Seasonal temperatures in West Antarctica during the Holocene.

The recovery of long-term climate proxy records with seasonal resolution is rare because of natural smoothing processes, discontinuities and limitations in measurement resolution. Yet insolation forcing, a primary driver of multimillennial-scale climate change, acts through seasonal variations with direct impacts on seasonal climate1. Whether the sensitivity of seasonal climate to insolation matches theoretical predictions has not been assessed over long timescales. Here, we analyse a continuous record of water-isotope ratios from the West Antarctic Ice Sheet Divide ice core to reveal summer and winter temperature changes through the last 11,000 years. Summer temperatures in West Antarctica increased through the early-to-mid-Holocene, reached a peak 4,100 years ago and then decreased to the present. Climate model simulations show that these variations primarily reflect changes in maximum summer insolation, confirming the general connection between seasonal insolation and warming and demonstrating the importance of insolation intensity rather than seasonally integrated insolation or season duration2,3. Winter temperatures varied less overall, consistent with predictions from insolation forcing, but also fluctuated in the early Holocene, probably owing to changes in meridional heat transport. The magnitudes of summer and winter temperature changes constrain the lowering of the West Antarctic Ice Sheet surface since the early Holocene to less than 162 m and probably less than 58 m, consistent with geological constraints elsewhere in West Antarctica4-7.

The Greenland spatial fingerprint of Dansgaard-Oeschger events in observations and models.

Pleistocene Ice Ages display abrupt Dansgaard-Oeschger (DO) climate oscillations that provide prime examples of Earth System tipping points-abrupt transition that may result in irreversible change. Greenland ice cores provide key records of DO climate variability, but gas-calibrated estimates of the temperature change magnitudes have been limited to central and northwest Greenland. Here, we present ice-core δ15N-N2 records from south (Dye 3) and coastal east Greenland (Renland) to calibrate the local water isotope thermometer and provide a Greenland-wide spatial characterization of DO event magnitude. We combine these data with existing records of δ18O, deuterium excess, and accumulation rates to create a multiproxy "fingerprint" of the DO impact on Greenland. Isotope-enabled climate models have skill in simulating the observational multiproxy DO event impact, and we use a series of idealized simulations with such models to identify regions of the North Atlantic that are critical in explaining DO variability. Our experiments imply that wintertime sea ice variation in the subpolar gyre, rather than the commonly invoked Nordic Seas, is both a sufficient and a necessary condition to explain the observed DO impacts in Greenland, whatever the distal cause. Moisture-tagging experiments support the idea that Greenland DO isotope signals may be explained almost entirely via changes in the vapor source distribution and that site temperature is not a main control on δ18O during DO transitions, contrary to the traditional interpretation. Our results provide a comprehensive, multiproxy, data-model synthesis of abrupt DO climate variability in Greenland.

Differential requirements for the Eps15 homology domain proteins EHD4 and EHD2 in the regulation of mammalian ciliogenesis.

The endocytic protein EHD1 controls primary ciliogenesis by facilitating fusion of the ciliary vesicle and by removal of CP110 from the mother centriole. EHD3, the closest EHD1 paralog, has a similar regulatory role, but initial evidence suggested that the other two more distal paralogs, EHD2 and EHD4 may be dispensable for ciliogenesis. Herein, we define a novel role for EHD4, but not EHD2, in regulating primary ciliogenesis. To better understand the mechanisms and differential functions of the EHD proteins in ciliogenesis, we first demonstrated a requirement for EHD1 ATP-binding to promote ciliogenesis. We then identified two sequence motifs that are entirely conserved between EH domains of EHD1, EHD3 and EHD4, but display key amino acid differences within the EHD2 EH domain. Substitution of either P446 or E470 in EHD1 with the aligning S451 or W475 residues from EHD2 was sufficient to prevent rescue of ciliogenesis in EHD1-depleted cells upon reintroduction of EHD1. Overall, our data enhance the current understanding of the EHD paralogs in ciliogenesis, demonstrate a need for ATP-binding and identify conserved sequences in the EH domains of EHD1, EHD3 and EHD4 that regulate EHD1 binding to proteins and its ability to rescue ciliogenesis in EHD1-depleted cells.

Patient Characteristics Impact Performance of AI Algorithm in Interpreting Negative Screening Digital Breast Tomosynthesis Studies.

