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Over the past 25 years, there has been significant research activity in development and application of methods for inverting acoustical field data to estimate parameters of geoacoustic models of the ocean bottom. Although the performance of various geoacoustic inversion methods has been benchmarked on simulated data, their performance with experimental data remains an open question. This article constitutes the first attempt of an experimental benchmark of geoacoustic inversion methods. To do so, the article focuses on data from experiments carried out at a common site during the Shallow Water 2006 (SW06) experiment. The contribution of the article is twofold. First, the article provides an overview of experimental inversion methods and results obtained with SW06 data. Second, the article proposes and uses quantitative metrics to assess the experimental performance of inversion methods. From a sonar performance point of view, the benchmark shows that no particular geoacoustic inversion method is definitely better than any other of the ones that were tested. All the inversion methods generated adequate sound-speed profiles, but only a few methods estimated attenuation and density. Also, acoustical field prediction performance drastically reduces with range for all geoacoustic models, and this performance loss dominates over intermodel variability. Overall, the benchmark covers the two main objectives of geoacoustic inversion: obtaining geophysical information about the seabed, and/or predicting acoustic propagation in a given area.

Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer1,2. The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability3. Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability4–6. Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material—these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers. TRIM37 overexpression promotes centrosome dysfunction that drives genomic instability in breast cancer cell lines containing the recurrent 17q23 amplicon, revealing a vulnerability that can be targeted to eliminate cancer cells.

Classical ocean acoustic experiments involve the use of synchronized arrays of sensors. However, the need to cover large areas and/or the use of small robotic platforms has evoked interest in single-hydrophone processing methods for localizing a source or characterizing the propagation environment. One such processing method is "warping," a non-linear, physics-based signal processing tool dedicated to decomposing multipath features of low-frequency transient signals (frequency f 500 Hz), after their propagation through shallow water (depth D 200 m) and their reception on a distant single hydrophone (range r 1 km). Since its introduction to the underwater acoustics community in 2010, warping has been adopted in the ocean acoustics literature, mostly as a pre-processing method for single receiver geoacoustic inversion. Warping also has potential applications in other specialties, including bioacoustics; however, the technique can be daunting to many potential users unfamiliar with its intricacies. Consequently, this tutorial article covers basic warping theory, presents simulation examples, and provides practical experimental strategies. Accompanying supplementary material provides matlab code and simulated and experimental datasets for easy implementation of warping on both impulsive and frequency-modulated signals from both biotic and man-made sources. This combined material should provide interested readers with user-friendly resources for implementing warping methods into their own research.

This paper reviews the progress in geoacoustic inversion over the past several decades. The review is separated into two parts. The first part reviews developments in model-based inversion methods that have led to present day usage of Bayesian inference. Theoretical foundations for the inversion methods are outlined, and limitations of model-based approaches are discussed. Examples are briefly described of applications of model-based inversion with different types of experimental data. The second part reviews recent developments in model-free inversion methods, focusing on discussion of distortion of estimated geoacoustic model parameters caused by model mismatch. It is shown that distortions in estimated model parameters lead to errors in interpreting characteristics of dispersion in the ocean waveguide, in particular the frequency dependence of sound attenuation in marine sediment. This review concludes with perspectives on new directions in research that promise improvement in inversion performance.

In the ocean waveguide, the sediment sound speed has a simple relationship with the group speed of the highest order mode that propagates close to the critical angle. The paper shows that robust estimates of the sound speed are obtained from estimates of the "critical" mode group speed determined from analysis of the energy distribution of the time-warped spectrum of a broadband signal. The method is applied to experimental data collected in the Yellow Sea of China. Estimated sound speeds agreed closely with expected values for clayey slit (1531 m/s) and sandy silt (1593 m/s) sediment at the sites.

