming and cooling periods of warm lakes than of cold lakes. Several expected differences in seasonal patterns of temperature and water movement in the deep water of warm and cold lakes are discussed.
Loss of Interleukin-21 Receptor Activation in Hypoxic Endothelial Cells Impairs Perfusion Recovery After Hindlimb Ischemia

Objective— Surgical hindlimb ischemia (HLI) in mice has become a valuable preclinical model to study peripheral arterial disease. We previously identified that the different phenotypic outcomes after HLI across inbred mouse strains is related to a region on the short arm of mouse chromosome 7. The gene coding the interleukin-21 receptor (IL-21R) lies at the peak of association in this region. Approach and Results— With quantitative real-time polymerase chain reaction, we found that a mouse strain with a greater ability to upregulate IL-21R after HLI had better perfusion recovery than a strain with no upregulation after HLI. Immunofluorescent staining of ischemic hindlimb tissue showed IL-21R expression on endothelial cells (ECs) from C57BL/6 mice. An EC-enriched fraction isolated from ischemic hindlimb muscle showed higher Il-21R levels than an EC-enriched fraction from nonischemic limbs. In vitro, human umbilical vein ECs showed elevated IL-21R expression after hypoxia and serum starvation. Under these conditions, IL-21 treatment increased cell viability, decreased cell apoptosis, and augmented tube formation. In vivo, either knockout Il21r or blocking IL-21 signaling by treating with IL-21R-Fc (fusion protein that blocks IL-21 binding to its receptor) in C57BL/6 mice resulted in less perfusion recovery after HLI. Both in vitro and in vivo modulation of the IL-21/IL-21R axis under hypoxic conditions resulted in increased signal transducer and activator of transcription 3 phosphorylation and a subsequent increase in the B-cell lymphoma leukemia-2/BCL-2–associated X protein ratio. Conclusion— Our data indicate that IL-21R upregulation and ligand activation in hypoxic ECs may help perfusion recovery by limiting/preventing apoptosis and favoring cell survival and angiogenesis through the signal transducer and activator of transcription 3 pathway.
High-Efficiency Subharmonic Oscillations from Silicon Diodes at Frequencies up to 6 GHz

Pulsed operation of Si avalanche diodes in an oscillator circuit has produced efficiencies exceeding 45 percent at frequencies of 2.0 to 3.0 GHz, and 17 percent at 6.4 GHz. The device has a lightly punched-through structure working in a coaxial cavity, which can support both the fundamental IMPATT and its subharmonic frequencies.
The transverse bone in cleft hand: a case cohort analysis of outcome after surgical reconstruction.

Purpose To evaluate the implications of the transverse bone in cleft hand by assessing outcomes after reconstruction in comparison with a control group. Methods This study is a retrospective review of 23 hands in 18 patients following surgical reconstruction of the cleft hand. Eleven hands had a transverse bone component, and 12 hands (control group) did not. Patients and their families were contacted to assess overall satisfaction following reconstruction. Clinical and radiographic records were reviewed to assess aesthetic and functional outcomes, the need for additional surgery, and radiographic divergence angles. Results There was no difference in aesthetic or functional subjective outcomes. There was no statistically significant difference in any objective outcome measure between the two groups. The use of the cleft for pinch was more dependent on the status of the index finger and the preoperative thumb-index webspace rather than the presence of a transverse bone. Eleven (4 transverse and 7 control) hands required additional surgery to address abnormal function or posture of the index and ring fingers. Preoperative radiographic divergence angles were larger in the transverse bone group than in the control group, whereas postoperative divergence angles were nearly equivalent. Conclusions Similar outcomes between the two groups demonstrate that the presence of a transverse bone in cleft hand was not associated with worse outcomes following cleft reconstruction. Preoperative narrowing of the thumb webspace and postoperative index finger metacarpophalangeal joint abnormality are associated with worse functional outcomes. Type of study/level of evidence Therapeutic Level III.
Micro-sized Si-C Composite with Interconnected Nanoscale Building Blocks as High-Performance Anodes for Practical Application in Lithium-Ion Batteries

