Columbia University

We measured the elastic properties and intrinsic breaking strength of free-standing monolayer graphene membranes by nanoindentation in an atomic force microscope. The force-displacement behavior is interpreted within a framework of nonlinear elastic stress-strain response, and yields second- and third-order elastic stiffnesses of 340 newtons per meter (N m(-1)) and -690 Nm(-1), respectively. The breaking strength is 42 N m(-1) and represents the intrinsic strength of a defect-free sheet. These quantities correspond to a Young's modulus of E = 1.0 terapascals, third-order elastic stiffness of D = -2.0 terapascals, and intrinsic strength of sigma(int) = 130 gigapascals for bulk graphite. These experiments establish graphene as the strongest material ever measured, and show that atomically perfect nanoscale materials can be mechanically tested to deformations well beyond the linear regime.

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics. The 1000 Genomes Project has sought to comprehensively catalogue human genetic variation across populations, providing a valuable public genomic resource. The data obtained so far have found applications ranging from association studies and fine mapping studies to the filtering of likely neutral variants in rare-disease cohorts. The authors now report on the final phase of the project, phase 3, which covers previously uncharacterized areas of human genetic diversity in terms of the populations sampled and categories of characterized variation. The sample now includes more than 2,500 individuals from 26 global populations, with low coverage whole-genome and deep exome sequencing, as well as dense microarray genotyping. They find that while most common variants are shared across populations, rarer variants are often restricted to closely related populations. The authors also demonstrate the use of the phase 3 dataset as a reference panel for imputation to improve the resolution in genetic association studies.

Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.

The electronic properties of ultrathin crystals of molybdenum disulfide consisting of N=1,2,…,6 S-Mo-S monolayers have been investigated by optical spectroscopy. Through characterization by absorption, photoluminescence, and photoconductivity spectroscopy, we trace the effect of quantum confinement on the material's electronic structure. With decreasing thickness, the indirect band gap, which lies below the direct gap in the bulk material, shifts upwards in energy by more than 0.6 eV. This leads to a crossover to a direct-gap material in the limit of the single monolayer. Unlike the bulk material, the MoS₂ monolayer emits light strongly. The freestanding monolayer exhibits an increase in luminescence quantum efficiency by more than a factor of 10⁴ compared with the bulk material.

We present the first public version (v0.2) of the open-source and community-developed Python package, Astropy. This package provides core astronomy-related functionality to the community, including support for domain-specific file formats such as flexible image transport system (FITS) files, Virtual Observatory (VO) tables, and common ASCII table formats, unit and physical quantity conversions, physical constants specific to astronomy, celestial coordinate and time transformations, world coordinate system (WCS) support, generalized containers for representing gridded as well as tabular data, and a framework for cosmological transformations and conversions. Significant functionality is under activedevelopment, such as a model fitting framework, VO client and server tools, and aperture and point spread function (PSF) photometry tools. The core development team is actively making additions and enhancements to the current code base, and we encourage anyone interested to participate in the development of future Astropy versions.

On September 14, 2015 at 09:50:45 UTC the two detectors of the Laser Interferometer Gravitational-Wave Observatory simultaneously observed a transient gravitational-wave signal. The signal sweeps upwards in frequency from 35 to 250 Hz with a peak gravitational-wave strain of 1.0×10(-21). It matches the waveform predicted by general relativity for the inspiral and merger of a pair of black holes and the ringdown of the resulting single black hole. The signal was observed with a matched-filter signal-to-noise ratio of 24 and a false alarm rate estimated to be less than 1 event per 203,000 years, equivalent to a significance greater than 5.1σ. The source lies at a luminosity distance of 410(-180)(+160) Mpc corresponding to a redshift z=0.09(-0.04)(+0.03). In the source frame, the initial black hole masses are 36(-4)(+5)M⊙ and 29(-4)(+4)M⊙, and the final black hole mass is 62(-4)(+4)M⊙, with 3.0(-0.5)(+0.5)M⊙c(2) radiated in gravitational waves. All uncertainties define 90% credible intervals. These observations demonstrate the existence of binary stellar-mass black hole systems. This is the first direct detection of gravitational waves and the first observation of a binary black hole merger.

