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At least 739 records · Page 41

Describing patterns of familial cancer risk in subfertile men using population pedigree data

STUDY QUESTION Can we simultaneously assess risk for multiple cancers to identify familial multicancer patterns in families of azoospermic and severely oligozoospermic men? SUMMARY ANSWER Here, distinct familial cancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in familial cancer risk by both type of subfertility and within subfertility type. WHAT IS KNOWN ALREADY Subfertile men and their relatives show increased risk for certain cancers including testicular, thyroid, and pediatric. STUDY DESIGN, SIZE, DURATION A retrospective cohort of subfertile men (N = 786) was identified and matched to fertile population controls (N = 5674). Family members out to third-degree relatives were identified for both subfertile men and fertile population controls (N = 337 754). The study period was 1966–2017. Individuals were censored at death or loss to follow-up, loss to follow-up occurred if they left Utah during the study period. PARTICIPANTS/MATERIALS, SETTING, METHODS Azoospermic (0 × 10 6 /mL) and severely oligozoospermic (<1.5 × 10 6 /mL) men were identified in the Subfertility Health and Assisted Reproduction and the Environment cohort (SHARE). Subfertile men were age- and sex-matched 5:1 to fertile population controls and family members out to third-degree relatives were identified using the Utah Population Database (UPDB). Cancer diagnoses were identified through the Utah Cancer Registry. Families containing ≥10 members with ≥1 year of follow-up 1966–2017 were included (azoospermic: N = 426 families, 21 361 individuals; oligozoospermic: N = 360 families, 18 818 individuals). Unsupervised clustering based on standardized incidence ratios for 34 cancer phenotypes in the families was used to identify familial multicancer patterns; azoospermia and severe oligospermia families were assessed separately. MAIN RESULTS AND THE ROLE OF CHANCE Compared to control families, significant increases in cancer risks were observed in the azoospermia cohort for five cancer types: bone and joint cancers hazard ratio (HR) = 2.56 (95% CI = 1.48–4.42), soft tissue cancers HR = 1.56 (95% CI = 1.01–2.39), uterine cancers HR = 1.27 (95% CI = 1.03–1.56), Hodgkin lymphomas HR = 1.60 (95% CI = 1.07–2.39), and thyroid cancer HR = 1.54 (95% CI = 1.21–1.97). Among severe oligozoospermia families, increased risk was seen for three cancer types: colon cancer HR = 1.16 (95% CI = 1.01–1.32), bone and joint cancers HR = 2.43 (95% CI = 1.30–4.54), and testis cancer HR = 2.34 (95% CI = 1.60–3.42) along with a significant decrease in esophageal cancer risk HR = 0.39 (95% CI = 0.16–0.97). Thirteen clusters of familial multicancer patterns were identified in families of azoospermic men, 66% of families in the azoospermia cohort showed population-level cancer risks, however, the remaining 12 clusters showed elevated risk for 2-7 cancer types. Several of the clusters with elevated cancer risks also showed increased odds of cancer diagnoses at young ages with six clusters showing increased odds of adolescent and young adult (AYA) diagnosis [odds ratio (OR) = 1.96–2.88] and two clusters showing increased odds of pediatric cancer diagnosis (OR = 3.64–12.63). Within the severe oligozoospermia cohort, 12 distinct familial multicancer clusters were identified. All 12 clusters showed elevated risk for 1–3 cancer types. An increase in odds of cancer diagnoses at young ages was also seen in five of the severe oligozoospermia familial multicancer clusters, three clusters showed increased odds of AYA diagnosis (OR = 2.19–2.78) with an additional two clusters showing increased odds of a pediatric diagnosis (OR = 3.84–9.32). LIMITATIONS, REASONS FOR CAUTION Although this study has many strengths, including population data for family structure, cancer diagnoses and subfertility, there are limitations. First, semen measures are not available for the sample of fertile men. Second, there is no information on medical comorbidities or lifestyle risk factors such as smoking status, BMI, or environmental exposures. Third, all of the subfertile men included in this study were seen at a fertility clinic for evaluation. These men were therefore a subset of the overall population experiencing fertility problems and likely represent those with the socioeconomic means for evaluation by a physician. WIDER IMPLICATIONS OF THE FINDINGS This analysis leveraged unique population-level data resources, SHARE and the UPDB, to describe novel multicancer clusters among the families of azoospermic and severely oligozoospermic men. Distinct overall multicancer risk and familial multicancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in cancer risk by type of subfertility and within subfertility type. Describing families with similar cancer risk patterns provides a new avenue to increase homogeneity for focused gene discovery and environmental risk factor studies. Such discoveries will lead to more accurate risk predictions and improved counseling for patients and their families. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): R01 HD106112). The authors have no conflicts of interest relevant to this work.