Background Artificial intelligence (AI) is increasingly used to manage radiologists' workloads. The impact of patient characteristics on AI performance has not been well studied. Purpose To understand the impact of patient characteristics (race and ethnicity, age, and breast density) on the performance of an AI algorithm interpreting negative screening digital breast tomosynthesis (DBT) examinations. Materials and Methods This retrospective cohort study identified negative screening DBT examinations from an academic institution from January 1, 2016, to December 31, 2019. All examinations had 2 years of follow-up without a diagnosis of atypia or breast malignancy and were therefore considered true negatives. A subset of unique patients was randomly selected to provide a broad distribution of race and ethnicity. DBT studies in this final cohort were interpreted by a U.S. Food and Drug Administration-approved AI algorithm, which generated case scores (malignancy certainty) and risk scores (1-year subsequent malignancy risk) for each mammogram. Positive examinations were classified based on vendor-provided thresholds for both scores. Multivariable logistic regression was used to understand relationships between the scores and patient characteristics. Results A total of 4855 patients (median age, 54 years [IQR, 46-63 years]) were included: 27% (1316 of 4855) White, 26% (1261 of 4855) Black, 28% (1351 of 4855) Asian, and 19% (927 of 4855) Hispanic patients. False-positive case scores were significantly more likely in Black patients (odds ratio [OR] = 1.5 [95% CI: 1.2, 1.8]) and less likely in Asian patients (OR = 0.7 [95% CI: 0.5, 0.9]) compared with White patients, and more likely in older patients (71-80 years; OR = 1.9 [95% CI: 1.5, 2.5]) and less likely in younger patients (41-50 years; OR = 0.6 [95% CI: 0.5, 0.7]) compared with patients aged 51-60 years. False-positive risk scores were more likely in Black patients (OR = 1.5 [95% CI: 1.0, 2.0]), patients aged 61-70 years (OR = 3.5 [95% CI: 2.4, 5.1]), and patients with extremely dense breasts (OR = 2.8 [95% CI: 1.3, 5.8]) compared with White patients, patients aged 51-60 years, and patients with fatty density breasts, respectively. Conclusion Patient characteristics influenced the case and risk scores of a Food and Drug Administration-approved AI algorithm analyzing negative screening DBT examinations. © RSNA, 2024.

Omission of Axillary Lymph Node Dissection in Patients with Residual Nodal Disease After Neoadjuvant Chemotherapy.

BACKGROUND: Axillary management after neoadjuvant chemotherapy (NAC) is evolving but axillary lymph node dissection (ALND) remains the standard of care for patients with residual nodal disease. The results of the Alliance A011202 trial evaluating the oncologic safety of ALND omission in this cohort are pending but we hypothesize that ALND omission is already increasing. METHODS: The National Cancer Database was queried to identify patients diagnosed with cT1-3N1M0 breast cancer who underwent NAC and had residual nodal disease (ypN1mi-2) from 2012 to 2021. Temporal trends in omission of completion ALND were assessed annually. Multivariable logistic and Cox regression models were used to identify factors associated with ALND omission and overall survival (OS), respectively. RESULTS: A total of 6101 patients were included; the majority presented with cT2 disease (57%), with 69% HER2+, 23% triple-negative, and 8% hormone receptor-positive/HER2-. Overall, 34% underwent sentinel lymph node biopsy (SLNB) alone. Rates of ALND were the lowest in the last 4 years of observation. After adjustment, treatment at community centers (vs. academic) and lower pathologic nodal burden were associated with omission of ALND. ALND omission was associated with a higher unadjusted OS (5-year OS: 86% SLNB alone vs. 84% ALND; log-rank p = 0.03), however this association was not maintained after adjustment. CONCLUSIONS: Despite the impending release of the Alliance A011202 results, omission of ALND in patients with residual nodal disease after NAC is increasing. This practice appears more prominent in community centers and in patients with a lower burden of residual nodal disease. No association with OS was noted.

9-Azahomocubane.

Homocubane, a highly strained cage hydrocarbon, contains two very different positions for the introduction of a nitrogen atom into the skeleton, e. g., a position 1 exchange results in a tertiary amine whereas position 9 yields a secondary amine. Herein reported is the synthesis of 9-azahomocubane along with associated structural characterization, physical property analysis and chemical reactivity. Not only is 9-azahomocubane readily synthesized, and found to be stable as predicted, the basicity of the secondary amine was observed to be significantly lower than the structurally related azabicyclo[2.2.1]heptane, although similar to 1-azahomocubane.