Protein ubiquitination at sites of DNA double-strand breaks (DSBs) by RNF168 recruits BRCA1 and 53BP11,2, which are mediators of the homologous recombination and non-homologous end joining DSB repair pathways, respectively3. Non-homologous end joining relies on 53BP1 binding directly to ubiquitinated lysine 15 on H2A-type histones (H2AK15ub)4,5 (which is an RNF168-dependent modification6), but how RNF168 promotes BRCA1 recruitment and function remains unclear. Here we identify a tandem BRCT-domain-associated ubiquitin-dependent recruitment motif (BUDR) in BRCA1-associated RING domain protein 1 (BARD1) (the obligate partner protein of BRCA1) that, by engaging H2AK15ub, recruits BRCA1 to DSBs. Disruption of the BUDR of BARD1 compromises homologous recombination and renders cells hypersensitive to PARP inhibition and cisplatin. We further show that BARD1 binds nucleosomes through multivalent interactions: coordinated binding of H2AK15ub and unmethylated H4 lysine 20 by its adjacent BUDR and ankyrin repeat domains, respectively, provides high-affinity recognition of DNA lesions in replicated chromatin and promotes the homologous recombination activities of the BRCA1–BARD1 complex. Finally, our genetic epistasis experiments confirm that the need for BARD1 chromatin-binding activities can be entirely relieved upon deletion of RNF168 or 53BP1. Thus, our results demonstrate that by sensing DNA-damage-dependent and post-replication histone post-translation modification states, BRCA1–BARD1 complexes coordinate the antagonization of the 53BP1 pathway with promotion of homologous recombination, establishing a simple paradigm for the governance of the choice of DSB repair pathway. A tandem BRCT-domain-associated ubiquitin-dependent recruitment motif in BARD1 recruits BRCA1 to DNA double-strand breaks (DSBs) to promote homologous recombination and antagonize the 53BP1 DSB repair pathway that mediates non-homologous end joining.

Summary Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers., Graphical Abstract, Highlights • Loss of ALC1 nucleosome remodeling confers PARPi, MMS, and formyl-dU sensitivity • ALC1 is required after lesion excision by DNA glycosylases prior to APEX1 • Loss of ALC1 is synthetic lethal with homologous recombination deficiency (HRD) • Endogenous alkylated base damage is a source of synthetic lethality with HRD, Hewitt et al. report that loss of the chromatin-remodeling enzyme ALC1 leads to persistent BER intermediates and a critical dependency on HR for repair. Combined loss of ALC1 and HR is synthetic lethal, which can be partially rescued by blocking excision of endogenous alkylation damage by the glycosylase MPG.

Although published studies have demonstrated that IFN-ε has a crucial role in regulating protective immunity in the mouse female reproductive tract, expression and regulation of IFN-ε in the human female reproductive tract (hFRT) have not been characterized to our knowledge. We obtained hFRT samples from a well-characterized cohort of women to enable us to comprehensively assess ex vivo IFN-ε expression in the hFRT at various stages of the menstrual cycle. We found that among the various types of IFNs, IFN-ε was uniquely, selectively, and constitutively expressed in the hFRT epithelium. It had distinct expression patterns in the surface and glandular epithelia of the upper hFRT compared with basal layers of the stratified squamous epithelia of the lower hFRT. There was cyclical variation of IFN-ε expression in the endometrial epithelium of the upper hFRT and not in the distal FRT, consistent with selective endometrial expression of the progesterone receptor and regulation of the IFNE promoter by progesterone. Because we showed IFN-ε stimulated important protective IFN-regulated genes in FRT epithelium, this characterization is a key element in understanding the mechanisms of hormonal control of mucosal immunity.