The emerging markets of electric vehicles (EV) and plug-in hybrid electric vehicles (PHEV) generate a tremendous demand for low-cost lithium-ion batteries (LIBs) with high energy and power densities and long cycling life. [ 1–4 ] The development of such LIBs requires development of low cost, high energy-density cathode and anode materials. Conventional anode materials in commercial LIBs are primarily synthetic graphite-based materials with a capacity of ∼ 370 mAh/g. [ 5 ] Improvements in anode performance, particularly in anode capacity, are essential to achieving high energy densities in LIBs for EV and PHEV applications. Silicon has been intensively pursued as the most promising anode material for high-energy-density LIBs because of its high specifi c capacity ( > 3500 mAh/g) and abundance. [ 6 ] Despite its high capacity, Si suffers from fast capacity fading caused by its large volume change ( > 300%) during lithiation/delithiation and the serious issues stemming from this volume change, e.g., unstable solid electrolyte interphase (SEI) and disintegration (cracking and crumbling) of the electrode structure. [ 7 , 8 ] The development of Si-C nanocomposites (e.g., nanowires, nanotubes, or nanoparticles) has been widely studied. [ 9–18 ] These nanocomposites proved to be an effective method of improving capacity and cycling stability, since nano-sized Si can alleviate fracture during volume changes and the contact between Si and carbon can maintain electrical contact and improve conductivity of the nanocomposites. However, practical application of nano-sized Si materials in LIBs is diffi cult. First, achieving a high tap density is important for fabrication of high-energy LIBs for EVs and PHEVs, because it offers a high volumetric energy density. Unfortunately, the tap density of nano-sized materials is generally low, which in turn holds down their volumetric capacity. [ 19 ] Furthermore, preparation of nano-sized Si either requires chemical/physical vapor deposition or involves complicated processes, leading to costly, low-yield synthesis that is diffi cult to scale up to practical levels. [ 20–22 ] To date, the abundance of Si has not been fully capitalized upon due to lack
Distinctive tracheid microstructure in stems of Victoria and Euryale (Nymphaeaceae).

Scanning electron microscopy (SEM) photographs of thick sections from liquid-preserved stems of Victoria cruziana and Euryale ferox show accretions of coarse fibrils on pit membranes of tracheids. The first-deposited fibrils are randomly orientated; on top of them (facing the tracheid lumina) are axially orientated coarse fibrils. The two systems are interconnected. Axially orientated fibrils were more extensively observed in Euryale than in Victoria and tips of fibrils in Euryale extend over the pit apertures onto secondary wall surfaces. Tracheid–parenchyma interfaces bear rudimentary coarse fibrils on the tracheid side. End walls of Victoria tracheids have highly porose pit membranes, thinner and less complex than those of the lateral intertracheid walls. The structures reported in Victoria and Euryale are consistent with those concurrently reported for stems of other Nymphaeaceae. Although also present in Cabombaceae, the coarse fibrils are otherwise not reported for stems of angiosperms and are not yet reported in roots of any species. Pit membrane remnants in perforation plates of various woody dicotyledons represent a nonhomologous phenomenon. The accretions of coarse fibrils in stem tracheids of Nymphaeaceae do not appear to enhance conduction, although they do contain porosities interconnecting tracheids. Removal of pit membrane remnants from perforation plates of primitive dicotyledon woods by hydrolysis does, on the contrary, suggest conduction enhancement. © 2009 The Linnean Society of London, Botanical Journal of the Linnean Society, 2009, 159, 52–57.
Training and Use of Lasers in Postgraduate Orthodontic Programs in the United States and Canada

This study was designed to determine if orthodontic residents are being trained to use lasers in the postgraduate orthodontic residency programs of the United States and Canada. An anonymous electronic survey was sent to the program director/chair of each of the seventy orthodontic residency programs, and thirty-seven (53 percent) of the programs responded. Of these thirty-seven programs, twenty-eight (76 percent) reported providing patient treatment with lasers in the orthodontic graduate program, eight (22 percent) said they do not provide treatment in the orthodontic graduate program, and one program (3 percent) reported providing laser training but not using lasers on patients. Gingivectomy and canine exposure were reported as the most common procedures that residents perform with a laser, while debonding of orthodontic brackets was the least common procedure performed with a laser. A diode laser was the most common type of laser used. Of the eight programs (22 percent) not offering laser training, four indicated having no plans to begin using lasers or training on their use. The other four indicated that they have plans to incorporate laser use in the future.
Maternal investment and male reproductive success in angiosperms: parent-offspring conflict or sexual selection?