60 APPLIED LIFE SCIENCES↗

Using quasar X-ray and UV flux measurements to constrain cosmological model parameters

ABSTRACT Risaliti and Lusso have compiled X-ray and UV flux measurements of 1598 quasars (QSOs) in the redshift range 0.036 ≤ z ≤ 5.1003, part of which, z ∼ 2.4 − 5.1, is largely cosmologically unprobed. In this paper we use these QSO measurements, alone and in conjunction with baryon acoustic oscillation (BAO) and Hubble parameter [H(z)] measurements, to constrain cosmological parameters in six different cosmological models, each with two different Hubble constant priors. In most of these models, given the larger uncertainties, the QSO cosmological parameter constraints are mostly consistent with those from the BAO + H(z) data. A somewhat significant exception is the non-relativistic matter density parameter Ωm0 where QSO data favour Ωm0 ∼ 0.5 − 0.6 in most models. As a result, in joint analyses of QSO data with H(z) + BAO data the 1D Ωm0 distributions shift slightly towards larger values. A joint analysis of the QSO + BAO + H(z) data is consistent with the current standard model, spatially-flat ΛCDM, but mildly favours closed spatial hypersurfaces and dynamical dark energy. Since the higher Ωm0 values favoured by QSO data appear to be associated with the z ∼ 2 − 5 part of these data, and conflict somewhat with strong indications for Ωm0 ∼ 0.3 from most z < 2.5 data as well as from the cosmic microwave background anisotropy data at z ∼ 1100, in most models, the larger QSO data Ωm0 is possibly more indicative of an issue with the z ∼ 2 − 5 QSO data than of an inadequacy of the standard flat ΛCDM model.

79 ASTRONOMY AND ASTROPHYSICS↗

Black hole spin in X-ray binaries: giving uncertainties an $\mathcal{f}$

The two established techniques for measuring black hole spin in X-ray binaries often yield conflicting results, which must be resolved before either method may be deemed robust. In practice, black hole spin measurements based on fitting the accretion disc continuum effectively do not marginalize over the colour-correction factor f col . This factor parametrizes spectral hardening of the disc continuum by the disc atmosphere, whose true properties are poorly constrained. We incorporate reasonable systematic uncertainties in f col into the eight (non-maximal) black hole spin measurements vetted by the disc continuum fitting community. In most cases, an f col uncertainty of ±0.2–0.3 dominates the black hole spin error budget. We go on to demonstrate that plausible departures in f col values from those adopted by the disc continuum fitting practitioners can bring the discrepant black hole spins into agreement with those from iron line modelling. Systematic uncertainties in f col , such as the effects of strong magnetization, should be better understood before dismissing their potentially dominant impact on the black hole spin error budget.

