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Gene families are growing rapidly, but standard methods for inferring phylogenies do not scale to alignments with over 10,000 sequences. We present FastTree, a method for constructing large phylogenies and for estimating their reliability. Instead of storing a distance matrix, FastTree stores sequence profiles of internal nodes in the tree. FastTree uses these profiles to implement Neighbor-Joining and uses heuristics to quickly identify candidate joins. FastTree then uses nearest neighbor interchanges to reduce the length of the tree. For an alignment with N sequences, L sites, and a different characters, a distance matrix requires O(N(2)) space and O(N(2)L) time, but FastTree requires just O(NLa + N ) memory and O(N log (N)La) time. To estimate the tree's reliability, FastTree uses local bootstrapping, which gives another 100-fold speedup over a distance matrix. For example, FastTree computed a tree and support values for 158,022 distinct 16S ribosomal RNAs in 17 h and 2.4 GB of memory. Just computing pairwise Jukes-Cantor distances and storing them, without inferring a tree or bootstrapping, would require 17 h and 50 GB of memory. In simulations, FastTree was slightly more accurate than Neighbor-Joining, BIONJ, or FastME; on genuine alignments, FastTree's topologies had higher likelihoods. FastTree is available at http://microbesonline.org/fasttree.

Recent studies indicate that Traditional Chinese medicine (TCM) can play an important role in the whole course of cancer treatment such as recovery stages of post-operative, radiotherapy or chemotherapy stages instead of only terminal stage of cancer. In this review, we have summarized current evidence for using TCM as adjuvant cancer treatment in different stages of cancer lesions. Some TCMs (e.g., TJ-41, Liu-jun-zi-tang, PHY906, Coumarin, and Aescine) are capable of improving the post-operative symptoms such as fatigue, pain, appetite, diarrhea, nausea, vomiting, and lymphedema. Some TCMs (e.g., Ginseng, Huang-Qi, BanZhiLian, TJ-48, Huachansu injection, Shenqi fuzheng injection, and Kanglaite injection) in combination with chemo- or radio-therapy are capable of enhancing the efficacy of and diminishing the side effects and complications caused by chemo- and radiotherapy. Taken together, they have great advantages in terms of suppressing tumor progression, relieving surgery complications, increasing the sensitivity of chemo- and radio- therapeutics, improving an organism's immune system function, and lessening the damage caused by surgery, chemo- or radio-therapeutics. They have significant effects on relieving breast cancer-related lymphedema, reducing cancer-related fatigue and pain, improving radiation pneumonitis and gastrointestinal side effects, protecting liver function, and even ameliorating bone marrow suppression. This review of those medicines should contribute to an understanding of Chinese herbal medicines as an adjunctive therapy in the whole course of cancer treatment instead of only terminal stage of cancer, by providing useful information for development of more effective anti-cancer drugs and making more patients "survival with cancer" for a long time.

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We propose a form for the exchange-correlation potential in local-density band theory, appropriate for Mott insulators. The idea is to use the ``constrained-local-density-approximation'' Hubbard parameter U as the quantity relating the single-particle potentials to the magnetic- (and orbital-) order parameters. Our energy functional is that of the local-density approximation plus the mean-field approximation to the remaining part of the U term. We argue that such a method should make sense, if one accepts the Hubbard model and the success of constrained-local-density-approximation parameter calculations. Using this ab initio scheme, we find that all late-3d-transition-metal monoxides, as well as the parent compounds of the high-${\mathit{T}}_{\mathit{c}}$ compounds, are large-gap magnetic insulators of the charge-transfer type. Further, the method predicts that ${\mathrm{LiNiO}}_{2}$ is a low-spin ferromagnet and NiS a local-moment p-type metal. The present version of the scheme fails for the early-3d-transition-metal monoxides and for the late 3d transition metals.

This review begins with a discussion of Meehl's (1957) query regarding when to use one's head (i.e., intuition) instead of the formula (i.e., statistical or mechanical procedure) for clinical prediction. It then describes the controversy that ensued and analyzes the complexity and contemporary relevance of the question itself. Going beyond clinical inference, it identifies select cognitive biases and constraints that cause decision errors, and proposes remedial correctives. Given that the evidence shows cognition to be flawed, the article discusses the linear regression, Bayesian, signal detection, and computer approaches as possible decision aids. Their cost-benefit trade-offs, when used either alone or as complements to one another, are examined and evaluated. The critique concludes with a note of cautious optimism regarding the formula's future role as a decision aid and offers several interim solutions.