It is possible to interpret components of seed development in angiosperms from the perspective of parent-offspring conflict (a special case of kin selection) or sexual selection. Available parentoffspring conflict models predict the evolution of traits determining the outcome of competition among related individuals soliciting maternal resources. In such models, ‘selfishness’ may spread even if it reduces female fecundity and thus population mean fitness may decline. These models are limited, however, because most of them do not simultaneously consider selection among maternal genotypes varying in the tendency to respond to their offspring. Available sexual selection models, in contrast, do consider the joint evolution of polygenic male traits (influencing viability, mating success and fecundity) and female preferences (influencing the mating success of different male phenotypes). These models have shown that male traits may evolve that are non-optimal with respect to viability. Only one recent sexual selection model explicitly incorporates direct fecundity selection upon females; this model concludes that fecundity will be maximized at equilibrium. Hence population mean fitness may decline due to reduced male viability but not due to diminished female fecundity. Available sexual selection models, however, are limited because they do not consider the effects of interactions among relatives. The assumptions and qualitative results of the two types of models are compared and discussed in the context of seed development. Differential allocation of maternal resources among genetically distinct developing seeds may be viewed from the perspective of either. Because the results of the available models of parent-offspring conflict and sexual selection are not wholly consistent and because data confirming the genetic basis of maternal patterns of investment or differential male reproductive success are scant, it is not clear which set of conclusions is most appropriate to apply to plants. To achieve the generality towards which mathematical approaches aspire, new models concerning the evolution of traits influencing resource allocation in plants must incorporate the components of both parent-offspring conflict and sexual selection.
A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28–let-7 pathway

The pluripotency factor Lin28 blocks the expression of let-7 microRNAs in undifferentiated cells during development, and functions as an oncogene in a subset of cancers. Lin28 binds to let-7 precursor (pre-let-7) RNAs and recruits 3' terminal uridylyl transferases to selectively inhibit let-7 biogenesis. Uridylated pre-let-7 is refractory to processing by Dicer, and is rapidly degraded by an unknown RNase. Here we identify Dis3l2 as the 3'-5' exonuclease responsible for the decay of uridylated pre-let-7 in mouse embryonic stem cells. Biochemical reconstitution assays show that 3' oligouridylation stimulates Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic stem cells leads to the stabilization of pre-let-7. Our study establishes 3' oligouridylation as an RNA decay signal for Dis3l2, and identifies the first physiological RNA substrate of this new exonuclease, which is mutated in the Perlman syndrome of fetal overgrowth and causes a predisposition to Wilms' tumour development.
Monovalent and divalent cation permeability and block of neuronal nicotinic receptor channels in rat parasympathetic ganglia.

Acetylcholine-evoked currents mediated by activation of nicotinic receptors in rat parasympathetic neurons were examined using whole-cell voltage clamp. The relative permeability of the neuronal nicotinic acetylcholine (nACh) receptor channel to monovalent and divalent inorganic and organic cations was determined from reversal potential measurements. The channel exhibited weak selectivity among the alkali metals with a selectivity sequence of Cs+ > K+ > Rb+ > Na+ > Li+, and permeability ratios relative to Na+ (Px/PNa) ranging from 1.27 to 0.75. The selectivity of the alkaline earths was also weak, with the sequence of Mg2+ > Sr2+ > Ba2+ > Ca2+, and relative permeabilities of 1.10 to 0.65. The relative Ca2+ permeability (PCa/PNa) of the neuronal nACh receptor channel is approximately fivefold higher than that of the motor endplate channel (Adams, D. J., T. M. Dwyer, and B. Hille. 1980. Journal of General Physiology. 75:493-510). The transition metal cation, Mn2+ was permeant (Px/PNa = 0.67), whereas Ni2+, Zn2+, and Cd2+ blocked ACh-evoked currents with half-maximal inhibition (IC50) occurring at approximately 500 microM, 5 microM and 1 mM, respectively. In contrast to the muscle endplate AChR channel, that at least 56 organic cations which are permeable to (Dwyer et al., 1980), the majority of organic cations tested were found to completely inhibit ACh- evoked currents in rat parasympathetic neurons. Concentration-response curves for guanidinium, ethylammonium, diethanolammonium and arginine inhibition of ACh-evoked currents yielded IC50's of approximately 2.5- 6.0 mM. The organic cations, hydrazinium, methylammonium, ethanolammonium and Tris, were measureably permeant, and permeability ratios varied inversely with the molecular size of the cation. Modeling suggests that the pore has a minimum diameter of 7.6 A. Thus, there are substantial differences in ion permeation and block between the nACh receptor channels of mammalian parasympathetic neurons and amphibian skeletal muscle which represent functional consequences of differences in the primary structure of the subunits of the ACh receptor channel.
Energy source, protein metabolism, and hunter-gatherer subsistence strategies