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation.

The unusual and sterically constrained amino acid, seco-1-azacubane-2-carboxylic acid, was incorporated into a range of bioactive chemical templates, including enalaprilat, perindoprilat, endomorphin-2 and isoniazid, and subjected to biological testing. The endomorphin-2 derivative displayed increased activity at the δ opioid receptor, but a loss in activity was observed in the other cases, although human normal cell line evaluation suggests limited cytotoxic effects.

Forensic Pathologists and Clinical Trauma Reviews: Performance Improvement, Public Health, and a Concise Autopsy Documentation Guide.

ABSTRACT: As a powerful tool for discovering and documenting injury, the forensic autopsy has been incorporated into trauma care quality improvement. Autopsy findings are used to determine the Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS) to assess a patient's trauma severity. Clinical trauma services use autopsy reports to educate, improve patient care, and strengthen the information used in epidemiological and injury prevention studies. However, there is sometimes a disconnect between the forensic pathologist's injury descriptions and the information needed by the trauma service and for AIS/ISS coding.We formed a collaboration between forensic pathologists and trauma teams to improve this communication. Accordingly, we describe injuries that are commonly overlooked or poorly described in autopsy reports, useful injury terminology, opportunities for trauma care improvement revealed by autopsies, and which medical examiner/coroner cases will most benefit from attention to specific injury details. We demonstrate how differences in injury description impact AIS/ISS results, and distill the detailed AIS manual into a pragmatic, concise, "quick reference" autopsy-directed guide for the forensic pathologist. Collaborations between trauma teams and forensic pathologists benefit each other and help communicate autopsy findings in a more clinically useful way to stakeholders to further benefit the living.

seco-1-Azacubane-2-carboxylic acid-Amide Bond Comparison to Proline.

seco-1-Azacubane-2-carboxylic acid, an unusual and sterically constrained amino acid, was found to undergo amide bond formation at both the N- and C-termini using proline based bioactive molecule templates as a concept platform.

Whole genome analysis of the koa wilt pathogen (Fusarium oxysporum f. sp. koae) and the development of molecular tools for early detection and monitoring.

BACKGROUND: Development and application of DNA-based methods to distinguish highly virulent isolates of Fusarium oxysporum f. sp. koae [Fo koae; cause of koa wilt disease on Acacia koa (koa)] will help disease management through early detection, enhanced monitoring, and improved disease resistance-breeding programs. RESULTS: This study presents whole genome analyses of one highly virulent Fo koae isolate and one non-pathogenic F. oxysporum (Fo) isolate. These analyses allowed for the identification of putative lineage-specific DNA and predicted genes necessary for disease development on koa. Using putative chromosomes and predicted gene comparisons, Fo koae-exclusive, virulence genes were identified. The putative lineage-specific DNA included identified genes encoding products secreted in xylem (e. g., SIX1 and SIX6) that may be necessary for disease development on koa. Unique genes from Fo koae were used to develop pathogen-specific PCR primers. These diagnostic primers allowed target amplification in the characterized highly virulent Fo koae isolates but did not allow product amplification in low-virulence or non-pathogenic isolates of Fo. Thus, primers developed in this study will be useful for early detection and monitoring of highly virulent strains of Fo koae. Isolate verification is also important for disease resistance-breeding programs that require a diverse set of highly virulent Fo koae isolates for their disease-screening assays to develop disease-resistant koa. CONCLUSIONS: These results provide the framework for understanding the pathogen genes necessary for koa wilt disease and the genetic variation of Fo koae populations across the Hawaiian Islands.

Quantum Rifling: Protecting a Qubit from Measurement Back Action.

Quantum mechanics postulates that measuring the qubit's wave function results in its collapse, with the recorded discrete outcome designating the particular eigenstate that the qubit collapsed into. We show that this picture breaks down when the qubit is strongly driven during measurement. More specifically, for a fast evolving qubit the measurement returns the time-averaged expectation value of the measurement operator, erasing information about the initial state of the qubit while completely suppressing the measurement backaction. We call this regime quantum rifling, as the fast spinning of the Bloch vector protects it from deflection into either of its eigenstates. We study this phenomenon with two superconducting qubits coupled to the same probe field and demonstrate that quantum rifling allows us to measure either one of the qubits on demand while protecting the state of the other from measurement backaction. Our results allow for the implementation of selective readout multiplexing of several qubits, contributing to the efficient scaling up of quantum processors for future quantum technologies.