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A general method is described for implementing a distributed system with any desired degree of faulttolerance. Instead of relying upon explicit timeouts, processes execute a simple clock-driven algorithm. Reliable clock synchronization and a solution to the Byzantine Generals Problem are assumed.

My title question, When should we use our heads instead of the formula? is not rhetorical. I am sincerely asking what I see as an important question. I find the two extreme answers to this question, namely, Always and Never, equally unacceptable. But to formulate a satisfactory answer upon the present evidence seems extraordinarily difficult. I put the question in the practical clinical context. This is where Sarbin put it in his pioneering study 14 years ago, and this is where it belongs. Some critics of my book (5) have repudiated the whole question by saying that, always and necessarily, we use both our heads and the formula. No, we do not. In research, we use both; the best clinical research involves a shuttling back and forth between clever, creative speculation and subsequent statistical testing of empirical derivations therefrom. So far as I am aware, nobody has ever denied this. Even the arch-actuary George Lundberg approved of the clinician as hypothesis-maker. In research one cannot design experiments or concoct theories without using his head, and he cannot test them rigorously without using a formula. This is so obvious that I am surprised to find that people will waste time in discussing it. The clinical-statistical issue can hardly be stated so as to make sense in the research context, and I should have thought it clear that a meaningful issue can be raised only in the context of daily clinical activity.

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BACKGROUND: The reasoning behind evaluating medical interventions is that a hierarchy of methods exists which successively produce improved and therefore more rigorous evidence based medicine upon which to make clinical decisions. At the foundation of this hierarchy are case studies, retrospective and prospective case series, followed by cohort studies with historical and concomitant non-randomized controls. Open-label randomized controlled studies (RCTs), and finally blinded, placebo-controlled RCTs, which offer most internal validity are considered the most reliable evidence. Rigorous RCTs remove bias. Evidence from RCTs forms the basis of meta-analyses and systematic reviews. This hierarchy, founded on a pharmacological model of therapy, is generalized to other interventions which may be complex and non-pharmacological (healing, acupuncture and surgery). DISCUSSION: The hierarchical model is valid for limited questions of efficacy, for instance for regulatory purposes and newly devised products and pharmacological preparations. It is inadequate for the evaluation of complex interventions such as physiotherapy, surgery and complementary and alternative medicine (CAM). This has to do with the essential tension between internal validity (rigor and the removal of bias) and external validity (generalizability). SUMMARY: Instead of an Evidence Hierarchy, we propose a Circular Model. This would imply a multiplicity of methods, using different designs, counterbalancing their individual strengths and weaknesses to arrive at pragmatic but equally rigorous evidence which would provide significant assistance in clinical and health systems innovation. Such evidence would better inform national health care technology assessment agencies and promote evidence based health reform.

In this paper we study a large market in which sellers compete by offering auctions to buyers instead of simple fixed price contracts. Two variants of the model are studied. One extends a model first analyzed by Wolinsky (Rev. Econ. Stud.55(1988), 71–84) in which buyers learn their valuations only after meeting sellers. The other variant extends the model of McAfee (Econometrica61(1993), 1281–1312) in which buyers know their valuations before they choose among available auctions. The equilibrium array of auctions is characterized for each case and the efficiency properties of the equilibria are analyzed.Journal of Economic LiteratureClassification Numbers: D41, D44, D82.

For complex diseases, most drugs are highly ineffective, and the success rate of drug discovery is in constant decline. While low quality, reproducibility issues, and translational irrelevance of most basic and preclinical research have contributed to this, the current organ-centricity of medicine and the 'one disease-one target-one drug' dogma obstruct innovation in the most profound manner. Systems and network medicine and their therapeutic arm, network pharmacology, revolutionize how we define, diagnose, treat, and, ideally, cure diseases. Descriptive disease phenotypes are replaced by endotypes defined by causal, multitarget signaling modules that also explain respective comorbidities. Precise and effective therapeutic intervention is achieved by synergistic multicompound network pharmacology and drug repurposing, obviating the need for drug discovery and speeding up clinical translation.