4U 1543–47↗

Clumpy structures within the turbulent primordial cloud

ABSTRACT The primordial clouds in the mini-haloes hatch the first generation stars of the Universe, which play a crucial role in cosmic evolution. In this paper, we investigate how turbulence impacts the structure of primordial star-forming clouds. Previous cosmological simulations of the first star formation predicted a typical mass of around $\mathrm{ 100 \, M_\odot }$. This conflicts with recent observations of extremely metal-poor stars, suggesting a lower mass scale of about $\mathrm{25 \, M_\odot }$. The discrepancy may arise from unresolved turbulence in the star-forming cloud, driven by primordial gas accretion during mini-halo formation in the previous simulations. To quantitatively examine the turbulence effect on the primordial cloud formation, we employ the adaptive mesh refinement code Enzo to model the gas cloud with primordial composition, including artificially driven turbulence on the cloud scale and relevant gas physics. This artificially driven turbulence utilizes a stochastic forcing model to mimic the unresolved turbulence inside mini-haloes. Our results show that the turbulence with high Mach number and compressional mode effectively fragments the cloud into several clumps, each with dense cores of $\mathrm{22.7 - 174.9 \, M_\odot }$ that undergo Jeans instability to form stars. Fragmentation caused by intense and compressive turbulence prevents a runaway collapse of the cloud. The self-bound clumps with smaller masses in the turbulent primordial clouds suggest a possible pathway to decrease the theoretical mass scale of the first stars, further reconciling the mass discrepancy between simulations and observations.

Astronomy & Astrophysics↗

DNA Breaks-Mediated Fitness Cost Reveals RNase HI as a New Target for Selectively Eliminating Antibiotic-Resistant Bacteria

Abstract Antibiotic resistance often generates defects in bacterial growth called fitness cost. Understanding the causes of this cost is of paramount importance, as it is one of the main determinants of the prevalence of resistances upon reducing antibiotics use. Here we show that the fitness costs of antibiotic resistance mutations that affect transcription and translation in Escherichia coli strongly correlate with DNA breaks, which are generated via transcription–translation uncoupling, increased formation of RNA–DNA hybrids (R-loops), and elevated replication–transcription conflicts. We also demonstrated that the mechanisms generating DNA breaks are repeatedly targeted by compensatory evolution, and that DNA breaks and the cost of resistance can be increased by targeting the RNase HI, which specifically degrades R-loops. We further show that the DNA damage and thus the fitness cost caused by lack of RNase HI function drive resistant clones to extinction in populations with high initial frequency of resistance, both in laboratory conditions and in a mouse model of gut colonization. Thus, RNase HI provides a target specific against resistant bacteria, which we validate using a repurposed drug. In summary, we revealed key mechanisms underlying the fitness cost of antibiotic resistance mutations that can be exploited to specifically eliminate resistant bacteria.

Balbontín, Roberto↗

Structural basis of chromatin regulation by histone variant H2A.Z

Abstract The importance of histone variant H2A.Z in transcription regulation has been well established, yet its mechanism-of-action remains enigmatic. Conflicting evidence exists in support of both an activating and a repressive role of H2A.Z in transcription. Here we report cryo-electron microscopy (cryo-EM) structures of nucleosomes and chromatin fibers containing H2A.Z and those containing canonical H2A. The structures show that H2A.Z incorporation results in substantial structural changes in both nucleosome and chromatin fiber. While H2A.Z increases the mobility of DNA terminus in nucleosomes, it simultaneously enables nucleosome arrays to form a more regular and condensed chromatin fiber. We also demonstrated that H2A.Z’s ability to enhance nucleosomal DNA mobility is largely attributed to its characteristic shorter C-terminus. Our study provides the structural basis for H2A.Z-mediated chromatin regulation, showing that the increase flexibility of the DNA termini in H2A.Z nucleosomes is central to its dual-functions in chromatin regulation and in transcription.

59 BASIC BIOLOGICAL SCIENCES↗

Cross-scale dynamics and the evolutionary emergence of infectious diseases

When emerging pathogens encounter new host species for which they are poorly adapted, they must evolve to escape extinction. Pathogens experience selection on traits at multiple scales, including replication rates within host individuals and transmissibility between hosts. We analyze a stochastic model linking pathogen growth and competition within individuals to transmission between individuals. Our analysis reveals a new factor, the cross-scale reproductive number of a mutant virion, that quantifies how quickly mutant strains increase in frequency when they initially appear in the infected host population. This cross-scale reproductive number combines with viral mutation rates, single-strain reproductive numbers, and transmission bottleneck width to determine the likelihood of evolutionary emergence, and whether evolution occurs swiftly or gradually within chains of transmission. We find that wider transmission bottlenecks facilitate emergence of pathogens with short-term infections, but hinder emergence of pathogens exhibiting cross-scale selective conflict and long-term infections. Furthermore, our results provide a framework to advance the integration of laboratory, clinical, and field data in the context of evolutionary theory, laying the foundation for a new generation of evidence-based risk assessment of emergence threats.