Protein ubiquitination at sites of DNA double-strand breaks (DSBs) by RNF168 recruits BRCA1 and 53BP1

This paper summarizes experiments carried out using towed line arrays in the Pacific Echo sea trials. Although John Preston was not a participant, the experiments are examples consistent with his efforts in promoting collaborative research at sea with horizontal arrays. The overall goal of Pacific Echo was to study the impact of thin sediment ocean bottom environments on sound propagation in deep water. The objective of the experiments described here was to study the evolution of young oceanic crust. The hypothesis was that the sound speed of young basalt increased with age of the crust. Sound speed was inferred from low frequency measurements of the reflection coefficient versus grazing angle at sites of increasing distance from the deep ocean spreading center. The experiments introduced a novel design for measuring the reflection coefficients using two ships and small explosive charges. The signals at the array were spatially filtered to resolve the specular reflections as the ships opened range on set courses. The data provided estimates of both the compressional and shear wave speeds of the basalt. Results from the broadside reflection technique showed that sound speed increased with crustal age and were consistent with measurements obtained from conventional seismic reflection surveys.

In this paper, broadband airgun data from the 1995 Shallow Water Acoustics in Random Media (SWARM'95) experiment are analyzed to study the influence of internal waves on sound propagation and modal behavior, and the subsequent effects on geoacoustic inversion. Modal behavior and fluctuation due to sound intensity focusing and defocusing, when the leading front of internal waves is parallel to and approaches or passes through the acoustic propagation track, are presented. A modal filtering technique, the time-warping transform, is applied to the airgun data to resolve dispersed modes. The extracted modes are used to estimate seabed model parameters by geoacoustic inversion. Two scenarios, defocusing and focusing periods containing 14 events, are selected for study. Seven data sets for each type (defocusing or focusing) are analyzed to extract dispersion curves and carry out geoacoustic inversion. The inversion results for each type of the events are similar with a small standard deviation from the mean. However, the mean values and standard deviations for the defocusing and focusing types are quite different. The impacts of internal waves on inversion results are presented and discussed.

This paper develops a Bayesian approach to the image source method (ISM) for efficient inversion of seabed reflection data to estimate geoacoustic parameters and uncertainties. Based on the representation of layered seafloor-reflected signals by image sources, ISM is a very efficient method which provides the local sound-speed profile (SSP) of the sediment structure. It is a two-step method: first, the image sources are detected and localized from the recorded signals, and second, from these locations, the thickness and sound speed of each sediment layer are estimated from the Snell–Descartes law of refraction. This work focuses on the definition and construction of the image sources with a distinction between real and virtual image sources which has consequences on the uncertainties of ISM. The localization of the image sources is performed within a Bayesian formulation based on sampling the posterior probability density to estimate the median SSP and uncertainties. The algorithm is tested first on synthetic data, with results in excellent agreement with Bayesian travel-time inversion but a much lower computational cost. Finally, the Bayesian ISM is applied to at-sea data measured in the Scattering And ReverberAtion from the sea Bottom (SCARAB) experiment, which took place near Elba Island off the west coast of Italy in 1998, and the resultant sediment SSP agrees well with previous results of other geoacoustic inversion methods.

Performance of matched-field source localization is highly dependent on the precision of the model to actual physical processes. Model mismatch, including sound propagation environmental mismatch, statistical mismatch, and system mismatch, causes severe performance degradation. Statistical mismatch occurs when an insufficient snapshot set is used to estimate the data covariance matrix. Diagonal loading can improve the widely used minimum variance distortionless response (MVDR) and minimum power distortionless response (MPDR) processors against statistical mismatch, however, the result relies on selection of the loading level. Previously, a new processor named the matched-covariance estimator (MCE) was shown to have statistically robust estimation capability under white noise conditions by matching the general-rank data covariance matrix with a covariance matrix of the modeled replicas. In this paper, the method is further developed in more realistic application scenarios with discrete point interferences and/or surface-generated noises. Simulations and analyses show that MCE can outperform classical MVDR/MPDR matched-field processors by: 1) exploiting both signal and noise data structure at the same time; 2) being less prone to mistaken nulling of the signal; 3) requiring no rank-1 signal space restriction; and 4) not needing signal-free and long duration training data.