During late winter and spring, hunter-gatherers in temperate, subarctic, and arctic environments often relied on diets that provided marginal or inadequate caloric intakes. During such periods, particularly when stored food supplies dwindled or were used up entirely, lean meat became the principal source of energy. Nutritional problems associated with high-protein, low-energy diets are discussed. These problems include elevated metabolic rates, with correspondingly higher caloric requirements, and deficiencies in essential fatty acids. The relative benefits of adding fat or carbohydrate to a diet of lean meat are evaluated in light of the protein-sparing capacities of these two nutrients. Experimental data indicate that although both enhance high-protein, low-energy diets, carbohydrate is a more effective supplement than fat. Given the nutritional inadequacies of a lean-meat diet, the paper concludes with a discussion of alternative subsistence strategies that increase the availability of carbohydrate or fat at the critical time of year.
Risk inflation of sequential tests controlled by alpha investing

Streaming feature selection is a greedy approach to variable selection that evaluates potential explanatory variables sequentially. It selects significant features as soon as they are discovered rather than testing them all and picking the best one. Because it is so greedy, streaming selection can rapidly explore large collections of features. If significance is defined by an alpha investing protocol, then the rate of false discoveries will be controlled. The focus of attention in variable selection, however, should be on fit rather than hypothesis testing. Little is known, however, about the risk of estimators produced by streaming selection and how the configuration of these estimators influences the risk. To meet these needs, we provide a computational framework based on stochastic dynamic programming that allows fast calculation of the minimax risk of a sequential estimator relative to an alternative. The alternative can be data driven or derived from an oracle. This framework allows us to compute and...
Understanding the impact of abnormal cardiac activation on cardiac function

Poor exercise tolerance is both a symptom of left ventricular (LV) dysfunction and a predictor of reduced survival in patients with known cardiac dysfunction [(1)][1]. Yet, poor exercise capacity in patients with reduced LV systolic function is not predicted by level of ejection fraction.
Etoposide and mitoxantrone in newly diagnosed acute myeloid leukemia patients with persistent leukemia after a course of induction therapy with cytarabine and idarubicin

7073 Background: The goal of induction chemotherapy in acute myeloid leukemia (AML) is complete remission with restoration of normal bone marrow. If residual leukemia is present after the first cou...
Dialectic as Experiment

Many biographics and autobiographics attest to the power that stories play within modern large-scale organizations. These autobiographics retell in a form strikingly similar to the great epic myths of the past (Murray, 1960), the life of the organization and that of the individual within it. They describe in heroic terms more dramatic than life itself, the difficult circumstances under which the organization was born, the tremendous struggle that had to be overcome to keep the organization alive in the early perilous years of its existence, how those involved made great personal sacrifices born out of intense dedication to the organization, how the organization began slowly to grow and, finally, how in later years, the organization achieved a success far greater than one had ever dared to dream. The story becomes the corporate myth and is the transcript which establishes and perpetuates corporate traditions. It is recounted at formal occasions and at coffee break ‘bull session’ and is used to indoctrinate new employees. The corporate myth is the ‘spirit’ of the organization and is infused into all levels of policy and decision-making. Most important of all, these biographical and autobiographical sketches give credence to the notion that an organization’s factual data, no matter how precise or accurate they may be, are not information unless they are integrated into one or more of the key motifs which define the symbolic nature of the organization.1
Successive interference canceller with residual interference reduction for M2M wireless access system

This paper proposes two residual interference reduction schemes for the successive interference canceller (SIC) in M2M wireless access systems. In general, it's difficult for SIC to completely eliminate interference due to channel estimation errors. Such errors are a serious problem if there are many terminals and the environment is multi-path. The first scheme, the Pre-FDE scheme, employs frequency domain pre-equalization (Pre-FDE) at the terminal side to alleviate the effect of multi-path propagation; it allows the base station to estimate the channel state information (CSI) precisely and also to reduce the residual interference. In the second scheme, the Path-SIC scheme, the base station estimates the CSI accurately by dealing with the interference replica of one path, not one terminal in one subtraction. Both schemes are simulated using actual temporal channel variations obtained by experiments. The simulation results show that the Pre-FDE scheme and the Path-SIC scheme improve the number of terminals transmitting simultaneously from 6 to over 10 compared with the conventional one. However, the PER performance of the Pre-FDE scheme degrades as the environmental speed increases.
Pseudomonas pseudomallei in a case of chronic melioidosis.