In this article the author reviews research evidence on the prevalence of mental disorders in lesbians, gay men, and bisexuals (LGBs) and shows, using meta-analyses, that LGBs have a higher prevalence of mental disorders than heterosexuals. The author offers a conceptual framework for understanding this excess in prevalence of disorder in terms of minority stress--explaining that stigma, prejudice, and discrimination create a hostile and stressful social environment that causes mental health problems. The model describes stress processes, including the experience of prejudice events, expectations of rejection, hiding and concealing, internalized homophobia, and ameliorative coping processes. This conceptual framework is the basis for the review of research evidence, suggestions for future research directions, and exploration of public policy implications.

Data Analysis Using Regression and Multilevel/Hierarchical Models, first published in 2007, is a comprehensive manual for the applied researcher who wants to perform data analysis using linear and nonlinear regression and multilevel models. The book introduces a wide variety of models, whilst at the same time instructing the reader in how to fit these models using available software packages. The book illustrates the concepts by working through scores of real data examples that have arisen from the authors' own applied research, with programming codes provided for each one. Topics covered include causal inference, including regression, poststratification, matching, regression discontinuity, and instrumental variables, as well as multilevel logistic regression and missing-data imputation. Practical tips regarding building, fitting, and understanding are provided throughout.

"Experience and Education offers educators and teachers a positive philosophy of education. It evaluates the practices of both the traditional and the progressive schools and lucidly sets forth the defects of each of them. The volume, however, is in no sense controversial. Dr. Dewey, while considering current educational issues, interprets the meaning of a philosophicy of experience and the educational implications of the scientific method. A learning situation is described and concretely illustrated. The meanings of freedom, activities, discipline, control, and organized subject matter are here expounded within the context of educative experience as a process implying both continuity and interaction. Experience and Education defends no "ism". It offers no compromise. It steers clear of eclectic patching. Education itself is interpreted. Professional educators and laymen alike will here find definite answers to moot questions, but these answers are integral parts of an educational philosophy which makes possible united efforts in educational leadership. Here is a new light which will dissolve the fog now enveloping educational theory." (4th cover of the 60th anniversary edition) (http://books.google.com/books?id=UE2EusaU53IC&printsec=frontcover&hl=fr#v=onepage&q&f=false)

PARKINSONISM, described in its entirety over one hundred and fifty years ago,' rarely presents itself as a diagnostic problem. In consequence, little scrutiny has been directed to the marked variability of this frequently encountered neurological syndrome and to the progression of the disease in large groups of patients. As with most chronic neurological disorders, marked diversity can be expected to exist in age and mode of onset, relative prominence of the cardinal signs and symptoms, rate of progression, and resultant degree of functional impairment. Controversy over the effectiveness of therapeutic measures for parkinsonism is due partially to this wide variability and to the paucity of clinical information about the natural history of the syndrome. It is also re-

We present the Met Office Hadley Centre's sea ice and sea surface temperature (SST) data set, HadISST1, and the nighttime marine air temperature (NMAT) data set, HadMAT1. HadISST1 replaces the global sea ice and sea surface temperature (GISST) data sets and is a unique combination of monthly globally complete fields of SST and sea ice concentration on a 1° latitude‐longitude grid from 1871. The companion HadMAT1 runs monthly from 1856 on a 5° latitude‐longitude grid and incorporates new corrections for the effect on NMAT of increasing deck (and hence measurement) heights. HadISST1 and HadMAT1 temperatures are reconstructed using a two‐stage reduced‐space optimal interpolation procedure, followed by superposition of quality‐improved gridded observations onto the reconstructions to restore local detail. The sea ice fields are made more homogeneous by compensating satellite microwave‐based sea ice concentrations for the impact of surface melt effects on retrievals in the Arctic and for algorithm deficiencies in the Antarctic and by making the historical in situ concentrations consistent with the satellite data. SSTs near sea ice are estimated using statistical relationships between SST and sea ice concentration. HadISST1 compares well with other published analyses, capturing trends in global, hemispheric, and regional SST well, containing SST fields with more uniform variance through time and better month‐to‐month persistence than those in GISST. HadMAT1 is more consistent with SST and with collocated land surface air temperatures than previous NMAT data sets.

