The Structural Biology of Catalase Evolution.

Catalases are essential enzymes for removal of hydrogen peroxide, enabling aerobic and anaerobic metabolism in an oxygenated atmosphere. Monofunctional heme catalases, catalase-peroxidases, and manganese catalases, evolved independently more than two billion years ago, constituting a classic example of convergent evolution. Herein, the diversity of catalase sequences is analyzed through sequence similarity networks, providing the context for sequence distribution of major catalase families, and showing that many divergent catalase families remain to be experimentally studied.

[Potentially inappropriate medication in older adults with palliative care at home]. / Medicación potencialmente inapropiada en adultos mayores con necesidades paliativas en domicilio.

INTRODUCTION: Older adults with advanced chronic diseases and palliative care needs are more exposed to polypharmacy and use of potentially inappropriate medication, which generates a high risk of adverse events and impaired quality of life. The objective of this study was to describe the frequency of potentially inappropriate medication use among older adults with palliative care needs receiving home care services after hospital discharge. METHODS: Observational cross-sectional study of pharmacy dispensing and electronic health records, of older adults in a home care system and with palliative care needs according to the screening with the NECPAL tool or the PROFUND and/or PALIAR indexes. Dispensed medications during 180 days after admission to home care were analyzed. Medications were classified as potentially inappropriate according to the LESS-CHRON criteria. RESULTS: We included 176 patients, mean age 87.4 years, 67% were women; 73% were pluripathologic patients and 22% had one chronic progressive disease. Mortality at 6 months was 73%. Median frequency of dispensed medications per patient was 9.1 (IQR = 4-9.7). The frequency of potentially inappropriate medication dispensation among patients was 87%, mainly antihypertensives, benzodiazepines and antipsychotics. CONCLUSION: This study observed that dispensation of potentially inappropriate medication among older adults with palliative care needs and home care services is very high. This emphasizes the need for effective patient-centered interventions to prevent inadequate prescription and stimulate de-prescription.

Introducción: Los adultos mayores con enfermedades crónicas avanzadas y necesidad de cuidados paliativos están más expuestos a la polifarmacia y a consumir medicación potencialmente inapropiada, la cual genera un alto riesgo de eventos adversos y alteración de la calidad de vida. El objetivo de este estudio fue describir la frecuencia de consumo de medicación potencialmente inapropiada de adultos mayores con necesidad de cuidados paliativos que ingresaron a cuidados domiciliarios luego de una hospitalización. Métodos: Estudio de corte transversal observacional de registros de dispensación e historias clínicas electrónicas, de adultos mayores en un sistema de cuidados domiciliarios y con necesidades de cuidados paliativos según el rastreo con la herramienta NECPAL, los índices PROFUND y/o PALIAR. Se analizó el consumo de fármacos durante los 180 días posteriores al ingreso a cuidados domiciliarios. Se clasificaron los fármacos como potencialmente inapropiados según criterios de LESS-CHRON. Resultados: Se incluyeron 176 pacientes, edad promedio 87.4 años, 67% mujeres; 78% eran pluripatológicos y 22% presentaban una enfermedad única crónica progresiva. La mortalidad a los 6 meses fue 73%. La mediana de consumo de fármacos por paciente fue 9.1 (RIC = 4-9.7). El 87% consumía medicación potencialmente inapropiada, principalmente antihipertensivos, benzodiacepinas y antipsicóticos. Conclusión: Este estudio observó que los adultos mayores, con necesidad de cuidados paliativos en cuidados domiciliarios, tienen un alto consumo de medicación potencialmente inapropiada. Esto refuerza la necesidad de implementar intervenciones efectivas centradas en el paciente, para prevenir la prescripción inadecuada y estimular la de-prescripción.

Navigated Anterior Full-Endoscopic Transcervical Approach Odontoidectomy for Traumatic Posterior Atlantoaxial Dislocation Without Odontoid Fracture.

BACKGROUND AND IMPORTANCE: Complete posterior atlantoaxial dislocation (PAAD) with an unfractured odontoid process is a rare condition where a dislocated but intact odontoid process is positioned ventrally to the anterior arch of C1. This lesion is related to transverse and alar ligament rupture secondary to hyperextension and rotatory traumatic injury and is often associated with neurological deficit. The treatment strategy remains controversial, and in many cases, odontoidectomy is required. Traditional approaches for odontoidectomy (transnasal and transoral) are technically demanding and are related to several complications. This article describes a 360° reduction and stabilization technique through a navigated anterior full-endoscopic transcervical approach (nAFETA) as a novel technique for odontoidectomy and C1-C2 anterior transarticular fixation supplemented with posterior fusion. CLINICAL PRESENTATION: A 21-year-old man presented to the emergency room by ambulance after a motorcycle accident. On evaluation, incomplete ASIA B spinal cord injury was documented. Imaging revealed a complete PAAD. We performed a two-staged procedure, a nAFETA odontoidectomy plus C1-C2 anterior transarticular fixation followed by posterior C1-C2 wired fusion. At a 2-year follow-up, the patient had a 10-point Oswestry Disability Index score and neurological improvement to ASIA E. CONCLUSION: PAAD can be successfully treated through minimally invasive nAFETA. Noteworthy, the risks of the transoral and endonasal routes were avoided through this approach. In addition, nAFETA allows anterior transarticular fixation during the same procedure providing spinal stability. Further studies are required to expand the use of nAFETA in this field.