Cultural biochemical, and morphologic characteristics of the organism Pseudomonas pseudomallei , isolated in pure culture from bronchial aspirations, are described. The organism was isolated from a 68-year-old Caucasian man with a 12-year history of chronic respiratory infection following his first visit to the Far East in 1957 and his many return visits while performing his occupation as a well driller. The study has emphasized the importance of certain key features in the identification of the organism.
Thallium-201-Chloride Lung Imaging for Bronchogenic Carcinoma

To evaluate the clinical utility of thallium-201-(201Tl) chloride lung imaging for patients with suspected lung tumor or recurrent tumor before and/or after thoracic surgery, 33 men (aged 50 to 79; mean 62) with recurrent or suspected carcinoma of the lung underwent201Tl-chloride planar lung imaging. Planar lung images (anterior, posterior, and lateral views) were obtained 15 min after i.v. injection of 2–4 mCi of201Tl-chloride. Thallium-201 lung images were compared with concurrent computed tomography of the chest and correlated to the pathologic results from bronchial washing, bronchoscopic biopsy, lobectomy and/or pneumonectomy. In 23 of 33 patients, planar images were compatible with carcinoma manifesting focal areas of uptake. Ten of the 33 patients had diffuse lung uptake or focal area of lung uptake, while six patients had diffuse or focal uptake of the lung in a nonmalignant condition which interfered with interpretation. Six benign lesions included one in chronic inflammation, one in pneumonia, one in granulomatous inflammation, one in squamous metaplasia, and two in nonmalignancy. Three of the six patients’ lung images showed focal areas of uptake and lung images of three others demonstrated diffuse lung uptake. Diffuse lung uptake in malignant lesions(s) of four patients interfered with scan interpretation. Four of these six patients with nonmalignant conditions and two of four patients with diffuse uptake in malignant lesion(s) had a history of smoking and/or obstructive lung disease, two had undergone recent thoracotomy and one postirradiation. These results suggest201Tl-chloride localized in the benign lesions of the lung and/or diffuse lung uptake may interfere with the interpretation of201Tl-chloride lung images.
Analysis of the Power Density at the Onset of Flash Sintering

The large bank of data for ceramics from experiments in flash sintering reveal a surprising characteristic: that the transition to a highly nonlinear rise in electrical conductivity—a signature event for the onset of the flash—occurs within a narrow range of power density. This condition holds for ceramics that are semiconductors, ionic conductors, electronic conductors, and insulators.They flash at temperatures that range from 300°C to 1300°C, and at electric fields from 10 V/cm to over 1000 V/cm. Yet, the power expenditure at the transition for all of them still falls within this narrow range. This, rather uniform value of power dissipation suggests that Joule heating is a key factor in instigating the flash. A general formulation is developed to test if indeed Joule heating alone can lead to the progression of such nonlinear behavior. It is concluded that Joule heating is a necessary but not a sufficient condition for flash sintering.
Reconstruction of Bulk Operators within the Entanglement Wedge in Gauge-Gravity Duality

In this Letter we prove a simple theorem in quantum information theory, which implies that bulk operators in the anti-de Sitter/conformal field theory (AdS/CFT) correspondence can be reconstructed as CFT operators in a spatial subregion A, provided that they lie in its entanglement wedge. This is an improvement on existing reconstruction methods, which have at most succeeded in the smaller causal wedge. The proof is a combination of the recent work of Jafferis, Lewkowycz, Maldacena, and Suh on the quantum relative entropy of a CFT subregion with earlier ideas interpreting the correspondence as a quantum error correcting code.
On the Threshold of Space: Toward a Cosmic Law Problems of the Upward Extent of Sovereignty

For the second time in our generation we are witnessing the unfolding of a great scientific evolution which, in the scope of its boundless aspirations, infinite promises, and challenge-ridden perspectives, represents a panoramic phase with hardly a parallel in our history.
Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL.

// Shruti Sharma 1, * , Natalie Galanina 2, * , Ailin Guo 1, * , Jimmy Lee 1 , Sabah Kadri 1, 3 , Charles Van Slambrouck 1 , Bradley Long 1 , Weige Wang 1 , Mei Ming 1 , Larissa V. Furtado 1 , Jeremy P. Segal 1 , Wendy Stock 2 , Girish Venkataraman 1 , Wei-Jen Tang 4 , Pin Lu 1 , Yue Lynn Wang 1 1 Department of Pathology, University of Chicago, Chicago, IL 60637, USA 2 Department of Medicine, University of Chicago, Chicago, IL 60637, USA 3 Center for Research Informatics, University of Chicago, Chicago, IL 60637, USA 4 Ben-May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA * These authors have contributed equally to this work Correspondence to: Yue Lynn Wang, email: ylwang@bsd.uchicago.edu Keywords: chronic lymphocytic leukemia, Richter transformation, ibrutinib resistance, BTK , molecular targeted therapy Received: June 04, 2016 Accepted: August 15, 2016 Published: September 10, 2016 ABSTRACT Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naive chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. Thus far, all described BTK mutations are located in its kinase domain and mutations outside this domain have never been described. Herein, we report a patient whose CLL progressed, was salvaged with ibrutinib and then relapsed. Serial analysis of samples throughout patient’s clinical course identified a structurally novel mutation ( BTK T316A ) in the SH2 domain, but not kinase domain, of Bruton tyrosine kinase which was associated with disease relapse. Functionally, cells carrying BTK T316A show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTK C481S . Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.
Desires, goods, and ‘good’: some philosophical issues