This paper addresses the problem of proud and buried targets detection and localization without the need of a probe source (PS) at the target’s location or the need of accurate environmental knowledge. There are three novel features in this paper. First, although the combination of time-reversal mirror (TRM) and virtual source array (VSA) method has been applied to remote imaging in previous literature, this paper further analyzes the mode leakage effect which causes the failure of some VSA implementations. Based on the analytical result, the effective deploying region for the VSA is derived. Second, to coherently focus on a buried target, the effect of sound refraction through the boundary of the water and sediment layers must be considered. The sound speeds of water and sediment layers are taken into account to correct the time-delay steering of the VSA. Since time-reversal processing (TRP) with a PS at the target location provides the best performance bound (TRB), we can quantitatively evaluate the performance improvement of our proposed modified TRM-VSA method in comparison with the conventional one according to their relationship with the TRB. This paper demonstrates that the performance of the TRM-VSA method with or without the knowledge of refraction at the boundary of different layers can differ significantly. Third, after we have successfully achieved active focusing on proud and buried targets with the modified TRM-VSA method, model-based algorithms such as matched-field processing (MFP) can extract array steering vectors from the active focusing method and achieve the task of target detection and localization. Results of simulations and tank experiments are presented as demonstrations of the three novel features of this paper.

International audience; This paper presents single receiver geoacoustic inversion of two independent data sets recorded during the 2017 seabed characterization experiment on the New England Mud Patch. In the experimental area, the water depth is around 70 m, and the seabed is characterized by an upper layer of fine grained sediments with clay (i.e., mud). The first data set considered in this paper is a combustive sound source signal, and the second is a chirp emitted by a J15 source. These two data sets provide differing information on the geoacoustic properties of the seabed, as a result of their differing frequency content, and the dispersion properties of the environment. For both data sets, source/receiver range is about 7 km, and modal time-frequency dispersion curves are estimated using warping. Estimated dispersion curves are then used as input data for a Bayesian trans-dimensional inversion algorithm. Subbottom layering and geoacoustic parameters (sound speed and density) are thus inferred from the data. This paper highlights important properties of the mud, consistent with independent in situ measurements. It also demonstrates how information content differs for two data sets collected on reciprocal tracks, but with different acoustic sources and modal content. OAPA

This paper questions how impact is measured in academic research and proposes that the United Nations' Sustainable Development Goals (SDGs) are an effective framework for determining real-world impact. Bibliometrics used to assess the quality of academic work are mostly quantitative and self-referential, and often adopted by funding bodies, putting additional pressure on academics and schools to increase compliance, thereby reducing focus on real-world impact. Beginning on the ambitious agenda of SDGs, data were collected on how researchers, institutions, and network organisations (such as ANZAM) can contribute to, and measure research aligned with SDGs. Results were generally positive toward using SDGs. Suggestions included aligning funding opportunities, changing KPIs, increasing cross-disciplinary work, aligning mission/vision statements, and legitimising SDG-focused projects at conferences.

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection.