The theory of the kinetics of phase change is developed with the experimentally supported assumptions that the new phase is nucleated by germ nuclei which already exist in the old phase, and whose number can be altered by previous treatment. The density of germ nuclei diminishes through activation of some of them to become growth nuclei for grains of the new phase, and ingestion of others by these growing grains. The quantitative relations between the density of germ nuclei, growth nuclei, and transformed volume are derived and expressed in terms of a characteristic time scale for any given substance and process. The geometry and kinetics of a crystal aggregate are studied from this point of view, and it is shown that there is strong evidence of the existence, for any given substance, of an isokinetic range of temperatures and concentrations in which the characteristic kinetics of phase change remains the same. The determination of phase reaction kinetics is shown to depend upon the solution of a functional equation of a certain type. Some of the general properties of temperature-time and transformation-time curves, respectively, are described and explained.

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.

Journal Article A Theory of the Allocation of Time Get access Gary S. Becker Gary S. Becker Columbia University Search for other works by this author on: Oxford Academic Google Scholar The Economic Journal, Volume 75, Issue 299, 1 September 1965, Pages 493–517, https://doi.org/10.2307/2228949 Published: 01 September 1965

Abstract Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

The dispersion and absorption of a considerable number of liquid and dielectrics are represented by the empirical formula ε*−ε∞=(ε0−ε∞)/[1+(iωτ0)1−α]. In this equation, ε* is the complex dielectric constant, ε0 and ε∞ are the ``static'' and ``infinite frequency'' dielectric constants, ω=2π times the frequency, and τ0 is a generalized relaxation time. The parameter α can assume values between 0 and 1, the former value giving the result of Debye for polar dielectrics. The expression (1) requires that the locus of the dielectric constant in the complex plane be a circular arc with end points on the axis of reals and center below this axis. If a distribution of relaxation times is assumed to account for Eq. (1), it is possible to calculate the necessary distribution function by the method of Fuoss and Kirkwood. It is, however, difficult to understand the physical significance of this formal result. If a dielectric satisfying Eq. (1) is represented by a three-element electrical circuit, the mechanism responsible for the dispersion is equivalent to a complex impedance with a phase angle which is independent of the frequency. On this basis, the mechanism of interaction has the striking property that energy is conserved or ``stored'' in addition to being dissipated and that the ratio of the average energy stored to the energy dissipated per cycle is independent of the frequency.

Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 A in nearly half of the cases and are greater than 2 A in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.

CONTEXT: The Primary Care Evaluation of Mental Disorders (PRIME-MD) was developed as a screening instrument but its administration time has limited its clinical usefulness. OBJECTIVE: To determine if the self-administered PRIME-MD Patient Health Questionnaire (PHQ) has validity and utility for diagnosing mental disorders in primary care comparable to the original clinician-administered PRIME-MD. DESIGN: Criterion standard study undertaken between May 1997 and November 1998. SETTING: Eight primary care clinics in the United States. PARTICIPANTS: Of a total of 3000 adult patients (selected by site-specific methods to avoid sampling bias) assessed by 62 primary care physicians (21 general internal medicine, 41 family practice), 585 patients had an interview with a mental health professional within 48 hours of completing the PHQ. MAIN OUTCOME MEASURES: Patient Health Questionnaire diagnoses compared with independent diagnoses made by mental health professionals; functional status measures; disability days; health care use; and treatment/referral decisions. RESULTS: A total of 825 (28%) of the 3000 individuals and 170 (29%) of the 585 had a PHQ diagnosis. There was good agreement between PHQ diagnoses and those of independent mental health professionals (for the diagnosis of any 1 or more PHQ disorder, kappa = 0.65; overall accuracy, 85%; sensitivity, 75%; specificity, 90%), similar to the original PRIME-MD. Patients with PHQ diagnoses had more functional impairment, disability days, and health care use than did patients without PHQ diagnoses (for all group main effects, P<.001). The average time required of the physician to review the PHQ was far less than to administer the original PRIME-MD (<3 minutes for 85% vs 16% of the cases). Although 80% of the physicians reported that routine use of the PHQ would be useful, new management actions were initiated or planned for only 117 (32%) of the 363 patients with 1 or more PHQ diagnoses not previously recognized. CONCLUSION: Our study suggests that the PHQ has diagnostic validity comparable to the original clinician-administered PRIME-MD, and is more efficient to use.

