KEY MESSAGE : QTLs controlling the concentrations elements in rice grain were identified in two mapping populations. The QTLs were clustered such that most genomic regions were associated with more ...than one element. In this study, quantitative trait loci (QTLs) affecting the concentrations of 16 elements in whole, unmilled rice (Oryza sativa L.) grain were identified. Two rice mapping populations, the ‘Lemont’ × ‘TeQing’ recombinant inbred lines (LT-RILs), and the TeQing-into-Lemont backcross introgression lines (TILs) were used. To increase opportunity to detect and characterize QTLs, the TILs were grown under two contrasting field conditions, flooded and irrigated-but-unflooded. Correlations between the individual elements and between each element with grain shape, plant height, and time of heading were also studied. Transgressive segregation was observed among the LT-RILs for all elements. The 134 QTLs identified as associated with the grain concentrations of individual elements were found clustered into 39 genomic regions, 34 of which were found associated with grain element concentration in more than one population and/or flooding treatment. More QTLs were found significant among flooded TILs (92) than among unflooded TILs (47) or among flooded LT-RILs (40). Twenty-seven of the 40 QTLs identified among the LT-RILs were associated with the same element among the TILs. At least one QTL per element was validated in two or more population/environments. Nearly all of the grain element loci were linked to QTLs affecting additional elements, supporting the concept of element networks within plants. Several of the grain element QTLs co-located with QTLs for grain shape, plant height, and days to heading; but did not always differ for grain elemental concentration as predicted by those traits alone. A number of interesting patterns were found, including a strong Mg–P–K complex.
Since researchers first began to uncover the mechanisms underlying allogeneic transplantation, the focus has been on T cells. T cells are a major instigator of graft-versus-host disease (GVHD). The ...clear association between GVHD occurrence and subsequent reduction in relapse supported concentrating on T cells as the masterminds behind graft-versus-tumor (GVT) effects. Recently, an alternative mediator of GVT has taken center stage: natural killer (NK) cells. Part of the appeal of NK cells is their potential to provide antitumor immunity without GVHD. Donor lymphocyte infusion has been the predominant treatment of relapse after allogeneic transplant, but the mix of lymphocytes includes CD8+ T cells and, consequently, a substantial risk for GVHD. In this issue of the JCI, Shapiro and colleagues developed an adoptive NK cell transfer platform to treat relapse after haploidentical allogeneic transplant. The study demonstrated safety, sought to determine resistance mechanisms, and provided avenues for future research.
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Advances in conditioning, graft-versus-host disease (GVHD) prophylaxis and antimicrobial prophylaxis have improved the safety of allogeneic hematopoietic cell transplantation (HCT), ...leading to a substantial increase in the number of patients transplanted each year. This influx of patients along with progress in remission-inducing and posttransplant maintenance strategies for hematologic malignancies has led to new GVHD risk factors and high-risk groups: HLA-mismatched related (haplo) and unrelated (MMUD) donors; older recipient age; posttransplant maintenance; prior checkpoint inhibitor and autologous HCT exposure; and patients with benign hematologic disorders. Along with the changing transplant population, the field of HCT has dramatically shifted in the past decade because of the widespread adoption of posttransplantation cyclophosphamide (PTCy), which has increased the use of HLA-mismatched related donors to levels comparable to HLA-matched related donors. Its success has led investigators to explore PTCy’s utility for HLA-matched HCT, where we predict it will be embraced as well. Additionally, combinations of promising new agents for GVHD prophylaxis such as abatacept and JAK inhibitors with PTCy inspire hope for an even safer transplant platform. Using 3 illustrative cases, we review our current approach to transplantation of patients at high risk of GVHD using our modern armamentarium.
Edited by Associate Editor Robert Zeiser, this How I Treat series focuses on post–allogeneic transplant management of high-risk patients. These patients are at risk for relapse of malignancy and severe graft-versus-host disease (GVHD). Two articles in the series discuss adoptive cellular immunotherapy and maintenance therapy to preempt relapse of acute myeloid leukemia. The third article addresses the state of the art for preventing GVHD in this subset of stem cell transplant recipients.
Degradable polymers are used widely in tissue engineering and regenerative medicine. Maturing capabilities in additive manufacturing coupled with advances in orthogonal chemical functionalization ...methodologies have enabled a rapid evolution of defect-specific form factors and strategies for designing and creating bioactive scaffolds. However, these defect-specific scaffolds, especially when utilizing degradable polymers as the base material, present processing challenges that are distinct and unique from other classes of materials. The goal of this review is to provide a guide for the fabrication of biodegradable polymer-based scaffolds that includes the complete pathway starting from selecting materials, choosing the correct fabrication method, and considering the requirements for tissue specific applications of the scaffold.
We present timing models for 20 millisecond pulsars in the Parkes Pulsar Timing Array. The precision of the parameter measurements in these models has been improved over earlier results by using ...longer data sets and modelling the non-stationary noise. We describe a new noise modelling procedure and demonstrate its effectiveness using simulated data. Our methodology includes the addition of annual dispersion measure (DM) variations to the timing models of some pulsars. We present the first significant parallax measurements for PSRs J1024−0719, J1045−4509, J1600−3053, J1603−7202, and J1730−2304, as well as the first significant measurements of some post-Keplerian orbital parameters in six binary pulsars, caused by kinematic effects. Improved Shapiro delay measurements have resulted in much improved pulsar mass measurements, particularly for PSRs J0437−4715 and J1909−3744 with M
p = 1.44 ± 0.07 and 1.47 ± 0.03 M⊙, respectively. The improved orbital period-derivative measurement for PSR J0437−4715 results in a derived distance measurement at the 0.16 per cent level of precision, D = 156.79 ± 0.25 pc, one of the most fractionally precise distance measurements of any star to date.