PRDM9 binding localizes almost all meiotic recombination sites in humans and mice. However, most PRDM9-bound loci do not become recombination hotspots. To explore factors that affect binding and subsequent recombination outcomes, we mapped human PRDM9 binding sites in a transfected human cell line and measured PRDM9-induced histone modifications. These data reveal varied DNA-binding modalities of PRDM9. We also find that human PRDM9 frequently binds promoters, despite their low recombination rates, and it can activate expression of a small number of genes including CTCFL and VCX. Furthermore, we identify specific sequence motifs that predict consistent, localized meiotic recombination suppression around a subset of PRDM9 binding sites. These motifs strongly associate with KRAB-ZNF protein binding, TRIM28 recruitment, and specific histone modifications. Finally, we demonstrate that, in addition to binding DNA, PRDM9's zinc fingers also mediate its multimerization, and we show that a pair of highly diverged alleles preferentially form homo-multimers., eLife digest Human cells have two copies of each chromosome: one from the mother, and one from the father. When cells divide to form sex cells, such as sperm or egg cells, the maternal and paternal chromosomes line up next to each other and swap some of their DNA. This process, known as genetic recombination, creates different versions of genes and ensures that we are all unique – or genetically diverse. Recombination is a complex process that is largely controlled by a protein called PRDM9. This protein binds DNA at particular spots on the chromosome and directs other proteins to carry out recombination nearby. However, not all of PRDM9’s binding sites are known, and not all regions that PRDM9 binds to undergo recombination. Until now, it was not understood why this is the case at fine scales. To investigate this further, Altemose et al. activated the human version of PRDM9 in human kidney cells grown in the laboratory. The results showed that PRDM9 often bound near the start sites of genes, although these regions rarely undergo recombination in humans. When PRDM9 bound near these sites, it sometimes turned the gene on, which suggests that it may also help to regulate the activity of genes. Moreover, a specific group of DNA-binding proteins, called KRAB-ZNF proteins, appear to suppress recombination wherever they bind, which explains why some PRDM9 binding sites do not recombine. Lastly, Altemose et al. discovered that the part of PRDM9 that binds to DNA can also bind to other copies of PRDM9 proteins. This self-binding ability might play a role in bringing together the maternal and paternal chromosomes at the correct spots during recombination. Together, these results shed new light on the recombination process, which is a driving force in the formation of new species and essential for fertility. A next step will be to study these results further in tissues of the reproductive organs. This will provide a better understanding of the forces that shape human evolution.

53BP1 governs a specialized, context-specific branch of the classical non-homologous end joining DNA double-strand break repair pathway. Mice lacking 53bp1 (also known as Trp53bp1) are immunodeficient owing to a complete loss of immunoglobulin classswitch recombination1,2, and reduced fidelity of long-range V(D)J recombination3. The 53BP1-dependent pathway is also responsible for pathological joining events at dysfunctional telomeres4, and its unrestricted activity in Brca1-deficient cellular and tumour models causes genomic instability and oncogenesis5–7. Cells that lack core non-homologous end joining proteins are profoundly radiosensitive8, unlike 53BP1-deficient cells9,10, which suggests that 53BP1 and its co-factors act on specific DNA substrates. Here we show that 53BP1 cooperates with its downstream effector protein REV7 to promote non-homologous end joining during class-switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. We identify shieldin—a four-subunit putative single-stranded DNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35A (SHLD2) and FLJ26957 (SHLD3)— as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end-protection and non-homologous end joining during class-switch recombination, and supports toxic non-homologous end joining in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments, which explains both the immunological differences between 53bp1- and Rev7- deficient mice and the context specificity of the pathway.

Dynamic protein interaction networks such as DNA double-strand break (DSB) signaling are modulated by post-translational modifications (PTMs). The DNA repair factor 53BP1 is a rare example of a protein whose PTM binding function can be switched on and off. 53BP1 is recruited to DSBs by recognizing histone lysine methylation in chromatin, an activity directly inhibited by 53BP1-binding protein TIRR. From X-ray structures of TIRR and a designer protein bound to 53BP1, we reveal a unique regulatory mechanism where an intricate binding area, centered on an essential TIRR arginine residue, blocks the methylated chromatin-binding surface of 53BP1 (the off switch). We find that abolishing TIRR-mediated regulation in cells via a separation-of-function 53BP1 mutation brings 53BP1 to a state of hyperactivation in response to DSBs, highlighting the key inhibitory function of TIRR. We show that this 53BP1 inhibition is relieved by TIRR-interacting RNA molecules, thus providing a proof-of-principle mechanism for RNA-triggered 53BP1 recruitment to DSBs (the on switch).