Desires, why they matter, what they are; what is it to have a good reason for desiring something? Human lives can go wrong in a variety of ways and from different causes: as a result of malnutrition, illness, injury, or untimely death, from the malice, envy, or insensitivity of others, because of lack of self-knowledge or excess of self-doubt – the list is a long one. I want to focus on lives that go wrong on account of misdirected or frustrated desire. These too can be of different kinds. Someone who had set her heart on just one thing – athletic success, fame as a celebrity, preeminence as a physicist – and fails to achieve it may thereafter lead the unhappy life of a disappointed woman. Someone who wants too many different things and is recurrently diverted from his pursuit of this by the attractions of that may suddenly find that he has squandered his life away without achieving very much. Someone who wants and aspires to too little, perhaps from fear of the pain of disappointment, may never recognize that their talents and skills have never been put to adequate use. Such examples make it clear that when lives go wrong in these various ways, frustrated or misdirected or inadequate desire has played a part, even if not the only part, in making them go wrong. The woman who had set her heart on athletic success perhaps failed to achieve it because of an injury. But it is her inability to find and pursue other objects of desire that makes her life one of disappointment. The man who wants and aspires to too little does so perhaps because of lack of self-knowledge or excess of self-doubt or both. The flibbertigibbet who pursued too many things may have had friends who encouraged him in his wasteful ways, not friends who might have given him good advice. The woman or man who invests all their hopes in a single lifelong project and is then defeated in their final attempt to complete that project will, like Gatsby in Scott Fitzgerald's novel, have “paid a high price for living too long with a single dream.”
Transbiliary intravascular ultrasound-guided diagnostic biopsy of an inaccessible pancreatic head mass

Percutaneous image-guided biopsies of pancreatic malignancies may prove challenging and nondiagnostic due to a variety of anatomic considerations. For patients with complex post-surgical anatomy, such as a Roux-en-Y gastric bypass, diagnosis via endoscopic ultrasound with fine-needle aspiration may not be possible because of an inability to reach the proximal duodenum. This report describes the first diagnostic case of transbiliary intravascular ultrasound-guided biopsy of a pancreatic head mass in a patient with prior Roux-en-Y gastric bypass for which a diagnosis could not be achieved via percutaneous and endoscopic approaches. Transbiliary intravascular ultrasound-guided biopsy resulted in a diagnosis of pancreatic adenocarcinoma, allowing the initiation of chemotherapy.
A model ecosystem for the evaluation of pesticide biodegradability and ecological magnification

A small laboratory ecosystem has been developed to study the biodegradability of pesticides. This simulates the application of pesticides to crop plants and the eventual contamination of an aquatic...
Role of glycocalyx in attenuation of shear stress on endothelial cells: From in vivo experiments to microfluidic circuits

Shear stress generated by blood flow is transmitted to endothelial cells lining blood vessels through the cell free layer at the blood/vessel interface, consisting of a blood plasma zone and the glycocalyx, a gel-like lining of the endothelium, composed of polysaccharides attached to the cell wall. This multilayered system determines how flow is sensed and converted into biochemical responses by the endothelium by mechanotransduction. Analysis of flow profiles in this system using particle velocimetry is not possible since the gel-like structure affects particle trajectories, precluding obtaining information on shear stress. Likewise using numerical simulations of flow and transport is not viable for fully resolving the mechanical effects within the glycocalyx and their transmission to the endothelial surface, and understanding how shear stress is sensed by the endothelium requires complex and expensive in vivo and in vitro experimentation. Equivalent microfluidic models/circuits would allow to explicitly study the impact of glycocalyx topology on shear stress in controlled systems at a fraction of the cost. We propose a continuum scale model that treats the glycocalyx as a porous medium with known porosity and permeability, while accounting for varying blood viscosity. The model is amenable to analytical solution for the time-averaged velocity profile within and above the glycocalyx, and its predictions match in vivo data, providing a framework to design microfluidic systems using micro patterns designed to simulate the macroscopic effects of the biological glycocalyx.
Comparison of Automated Oscillometric Measurement of Ankle Brachial Index with Standard Doppler Measurement as a Screening Tool for Peripheral Artery Disease