More than three-quarters of the baryonic content of the Universe resides in a highly diffuse state that is difficult to detect, with only a small fraction directly observed in galaxies and galaxy ...clusters
. Censuses of the nearby Universe have used absorption line spectroscopy
to observe the 'invisible' baryons, but these measurements rely on large and uncertain corrections and are insensitive to most of the Universe's volume and probably most of its mass. In particular, quasar spectroscopy is sensitive either to the very small amounts of hydrogen that exist in the atomic state, or to highly ionized and enriched gas
in denser regions near galaxies
. Other techniques to observe these invisible baryons also have limitations; Sunyaev-Zel'dovich analyses
can provide evidence from gas within filamentary structures, and studies of X-ray emission are most sensitive to gas near galaxy clusters
. Here we report a measurement of the baryon content of the Universe using the dispersion of a sample of localized fast radio bursts; this technique determines the electron column density along each line of sight and accounts for every ionized baryon
. We augment the sample of reported arcsecond-localized
fast radio bursts with four new localizations in host galaxies that have measured redshifts of 0.291, 0.118, 0.378 and 0.522. This completes a sample sufficiently large to account for dispersion variations along the lines of sight and in the host-galaxy environments
, and we derive a cosmic baryon density of Formula: see text (95 per cent confidence; h
= H
/(70 km s
Mpc
) and H
is Hubble's constant). This independent measurement is consistent with values derived from the cosmic microwave background and from Big Bang nucleosynthesis
.
There has been exponential growth in research on emotion regulation and substance use in the past decade. The current meta-analysis evaluated variability in the magnitude of the relation between ...aspects of emotion regulation and substance use. A search of PsycINFO, Embase, PubMed, CINAHL Plus, and PILOTS in December 2020 resulted in 6642 initial studies, of which 95 met inclusion criteria (association between emotion regulation and substance use was reported, participants were > 18 years old, article was in English). A total of 445 effects were obtained (N = 156,025 participants; weighted Mage = 29.31; 59.5% female; 66.1% White; 76.6% non-clinical). Emotion regulation and substance use were significantly related (r = 0.19; p < 0.001; 95%CI 0.17, 0.20). Emotion regulation abilities were generally more strongly related to substance use than emotion regulation strategies; this pattern was stronger for behavioral vs. cognitive abilities and extended to both negative and positive emotions. Relations were stronger for older and clinical samples; mixed effects were found for sex and no conclusive effects were found for race. Despite limitations of the existing literature (e.g., cross-sectional, self-reports), results indicated that the magnitude of the relation between emotion regulation and substance use varied considerably as a function of emotion regulation and substance use constructs and sample characteristics.
•The emotion regulation and substance use relation was significant and small-to-medium.•Emotion regulation abilities vs. strategies were more strongly related to substance use.•Behavioral vs. cognitive abilities were more strongly related to substance use.•Both negative and positive emotion regulation abilities were related to substance use.•Relations were stronger for older and clinical samples; mixed effects were found for sex.
ABSTRACT The dispersion measure (DM), the column density of free electrons to a pulsar, is shown to be frequency dependent because of multipath scattering from small-scale electron-density ...fluctuations. DMs vary between propagation paths whose transverse extent varies strongly with frequency, yielding arrival times that deviate from the high-frequency scaling expected for a cold, uniform, unmagnetized plasma (1/frequency2). Scaling laws for thin phase screens are verified with simulations; extended media are also analyzed. The rms DM difference across an octave band near 1.5 GHz is ∼ 4 × 10−5 pc cm−3 for pulsars at ∼1 kpc distance. The corresponding arrival-time variations are a few to hundreds of nanoseconds for DM 30 pc cm−3 but increase rapidly to microseconds or more for larger DMs and wider frequency ranges. Chromatic DMs introduce correlated noise into timing residuals with a power spectrum of "low pass" form. The correlation time is roughly the geometric mean of the refraction times for the highest and lowest radio frequencies used, ranging from days to years, depending on the pulsar. We discuss implications for methodologies that use large frequency separations or wide bandwidth receivers for timing measurements. Chromatic DMs are partially mitigable by including an additional chromatic term in arrival time models. Without mitigation, an additional term in the noise model for pulsar timing is implied. In combination with measurement errors from radiometer noise, an arbitrarily large increase in total frequency range (or bandwidth) will yield diminishing benefits and may be detrimental to overall timing precision.
HLA-haploidentical hematopoietic stem cell transplantation is now one of the most commonly employed alternative donor techniques, with most centers applying T-cell–replete strategies such as that ...developed by the Baltimore group using high-dose posttransplant cyclophosphamide. HLA-haploidentical hematopoietic stem cell transplantation using posttransplant cyclophosphamide is associated with low rates of severe graft-versus-host disease and nonrelapse mortality and does not require graft manipulation or storage, which results in a low graft acquisition cost. Its remarkable safety when used with reduced-intensity conditioning has been demonstrated in patients up to 75 years old with outcomes similar to those of patients in their 50s. Several large, registry-based retrospective studies have confirmed the efficacy of HLA-haploidentical hematopoietic stem cell transplantation with posttransplant cyclophosphamide, achieving results comparable to those of HLA-matched hematopoietic stem cell transplantation. In this article, we describe our approach to this rapidly available and clinically simple platform and address some of the key clinical questions associated with its use.
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The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute ...respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein
show promise therapeutically and are being evaluated clinically
. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies
in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs
. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.
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