This paper presents single receiver geoacoustic inversion of a combustive sound source signal, recorded during the 2017 Seabed Characterization Experiment on the New England Mud Patch, in an area where water depth is around 70 m. There are two important features in this study. First, it is shown that high-order modes can be resolved and estimated using warping (up to mode number 18 over the frequency band 20–440 Hz). However, it is not possible to determine mode numbers from the data, so that classical inversion methods that require mode identification cannot be applied. To solve this issue, an inversion algorithm that jointly estimates geoacoustic properties and identifies mode number is proposed. It is successfully applied on a range-dependent track, and provides a reliable range-average estimation of geoacoustic properties of the mud layer, an important feature of the seabed on the experimental area.This paper presents single receiver geoacoustic inversion of a combustive sound source signal, recorded during the 2017 Seabed Characterization Experiment on the New England Mud Patch, in an area where water depth is around 70 m. There are two important features in this study. First, it is shown that high-order modes can be resolved and estimated using warping (up to mode number 18 over the frequency band 20–440 Hz). However, it is not possible to determine mode numbers from the data, so that classical inversion methods that require mode identification cannot be applied. To solve this issue, an inversion algorithm that jointly estimates geoacoustic properties and identifies mode number is proposed. It is successfully applied on a range-dependent track, and provides a reliable range-average estimation of geoacoustic properties of the mud layer, an important feature of the seabed on the experimental area.

Summary Selective elimination of BRCA1-deficient cells by inhibitors of poly(ADP-ribose) polymerase (PARP) is a prime example of the concept of synthetic lethality in cancer therapy. This interaction is counteracted by the restoration of BRCA1-independent homologous recombination through loss of factors such as 53BP1, RIF1, and REV7/MAD2L2, which inhibit end resection of DNA double-strand breaks (DSBs). To identify additional factors involved in this process, we performed CRISPR/SpCas9-based loss-of-function screens and selected for factors that confer PARP inhibitor (PARPi) resistance in BRCA1-deficient cells. Loss of members of the CTC1-STN1-TEN1 (CST) complex were found to cause PARPi resistance in BRCA1-deficient cells in vitro and in vivo. We show that CTC1 depletion results in the restoration of end resection and that the CST complex may act downstream of 53BP1/RIF1. These data suggest that, in addition to its role in protecting telomeres, the CST complex also contributes to protecting DSBs from end resection., Graphical Abstract, Highlights • PARP inhibitor resistance screens independently identify loss of CTC1 as major hit • The CST complex promotes PARP inhibitor sensitivity in BRCA1-deficient cells • Depletion of CTC1 restores end resection in BRCA1-deficient cells • CTC1 facilitates double-strand break repair via canonical non-homologous end joining, Using CRISPR/SpCas9-based loss-of-function screens, Barazas et al. show that loss of the CTC1-STN1-TEN1 (CST) complex promotes PARP inhibitor resistance in BRCA1-deficient cells. Mechanistically, the CST complex maintains double-strand break end stability in addition to its role in protecting telomeric ends.

An important issue in understanding seabed geoacoustic properties at the site of the 2017 Seabed Characterization Experiment (SBCEX) on the New England Mud Patch is the extent to which gradients exist in geoacoustic properties (sound speed and density) over the upper mud layer. This paper applies Bayesian inversion and uncertainty quantification to modal dispersion data, resolved by warping analysis, to consider whether mud-layer gradients are required to fit the data. The inversion is based on a hybrid seabed-model parameterized in terms of an upper sediment layer with a general representation of smooth, continuous gradients in geoacoustic properties based on Bernstein-polynomial basis functions, above an unknown number of discrete layers formulated trans-dimensionally. The inversion results are compared to those from other acoustic data sets collected in the region as well as to nearby core measurements.

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn

This paper presents an application to validate an acoustic signal characterization scheme for ocean acoustic tomography and geoacoustic inversions proposed by Taroudakis, Tzagkarakis, and Tsakalides [J. Acoust. Soc. Am. 119, 1396-1405 (2006)] using data from an experiment at sea. The data were collected during the Shallow water '06 (SW06) experiment off the New Jersey Continental Shelf and the inversion results (sea-bed geoacoustic parameters and source range) are compared with those reported from the same data by Bonnel and Chapman [J. Acoust. Soc. Am. 130(2), EL101-EL107 (2011)]. The comparison and the signal reconstruction using estimated values of the model parameters are satisfactory indicating that the new signal characterization method is useful for practical applications of acoustical oceanography.