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement.

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.

Trends and Outcomes of Synchronous Resection of Colorectal Metastasis in the Modern Era-Analysis of Targeted Hepatic NSQIP Database.

BACKGROUND: Previous studies using the NSQIP database to study hepatectomies lacked hepatic specific variables and outcomes. We used the targeted NSQIP hepatectomy database to examine the nationwide trend and the safety profile of synchronous liver and colorectal resection compared with hepatectomy alone for colorectal liver metastasis. METHODS: The targeted NSQIP hepatectomy database from 2014 was used to study patients who underwent hepatectomy for diagnosis of adenocarcinoma of the colon and rectum. RESULTS: Of the 3064 hepatic resections in the database, 1138 cases were performed for colorectal metastasis. Of these, 1040 were liver-alone surgery and 98 were synchronous liver and colorectal resection. Most (58.7%) patients received neoadjuvant therapy. The rate of neoadjuvant therapy, intraoperative ablation, biliary reconstruction, and the use of minimally invasive technique were similar between the two groups. The overall 30-d mortality in this cohort was low (1.1%). While the mortality rate in the synchronous group was similar to liver-only group (3.1% versus 0.9%, P = 0.077). The rate of liver failure (3.3% versus 4.1%, P = 0.722) and biliary leak (5.3% versus 9.6%, P = 0.084) were similar between the two groups. However, the rate of major complications was higher on multivariable analyses (25.5% versus 12.1%, OR 2.5, 95% CI 1.5-4.1, P < 0.001) for the synchronous group. CONCLUSIONS: Hepatic resection for colorectal metastasis in the modern era has low short-term mortality. While synchronous resection was associated with a higher incidence of major complications, liver-specific complications did not increase with synchronous resection.

The cubane paradigm in bioactive molecule discovery: further scope, limitations and the cyclooctatetraene complement.

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.

An information-theoretic approach to extracting climate signals from deep polar ice cores.

Paleoclimate records are rich sources of information about the past history of the Earth system. Information theory provides a new means for studying these records. We demonstrate that weighted permutation entropy of water-isotope data from the West Antarctica Ice Sheet (WAIS) Divide ice core reveals meaningful climate signals in this record. We find that this measure correlates with accumulation (meters of ice equivalent per year) and may record the influence of geothermal heating effects in the deepest parts of the core. Dansgaard-Oeschger and Antarctic Isotope Maxima events, however, do not appear to leave strong signatures in the information record, suggesting that these abrupt warming events may actually be predictable features of the climate's dynamics. While the potential power of information theory in paleoclimatology is significant, the associated methods require well-dated and high-resolution data. The WAIS Divide core is the first paleoclimate record that can support this kind of analysis. As more high-resolution records become available, information theory could become a powerful forensic tool in paleoclimate science.

Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11).

BACKGROUND: Combined immunodeficiency (CID) is a T-cell defect frequently presenting with recurrent infections, as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation. OBJECTIVE: We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity. METHODS: We performed whole-exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function. RESULTS: A heterozygous novel c.C88T 1-bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole-exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects. We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild-type CARD11. The CARD11 defect altered the classical nuclear factor κB pathway, resulting in poor in vitro T-cell responses to mitogens and antigens caused by reduced secretion of IFN-γ and IL-2. CONCLUSION: Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.

Anomaly Detection in Paleoclimate Records Using Permutation Entropy.

Permutation entropy techniques can be useful for identifying anomalies in paleoclimate data records, including noise, outliers, and post-processing issues. We demonstrate this using weighted and unweighted permutation entropy with water-isotope records containing data from a deep polar ice core. In one region of these isotope records, our previous calculations (See Garland et al. 2018) revealed an abrupt change in the complexity of the traces: specifically, in the amount of new information that appeared at every time step. We conjectured that this effect was due to noise introduced by an older laboratory instrument. In this paper, we validate that conjecture by reanalyzing a section of the ice core using a more advanced version of the laboratory instrument. The anomalous noise levels are absent from the permutation entropy traces of the new data. In other sections of the core, we show that permutation entropy techniques can be used to identify anomalies in the data that are not associated with climatic or glaciological processes, but rather effects occurring during field work, laboratory analysis, or data post-processing. These examples make it clear that permutation entropy is a useful forensic tool for identifying sections of data that require targeted reanalysis-and can even be useful for guiding that analysis.