59 BASIC BIOLOGICAL SCIENCES↗

Toughening materials: enhancing resistance to fracture

It has been said that ‘God invented plasticity, but the Devil invented fracture!’ Both mechanisms represent the two prime modes of structural failure, respectively, plastic collapse and the rupture/breaking of a component, but the concept of developing materials with enhanced resistance to fracture can be difficult. This is because fracture resistance invariably involves a compromise—between strength and ductility, between strength and toughness—fundamentally leading to a ‘conflict’ between nano-/micro-structural damage and the mechanisms of toughening. Here, we examine the two major classes of such toughening: (i) intrinsic toughening, which occurs ahead of a crack tip and is motivated by plasticity—this is the principal mode of fracture resistance in ductile materials, and (ii) extrinsic toughening, which occurs at, or in the wake of, a crack tip and is associated with crack-tip shielding—this is generally the sole mode of fracture resistance in brittle materials. We briefly examine how these distinct mechanistic processes have been used to toughen synthetic materials—intrinsically in gradient materials and in multiple principal-element metallic alloys with the example of metallic glasses and high-entropy alloys, and extrinsically in ceramics with the example of ceramic-matrix composites—in comparison to Nature which has been especially adept in creating biological/natural materials which are toughened by one or both mechanistic classes, despite often consisting of constituents with meagre mechanical properties. The success of Nature has been driven by its ability to cultivate the development of materials with multiple length-scale hierarchical structures that display ingenious gradients and structural adaptability, a philosophy which we need to emulate and more importantly learn to synthesize to make structural materials of the future with unprecedented combinations of mechanical properties.

36 MATERIALS SCIENCE↗

Persistent trade-offs balance competition and colonization across centuries

When a microbe colonizes a host, it must both establish infection and outcompete other organisms. Short-term experiments show that gains in competitive ability can reduce colonization, creating trade-offs, but whether microbes resolve these conflicts over long evolutionary timescales is unknown. We show that a trade-off between competitive killing and host colonization has been stably maintained for centuries in natural Pseudomonas populations infecting Arabidopsis thaliana. Tailocins—phage-derived weapons—provide strong competitive advantages, yet their production reduces colonization success, explaining why the most broadly lethal variants remain rare. Genomic surveys and historical genomes spanning two centuries reveal that the polymorphisms underlying this trade-off have persisted across 10⁵-10⁶ generations. Understanding such long-lived constraints can inform antimicrobial strategies that exploit evolutionary trade-offs.

Backman, Talia↗

Optically accessible high-finesse millimeter-wave resonator for cavity quantum electrodynamics with atom arrays

Cavity quantum electrodynamics (QED) is a powerful tool in quantum science, enabling preparation of nonclassical states of light and scalable entanglement of many atoms coupled to a single field mode. While the most coherent atom-photon interactions have been achieved using superconducting millimeter-wave cavities coupled to Rydberg atoms, these platforms so far lack the optical access required for trapping and addressing individual atomic qubits. We present a millimeter-wave Fabry-Pérot cavity with finesse 5.8⁢(1) ×10 7 at a temperature of 1 K providing generous transverse optical access (numerical aperture 0.56). Conflicting goals of strong atom-photon coupling and optical access motivate a near-confocal geometry. Close to confocality, however, postparaxial corrections to the cavity spectrum introduce unexpected degeneracies between transverse modes, leading to excess cavity loss. Modeling these corrections allows for tuning the cavity geometry to evade this loss, producing a high finesse that will enable cavity QED experiments with trapped atoms deep in the strong coupling regime.