This paper presents geoacoustic inversion of modal dispersion data in the South China Sea using a single hydrophone and multiple impulsive sources at ranges from 5–100 km along a shallow-water track with slowly varying bathymetry. As a first step, the source waveform and bubble pulse are deconvolved from the recorded time series using a short-range source recording, corrected for the surface reflection. A time-frequency warping analysis is used to filter individual modes and obtain dispersion (arrival time as a function of frequency) data for three modes. Trans-dimensional Bayesian inversion is applied to the modal dispersion data, based on probabilistic sampling over an unknown number of seabed layers. Range-dependent inversion is considered, based on separating the environment into a sequence of range-independent sections, with frequency-dependent modal propagation times summed over segments. The inversion results are compared to core samples collected at sites along the survey line and to an independent headwave arrival-time analysis of the impulsive-source data.

This paper examines the impact of Mike’s research on geoacoustic inversion for characterization of sea bed sediments. First is his paper in 1987 that reported the use of vertical coherence of ambient ocean noise for estimating critical angles of sea bed sediment. Apart from the novel use of ambient noise as a sound source, his work opened the idea to make use of information about the ocean bottom contained in spatial phase relationships in vertical hydrophone array data. The practice was quickly adapted and widely applied as matched field inversion. However, the inversions were generally carried out using visco-elastic theory of sound propagation, an approach that is not the most appropriate for applications with porous sediment material. Mike’s next contribution addressed this issue in his series of papers starting around 1997 on the grain-shearing and viscous grain-shearing models of sound propagation in porous media. His theory provided a physical basis for the model parameters that are used to describe the interaction of sound with porous sediment media in geoacoustic inversions. Recent examples are shown that indicate how these innovations have become standard practice in geoacoustic inversions.This paper examines the impact of Mike’s research on geoacoustic inversion for characterization of sea bed sediments. First is his paper in 1987 that reported the use of vertical coherence of ambient ocean noise for estimating critical angles of sea bed sediment. Apart from the novel use of ambient noise as a sound source, his work opened the idea to make use of information about the ocean bottom contained in spatial phase relationships in vertical hydrophone array data. The practice was quickly adapted and widely applied as matched field inversion. However, the inversions were generally carried out using visco-elastic theory of sound propagation, an approach that is not the most appropriate for applications with porous sediment material. Mike’s next contribution addressed this issue in his series of papers starting around 1997 on the grain-shearing and viscous grain-shearing models of sound propagation in porous media. His theory provided a physical basis for the model parameters that are used to describ...

The arrival time and amplitude fluctuations of about 230-m propagation were analyzed for various source–receiver configurations using experimental data of Shallow Water’06. The minutes-scale and seconds-scale fluctuations of the arrival time were observed on both the direct (D), surface reflected (SR) and bottom reflected (BR) arrivals. Correlation analysis and simulations based on the ray theory demonstrated that the minutes-scale fluctuation was due to the horizontal range variation between the source and receivers while the seconds-scale fluctuation was caused by the source swing in both the vertical and horizontal directions. A noteworthy phenomenon was that the minutes-scale fluctuation of the amplitude was only observed in the D arrivals while it was absent in the SR and BR arrivals. Furthermore, rather strong fluctuation of the D arrival amplitude could not be explained when the environment was modeled using a smoothed sound speed profile. Simulations showed that the layered microstructures, interference of the multiple eigenrays and the surface duct can strengthen the fluctuation of the direct arrival. The variability of the ocean structures combined with the above three factors resulted in the minutes-scale fluctuations of the D arrival amplitude while the source swing combined with the three factors resulted in the seconds-scale fluctuations.