Objective—The use of continuous-wave Doppler ultrasound to determine ankle brachial index (ABI) is the gold standard for diagnosing asymptomatic peripheral artery disease. This method is labor inte...
Shift Work, Obesity, and Cancer

Experimental data has consistently demonstrated that disruption of circadian rhythm can promote carcinogenesis in animal models, and epidemiologic data continues to accumulate indicating that disrupting circadian rhythm by shift work increases the risk of cancer in humans. In this chapter, we provide a comprehensive review of epidemiologic studies, both retrospective and prospective, on a worldwide basis, examining the association of shift work with cancer, particularly breast and prostate cancer. We also provide information on the relation of shift work to colorectal, endometrial, lung, skin, and bladder cancer. Also discussed are issues surrounding the relation of shift work to weight gain and obesity and the possibility that obesity may mediate the effect of shift work on cancer.
Digital preservation and workflow process

The digital societies of E-government, E-learning, and E-business have grown by leaps and bounds worldwide during the last several years. While we have invested significant time and effort to create and maintain those workflow processes, we do not have the ability to make digital objects generated by the processes all available across generations of information technology, making it accessible with future technology and enabling people to determine whether it is authentic and reliable. This is a very serious problem for which no complete solutions have been devised yet. This paper discusses three important factors – archival stability, organizational process, and technology continuity – for digital preservation to succeed, and describes a general framework of digital libraries (or the life cycle of information) to address this important problem so that we may find reasonable ways to preserve digital objects that can be analyzed and evaluated in quantitative measures and incremental manners.
Identität und Erinnerung im Umbruch: Ein weites Feld von Günter Grass

This paper investigates the link between memory and identity in Grass's novel "Too Far Afield." As the protagonist Theodore Wuttke, a Theodore Fontane replica, interprets the events of 1989/90 in Germany through "memories," the importance of remembrance for personal and collective identities becomes apparent. The analysis of various East and West German memories in the novel reveals strikingly different modes of memory on either side. These can each be explained by each side's need to reinforce or modify identity in view of change. Furthermore, the author points out that Wuttke's personality is overwhelmed by his historical model and interprets the protagonist's final escape to France as a release from Fontane's biography. Finally, the novel's focus on memory and identity is explained by the pervading sense of loss, visible both in the characters' reactions to upheaval and in Grass's perception of waning historical awareness.
Automated Validation of Requirement Reviews: A Machine Learning Approach

Software development is fault-prone especially during the fuzzy phases (requirements and design). Software inspections are commonly used in industry to detect and fix problems in requirements and design artifacts thereby mitigating the fault propagation to later phases where same faults are harder to find and fix. The output of an inspection process is natural language (NL) reviews that report the location and description of faults in software requirements specification document (SRS). The artifact author must manually read through the reviews and differentiate between true-faults and false-positives before fixing the faults. The time spent in making effective post-inspection decisions (number of true faults and deciding whether to re-inspect) could be spent in doing actual development work. The goal of this research is to automate the validation of inspection reviews, finding common patterns that describe high-quality requirements, identify fault prone requirements pre-inspection, and interrelated requirements to assist fixation of reported faults post-inspection. To accomplish these goals, this research employs various classification approaches, NL processing with semantic analysis and mining solutions from graph theory to requirement reviews and NL requirements. Initial results w.r.t. validation of inspection reviews have shown that our proposed approaches were able to successfully categorize useful and non-useful reviews.
NAD+ DEPLETION AS A CAUSE OF INFLAMMAGING

AbstractChronic inflammation, in the absence of infection, is a conserved characteristic of aging. Such inflammation underlies susceptibility to many age-related diseases including cancer, diabetes, and neurodegenerative disorders, and limits longevity. However, the causes of age-related chronic inflammation, also known as “inflammaging”, are not well understood. Levels of the metabolite NAD+ decline with age and promote inflammation through multiple mechanisms, including by limiting the activity of sirtuins and poly-ADP-ribose polymerases (PARPs). Interestingly, in bone marrow-derived macrophages and immortalized RAW264.7 mouse macrophages, NAD+ levels rapidly fall upon exposure to the pro-inflammatory stimulus LPS. This loss is due to consumption of the metabolite, rather than reduction, as levels of NADH also decline. We have implicated members of the PARP family as the cause of declining NAD+ during inflammation, and hypothesize that this NAD+ loss promotes inflammation during aging. To understand the effects of declining NAD+, we have treated macrophages with NAD+-precursors and PARP inhibitors, which limit the LPS-driven NAD+ loss. These molecules the secretion of cytokines, and may reduce DNA damage and NLRP3 inflammasome activation. We hypothesize that low NAD+ promotes age-related inflammation, and may be a target for pharmacological intervention. United States
Increased neural sensitivity to self-relevant stimuli in major depressive disorder