Zhang, Tony [Stanford Univ., CA (United States); S↗

Medium-Range Order, Density Fluctuations, and Activated Relaxation in the Equilibrated Deep Glass Regime

A successful microscopic theory of activated relaxation in metastable supercooled liquids is extended to the equilibrated deep glass regime. Surprisingly, the predicted power-law scaling connections of the dynamic barrier with diverse scalar order parameters (medium-range order correlation length, dimensionless compressibility, shear modulus) remain unchanged up to astronomically long timescales, despite a fundamental crossover of equilibrium thermodynamics and structure near the laboratory kinetic vitrification point. Quantitative tests against experiments on aged to equilibrium glass-forming liquids up to nearly 20 decades in time scale reveal good agreement. This conflicts with the idea of a crossover from super-Arrhenius to literal Arrhenius relaxation around the laboratory glass transition temperature, and supports the robustness of the theoretical idea that ultraslow dynamics is causally related to medium-range structural order. Here, new avenues of experimental and theoretical research in the deep glass regime are suggested.

Amorphous materials↗

Topological descendants of a multicritical Dirac semimetal with magnetism and strain

The past decades have witnessed a transformation in characterizing condensed matter systems with topology. Aided by a refined understanding of topological band structures with crystalline symmetries that has emerged recently, many electronic phases have been identified, and a plethora of materials have been predicted to host properties and functionalities. A key underlying question, also with respect to future application, is to what extent the related physical features can be manipulated, especially in the context of magnetic order. Here, we describe a paradigmatic semimetal that simultaneously incorporates multiple and sometimes conflicting topology which guarantees gaplessness and leads to an exceptionally rich family of descendent phases on lowering symmetry. We predict that this multicritical phase is realized in EuTl 2 . Starting from the parent semimetallic state, which already separates two topological insulating regimes, the interplay of inherent magnetism and strain allows for an exceptionally rich phase diagram of topological descendant states.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

Lattice flexibility in Ca 3 Ru 2 O 7 : Control of electrical transport via anisotropic magnetostriction

We report that Ca 3 Ru 2 O 7 is a correlated and spin-orbit coupled system with an extraordinary anisotropy. It is both interesting and unique largely because this material exhibits conflicting phenomena that are often utterly inconsistent with traditional precedents, particularly, the quantum oscillations in the nonmetallic state and colossal magnetoresistivity achieved by avoiding a fully spin-polarized state. This work focuses on the relationship between the lattice and transport properties along each crystalline axis and reveals that application of magnetic field, H, along different crystalline axes readily stretches or shrinks the lattice in a uniaxial manner, resulting in distinct electronic states. Furthermore, application of modest pressure drastically amplifies the anisotropic magnetoelastic effect, leading to either an occurrence of a robust metallic state at H $∥$ hard axis or a reentrance of the nonmetallic state at H $∥$ easy axis. Ca3Ru2O7 presents a rare lattice-dependent magnetotransport mechanism, in which the extraordinary lattice flexibility enables an exquisite control of the electronic state via magnetically stretching or shrinking the crystalline axes, and the spin polarization plays an unconventional role unfavorable for maximizing conductivity. At the heart of the intriguing physics is the anisotropic magnetostriction that leads to exotic states.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

Examination of the cerium α-ε phase transition under dynamic loading with x-ray diffraction

Recent examination of the cerium Hugoniot with pyrometry and x-ray diffraction (XRD) has revealed a narrow solid-liquid two-phase region. It has been suggested that nonequilibrium melting may be occurring along the Ce Hugoniot, with either melt kinetics or a sluggish α-ε transition impeding the transition. In particular, the kinetics of the α-ε is unknown and the location of the phase boundary is in dispute. Static measurements suggest a nearly vertical phase boundary that intersects the Hugoniot at 6–7 GPa. This lies in direct conflict with dynamic measurements along the Hugoniot observing α-Ce through incipient melt. This work presents dynamic experiments using XRD to examine the behavior of the α-ε phase transition. The results show that the α-ε phase transition occurs through a tetragonal distortion, with the transition beginning at temperatures below the solid Hugoniot. Following the initial deviation from an ideal fcc structure, the c/a ratio is found to gradually increase with no steady value observed in the ε phase within the range of these experiments (below 17 GPa). Multiple diffraction patterns captured during the peak stress state show no significant change in c/a ratio prior to uniaxial release, upon which Ce reverts to an fcc structure. Furthermore, the results indicate that the α-ε transition occurs rapidly, both on loading and release. An examination of the c/a ratio with increasing temperatures suggests 11.5 GPa as a lower bound for the location of the α-ε-liquid triple point.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