The agonist-dependent hydrolysis of inositol phospholipids was investigated by studying the breakdown of prelabelled lipid or by measuring the accumulation of inositol phosphates. Stimulation of insect salivary glands with 5-hydroxytryptamine for 6 min provoked a rapid disappearance of [3H]phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] and [3H]phosphatidylinositol 4-phosphate (PtdIns4P) but had no effect on the level of [3H]phosphatidylinositol (PtdIns). The breakdown of PtdIns(4,5)P2 was associated with a very rapid release of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], which reached a peak 5 1/2 times that of the resting level after 5 s of stimulation. This high level was not maintained but declined to a lower level, perhaps reflecting the disappearance of PtdIns(4,5)P2. 5-Hydroxytryptamine also induced a rapid and massive accumulation of inositol 1,4-bisphosphate [Ins(1,4)P2]. The fact that these increases in Ins(1,4,5)P3 and Ins(1,4)P2 precede in time any increase in the level of inositol 1-phosphate or inositol provides a clear indication that the primary action of 5-hydroxytryptamine is to stimulate the hydrolysis of PtdIns(4,5)P2 to yield diacylglycerol and Ins(1,4,5)P3. The latter is then hydrolysed by a series of phosphomonoesterases to produce Ins(1,4)P2, Ins1P and finally inositol. The very rapid agonist-dependent increases in Ins(1,4,5)P3 and Ins(1,4)P2 suggests that they could function as second messengers, perhaps to control the release of calcium from internal pools. The PtdIns(4,5)P2 that is used by the receptor mechanism represents a small hormone-sensitive pool that must be constantly replenished by phosphorylation of PtdIns. Small changes in the size of this small energy-dependent pool of polyphosphoinositide will alter the effectiveness of the receptor mechanism and could account for phenomena such as desensitization and super-sensitivity.

An increasing number of peptides with specific binding affinity to various protein and even non-protein targets are being discovered from phage display libraries. The power of this method lies in its ability to efficiently and rapidly identify ligands with a desired target property from a large population of phage clones displaying diverse surface peptides. However, the search for the needle in the haystack does not always end successfully. False positive results may appear. Thus instead of specific binders phage with no actual affinity toward the target are recovered due to their propagation advantages or binding to other components of the screening system, such as the solid phase, capturing reagents, contaminants in the target sample or blocking agents, rather than the target. Biopanning experiments on different targets performed in our laboratory revealed some previously identified and many new target-unrelated peptide sequences, which have already been frequently described and published, but not yet recognized as target-unrelated. Distinguishing true binders from false positives is an important step toward phage display selections of greater integrity. This article thoroughly reviews and discusses already identified and new target-unrelated peptides and suggests strategies to avoid their isolation.

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A new technique is proposed for the mathematical process of reconstruction of a three-dimensional object from its transmission shadowgraphs; it uses convolutions with functions defined in the real space of the object, without using Fourier transforms. The object is rotated about an axis at right angles to the direction of a parallel beam of radiation, and sections of it normal to the axis are reconstructed from data obtained by scanning the corresponding linear strips in the shadowgraphs at different angular settings. Since the formulae in the convolution method involve only summations over one variable at a time, while a two-dimensional reconstruction with the Fourier transform technique requires double summations, the convolution method is much faster (typically by a factor of 30); the relative increase in speed is larger where greater resolution is required. Tests of the convolution method with computer-simulated shadowgraphs show that it is also more accurate than the Fourier transform method. It has good potentialities for application in electron microscopy and x-radiography. A new method of reconstructing helical structures by this technique is also suggested.

When comparing two independent groups, psychology researchers commonly use Student’s t-tests. Assumptions of normality and homogeneity of variance underlie this test. More often than not, when these conditions are not met, Student’s t-test can be severely biased and lead to invalid statistical inferences. Moreover, we argue that the assumption of equal variances will seldom hold in psychological research, and choosing between Student’s t-test and Welch’s t-test based on the outcomes of a test of the equality of variances often fails to provide an appropriate answer. We show that the Welch’s t-test provides a better control of Type 1 error rates when the assumption of homogeneity of variance is not met, and it loses little robustness compared to Student’s t-test when the assumptions are met. We argue that Welch’s t-test should be used as a default strategy. Publisher’s Note: A correction article relating to this paper has been published and can be found at https://www.rips-irsp.com/articles/10.5334/irsp.661/.