The current research examined how individuals with depression process emotional, self-relevant stimuli. Across two studies, individuals with depression and healthy controls read stimuli that varied in self-relevance while EEG data were recorded. We examined the late positive potential (LPP), an ERP component that captures the dynamic allocation of attention to motivationally salient stimuli. In Study 1, participants read single words in a passive-viewing task. Participants viewed negative, positive, or neutral words that were either normative or self-generated. Exploratory analyses indicated that participants with depression exhibited affective modulation of the LPP for self-generated stimuli only (both positive and negative) and not for normative stimuli; healthy controls exhibited similar affective modulation of the LPP for both self-relevant and normative stimuli. In Study 2, using a separate sample and a different task, stimuli were provided within the context of sentence stems referring to the self or other people. Participants with depression were more likely to endorse negative self-referent sentences and reject positive ones compared to healthy controls. Depressed participants also exhibited an increased LPP to negative stimuli compared to positive or neutral stimuli. Together, these two studies suggest that depression is characterized by relatively increased sensitivity to affective self-relevant stimuli, perhaps in the context of a broader reduction in emotional reactivity to stimuli that are not self-relevant. Thus, depression may be characterized by a more nuanced pattern based on the degree of stimulus self-relevance than either a global decrease or increase in reactivity to affective stimuli.
Transcription factors involved in the regulatory networks governing the Calvin–Benson–Bassham cycle

Transcription factors (TFs) play crucial roles in the regulation of photosynthesis; elucidating these roles will facilitate our understanding of photosynthesis and thus accelerate its improvement for enhancing crop yield. Promoter analysis of 52 nuclear-encoded Populus tomentosa Carr. genes involved in the Calvin-Benson-Bassham (CBB) cycle revealed 706 motifs and 326 potentially interacting TFs. A backward elimination random forest (BWERF) algorithm reduced the number of TFs to 40, involved in a three-layer gene regulatory network (GRN) including 46 photosynthesis genes (bottom layer), 25 TFs (second layer) and 15 TFs (top layer). Phenotype-genotype association identified 248 single-nucleotide polymorphisms (SNPs) within 72 genes associated with 11 photosynthesis traits. Of the regulatory pairs identified by the BWERF (202 pairs), 77 TF-target combinations harbored SNPs associated with the same trait, supporting similar mechanisms of phenotype modulation. We used expression quantitative trait nucleotide (eQTN) analysis to identify causal SNPs affecting gene expression, identifying 1851 eQTN signals for 50 eGenes (genes whose expressions are regulated by eQTNs). Distribution patterns identified 14 eQTNs from seven TFs associated with eight expression levels of their downstream targets (defined in the GRN), whereas seven TF-target pairs were also identified by phenotype-genotype associations. To further validate the roles of TFs at the metabolic level, we selected 6764 SNPs from 55 genes (identified by GRN-association or GRN-eQTN pairs or both) for metabolic association, identifying variants within 10 TFs affecting metabolic processes underlying the CBB cycle. Our study provides new insights into the photosynthesis pathway in poplar and may facilitate understanding of processes underlying photosynthesis improvement.
Normalcy Modeling Using a Dictionary of Activities Learned from Motion Imagery Tracking Data

Target tracking derived from motion imagery provides a capability to detect, recognize, and analyze activities in a manner not possible with still images. Target tracking enables automated activity analysis. In this paper, we develop methods for automatically exploiting the tracking data derived from motion imagery, or other tracking data, to detect and recognize activities, develop models of normal behavior, and detect departure from normalcy. The critical steps in our approach are to construct a syntactic representation of the track behaviors and map this representation to a small set of learned activities. We have developed methods for representing activities through syntactic analysis of the track data, by "tokenizing" the track, i.e. converting the kinematic information into strings of symbols amenable to further analysis. The syntactic analysis of target tracks is the foundation for constructing an expandable dictionary of activities. Through unsupervised learning on the tokenized track data we discovery the common activities. The probability distribution of these learned activities is the "dictionary". Newly acquired track data is compared to the dictionary to flag atypical behaviors as departures from normalcy. We demonstrate the methods with two relevant data sets: the Porto taxi data and a set of video data acquired at Draper. These data sets illustrate the flexibility and power of these methods for activity analysis.