Ground state of Ce 3 Bi 4 Pd 3 unraveled by hydrostatic pressure

Noncentrosymmetric Ce 3 Bi 4 Pd 3 has attracted a lot of attention as a candidate for strongly correlated topological material, yet its experimental ground state remains a matter of contention. Two conflicting scenarios have emerged from a comparison to the prototypical Kondo insulator Ce 3 Bi 4 Pd 3 : Either Ce 3 Bi 4 Pd 3 is a spin-orbit-driven topological semimetal or a Kondo insulator with smaller Kondo coupling than its Pt counterpart. Here, we determine the ground state of Ce 3 Bi 4 Pd 3 via electrical resistivity measurements under hydrostatic pressure, which is a clean symmetry-preserving tuning parameter that increases hybridization but virtually preserves spin-orbit coupling. Ce 3 Bi 4 Pd 3 becomes more insulating under pressures up to 2.3 GPa, which is a signature of Ce-based Kondo insulating materials in the considered pressure range. Its small zero-pressure gap increases quadratically with pressure, similar to the behavior observed in the series Ce 3 Bi 4 (Pt 1 - x Pd x ) 3 , which indicates that Pt substitution and applied pressure have a similar effect. Finally, our result not only demonstrates that Kondo coupling, rather than spin-orbit coupling, is the main tuning parameter in this class of materials, but it also establishes that Ce 3 Bi 4 Pd 3 has a narrow-gap Kondo insulating ground state.

36 MATERIALS SCIENCE↗

Superconducting penetration depth through a Van Hove singularity: Sr 2 ⁢RuO 4 under uniaxial stress

A plethora of experiments in Sr 2 RuO 4 have reached conflicting conclusions about the symmetry of the superconducting gap. To probe the gap’s structure in k-space, we use strain to continuously tune the band structure through a Van Hove singularity (VHS) while imaging the superconductivity with scanning SQUID microscopy. We find that the superfluid density peaks at the VHS and that the temperature dependence of the penetration depth is T 2 -quadratic over the entire measured range of strain ε. These results are consistent with a gap structure that has vertical line nodes, experimentally confirming that non-local effects in the Meissner screening can lead to T 2 behavior and clarifying the nature of the low-energy excitations in Sr 2 RuO 4 .

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

Indirect determination of the astrophysical S factor for the Li 6 ( p , γ ) Be 7 reaction using the asymptotic normalization coefficient method

The 6 Li(p,γ) 7 Be cross section influences a variety of astrophysical scenarios, including big-bang and stellar nucleosynthesis. In recent years, conflicting results of direct measurements have been published, reporting contradictory low-energy trends. To shed light on the contradiction between the existing data sets, the reaction was studied using the asymptotic normalization coefficient (ANC) technique which was up-to-now never used for this reaction. To derive the ANC, the 6 Li( 3 He,d) 7 Be transfer reaction, studied at the Department of Physics and Astronomy of the University of Catania and at the John. D. Fox Superconducting Accelerator Laboratory at Florida State University, was re-analyzed, focusing on the proton transfer mechanism [the α transfer process is discussed by Kiss et al. [Phys. Lett. B 807, 135606 (2020)]. Here, the energy of the 3 He beam impinging on a 6 Li target was E lab = 3 MeV and E lab = 5 MeV. The yield of the emitted deuterons was measured with high precision by using silicon ΔE – E telescopes.

6 ≤ A ≤ 19↗

Coupled fission fragment angular momenta

Here, nuclear fission produces fragments whose spins are coupled to the relative angular motion via angular momentum conservation. It is shown how ensembles of such spins can readily be obtained by either direct microcanonical sampling or by sampling of the associated normal modes of rotation. The resulting distribution of the spin-spin opening angle is illustrated in various three- and two-dimensional scenarios and it is demonstrated how recent mutually conflicting model calculations can be well reproduced with different assumptions about the scission geometry.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