Cell wall metabolism and hexose allocation contribute to biomass accumulation in high yielding extreme segregants of a Saccharum interspecific F2 population.

BACKGROUND: Sugarcane is an emerging dual-purpose biofuel crop for energy and sugar production, owing to its rapid growth rate, high sucrose storage in the stems, and high lignocellulosic yield. It has the highest biomass production reaching 1.9 billion tonnes in 2014 worldwide. RESULTS: To improve sugarcane biomass accumulation, we developed an interspecific cross between Saccharum officinarum 'LA Purple' and Saccharum robustum 'MOL5829'. Selected F1 individuals were self-pollinated to generate a transgressive F2 population with a wide range of biomass yield. Leaf and stem internodes of fourteen high biomass and eight low biomass F2 extreme segregants were used for RNA-seq to decipher the molecular mechanism of rapid plant growth and dry weight accumulation. Gene Ontology terms involved in cell wall metabolism and carbohydrate catabolism were enriched among 3274 differentially expressed genes between high and low biomass groups. Up-regulation of cellulose metabolism, pectin degradation and lignin biosynthesis genes were observed in the high biomass group, in conjunction with higher transcript levels of callose metabolic genes and the cell wall loosening enzyme expansin. Furthermore, UDP-glucose biosynthesis and sucrose conversion genes were differentially expressed between the two groups. A positive correlation between stem glucose, but not sucrose, levels and dry weight was detected. CONCLUSIONS: We thus postulated that the high biomass sugarcane plants rapidly convert sucrose to UDP-glucose, which is the building block of cell wall polymers and callose, in order to maintain the rapid plant growth. The gene interaction of cell wall metabolism, hexose allocation and cell division contributes to biomass yield.

Laser wavelength metrology with color sensor chips.

We present a laser wavelength meter based on a commercial color sensor chip. The chip consists of an array of photodiodes with different absorptive color filters. By comparing the relative amplitudes of light on the photodiodes, the wavelength of light can be determined. In addition to absorption in the filters, etalon effects add additional spectral features which improve the precision of the device. Comparing the measurements from the device to a commercial wavelength meter and to an atomic reference, we found that the device has picometer-level precision and picometer-scale drift over a period longer than a month.

Identification of male sterility-related genes in Saccharum officinarum and Saccharum spontaneum.

KEY MESSAGE: Candidate male sterility genes were identified in sugarcane, which interacts with kinase-related proteins, transcription factors, and plant hormone signaling pathways to regulate stamen and anther development. Saccharum officinarum is a cultivated sugarcane species that its predominant feature is high sucrose content in stems. Flowering is necessary for breeding new cultivars but will terminate plant growth and reduce sugar yield. The wild sugarcane species Saccharum spontaneum has robust and viable pollen, whereas most S. officinarum accessions are male sterile, which is a desirable trait of a maternal parent in sugarcane breeding. To study male sterility and related regulatory pathways in sugarcane, we carried out RNAseq using flowers in different developmental stages between male-sterile S. officinarum accession 'LA Purple' and fertile S. spontaneum accession 'SES208'. Gene expression profiles were used to detect how genes are differentially expressed between male sterile and fertile flowers and to identify candidate genes for male sterility. Weighted gene correlation networks analysis (WGCNA) was conducted to investigate the regulatory networks. Transcriptomic analyses showed that 988 genes and 2888 alleles were differentially expressed in S. officinarum compared to S. spontaneum. Ten differentially expressed genes and thirty alleles were identified as candidate genes and alleles for male sterility in sugarcane. The gene Sspon.03G0007630 and two alleles of the gene Sspon.08G0002270, Sspon.08G0002270-2B and Sspon.08G0014700-1A, were involved in the early stamen or carpel development stages, while the remaining genes were classified into the post-meiosis stage. Gibberellin, auxin, and jasmonic acid signaling pathways are involved in the stamen development in sugarcane. The results expanded our knowledge of male sterility-related genes in sugarcane and generated genomic resources to facilitate the selection of ideal maternal parents to improve breeding efficiency.