On August 17, 2017 at 12∶41:04 UTC the Advanced LIGO and Advanced Virgo gravitational-wave detectors made their first observation of a binary neutron star inspiral. The signal, GW170817, was detected with a combined signal-to-noise ratio of 32.4 and a false-alarm-rate estimate of less than one per <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" display="inline"><a:mrow><a:mrow><a:mn>8.0</a:mn><a:mo>×</a:mo><a:msup><a:mrow><a:mn>10</a:mn></a:mrow><a:mrow><a:mn>4</a:mn></a:mrow></a:msup></a:mrow><a:mtext> </a:mtext><a:mtext> </a:mtext><a:mi>years</a:mi></a:mrow></a:math>. We infer the component masses of the binary to be between 0.86 and <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" display="inline"><c:mrow><c:mn>2.26</c:mn><c:mtext> </c:mtext><c:mtext> </c:mtext><c:msub><c:mrow><c:mi>M</c:mi></c:mrow><c:mrow><c:mo stretchy="false">⊙</c:mo></c:mrow></c:msub></c:mrow></c:math>, in agreement with masses of known neutron stars. Restricting the component spins to the range inferred in binary neutron stars, we find the component masses to be in the range <f:math xmlns:f="http://www.w3.org/1998/Math/MathML" display="inline"><f:mrow><f:mn>1.17</f:mn><f:mi>–</f:mi><f:mn>1.60</f:mn><f:mtext> </f:mtext><f:mtext> </f:mtext><f:msub><f:mrow><f:mi>M</f:mi></f:mrow><f:mrow><f:mo stretchy="false">⊙</f:mo></f:mrow></f:msub></f:mrow></f:math>, with the total mass of the system <i:math xmlns:i="http://www.w3.org/1998/Math/MathML" display="inline"><i:mrow><i:mn>2.7</i:mn><i:msubsup><i:mrow><i:mn>4</i:mn></i:mrow><i:mrow><i:mo>−</i:mo><i:mn>0.01</i:mn></i:mrow><i:mrow><i:mo>+</i:mo><i:mn>0.04</i:mn></i:mrow></i:msubsup><i:msub><i:mrow><i:mi>M</i:mi></i:mrow><i:mrow><i:mo stretchy="false">⊙</i:mo></i:mrow></i:msub></i:mrow></i:math>. The source was localized within a sky region of <l:math xmlns:l="http://www.w3.org/1998/Math/MathML" display="inline"><l:mrow><l:mn>28</l:mn><l:mtext> </l:mtext><l:mtext> </l:mtext><l:mrow><l:msup><l:mrow><l:mi>deg</l:mi></l:mrow><l:mrow><l:mn>2</l:mn></l:mrow></l:msup></l:mrow></l:mrow></l:math> (90% probability) and had a luminosity distance of <n:math xmlns:n="http://www.w3.org/1998/Math/MathML" display="inline"><n:mrow><n:mrow><n:mn>4</n:mn><n:msubsup><n:mrow><n:mn>0</n:mn></n:mrow><n:mrow><n:mo>−</n:mo><n:mn>14</n:mn></n:mrow><n:mrow><n:mo>+</n:mo><n:mn>8</n:mn></n:mrow></n:msubsup><n:mtext> </n:mtext><n:mtext> </n:mtext></n:mrow><n:mrow><n:mi>Mpc</n:mi></n:mrow></n:mrow></n:math>, the closest and most precisely localized gravitational-wave signal yet. The association with the <p:math xmlns:p="http://www.w3.org/1998/Math/MathML" display="inline"><p:mi>γ</p:mi></p:math>-ray burst GRB 170817A, detected by Fermi-GBM 1.7 s after the coalescence, corroborates the hypothesis of a neutron star merger and provides the first direct evidence of a link between these mergers and short <r:math xmlns:r="http://www.w3.org/1998/Math/MathML" display="inline"><r:mi>γ</r:mi></r:math>-ray bursts. Subsequent identification of transient counterparts across the electromagnetic spectrum in the same location further supports the interpretation of this event as a neutron star merger. This unprecedented joint gravitational and electromagnetic observation provides insight into astrophysics, dense matter, gravitation, and cosmology. Published by the American Physical Society 2017

The settlement of soils under load is caused by a phenomenon called consolidation, whose mechanism is known to be in many cases identical with the process of squeezing water out of an elastic porous medium. The mathematical physical consequences of this viewpoint are established in the present paper. The number of physical constants necessary to determine the properties of the soil is derived along with the general equations for the prediction of settlements and stresses in three-dimensional problems. Simple applications are treated as examples. The operational calculus is shown to be a powerful method of solution of consolidation problems.