Multiscale Heterogeneous Polymer Composites for High Stiffness 4D Printed Electrically Controllable Multifunctional Structures.

4D printing is an emerging field where 3D printing techniques are used to pattern stimuli-responsive materials to create morphing structures, with time serving as the fourth dimension. However, current materials utilized for 4D printing are typically soft, exhibiting an elastic modulus (E) range of 10-4 to 10 MPa during shape change. This restricts the scalability, actuation stress, and load-bearing capabilities of the resulting structures. To overcome these limitations, multiscale heterogeneous polymer composites are introduced as a novel category of stiff, thermally responsive 4D printed materials. These inks exhibit an E that is four orders of magnitude greater than that of existing 4D printed materials and offer tunable electrical conductivities for simultaneous Joule heating actuation and self-sensing capabilities. Utilizing electrically controllable bilayers as building blocks, a flat geometry is designed and printed that morphs into a 3D self-standing lifting robot, setting new records for weight-normalized load lifted and actuation stress when compared to other 3D printed actuators. Furthermore, the ink palette is employed to create and print planar lattice structures that transform into various self-supporting complex 3D shapes. These contributions are integrated into a 4D printed electrically controlled multigait crawling robotic lattice structure that can carry 144 times its own weight.

Complications of Carotid Interventions for Symptomatic Lesions after Systemic Thrombolysis.

BACKGROUND: Series detailing complications after carotid endarterectomy (CEA) and transfemoral carotid stenting (tfCAS) for patients presenting with neurologic symptoms that are treated with systemic thrombolysis (ST) are sparse. We sought to determine if treatment with ST was associated with a higher rate of post-carotid intervention complications. METHODS: A multispecialty, institutional, prospectively maintained database was queried for symptomatic patients treated with CEA or tfCAS from 2007 to 2019. The primary outcomes of interest were bleeding complications (access/wound complications, hematuria, intracranial hemorrhage) or need for reintervention, stroke, and death. We compared rates of these outcomes between patients who were and were not treated with ST. To adjust for preoperative patient factors and confounding variables, propensity scores for assignment to ST and non-ST were calculated. RESULTS: There were 1,139 patients included (949 [82%] CEA and 190 [17%] tfCAS. All treated lesions were symptomatic (550 [48%] stroke, 603 [52%] transient ischemic attack). Fifty-six patients (5%) were treated with ST. Fifteen of 56 patients also underwent catheter-based intervention for stroke. ST was administered 0 to 1 day preoperatively in 21 (38%) patients, 2 to 6 days preoperatively in 27 (48%) patients, and greater than 6 days preoperatively in 8 (14%) patients. ST patients were more likely to present with stroke (93% vs. 45%; P < 0.001) and have higher preoperative Rankin scores. Unadjusted rate of bleeding/return to operating room was 3% for ST group and 3% for non-ST group (P = 0.60). Unadjusted rate of stroke was 4% for ST group and 3% for the non-ST group (P = 0.91), while perioperative mortality was 5% for ST group and 1% for non-ST group (P = 0.009). After adjusting for patient factors, preoperative antiplatelet/anticoagulation, and operative factors, ST was not associated with an increased odds of perioperative bleeding/return to the operating room (odds ratio 0.37; 95% confidence interval: 0.02-1.63; P = 0.309) or stroke (odds ratio 0.62; 95% confidence interval: 0.16-2.40; P = 0.493). CONCLUSIONS: ST does not convey a higher risk of complications after CEA or tfCAS. After controlling for other factors, patients that received ST had similar rates of local complications and stroke when compared to non-ST patients. Early carotid intervention is safe in patients that have received ST, and delays should be avoided in symptomatic patients given the high risk of recurrent stroke.

Analysis of player speed and angle toward the ball in soccer.

The study analyzes how the magnitude and angle of the speed of soccer players change according to the distance to the ball and the phases of the game, namely the defensive and attacking phases. We observed how the role played in the team (goalkeeper, defender, midfielder, or forward) strongly determines the speed pattern of players. As a general trend, the speed's modulus is incremented as their position is closer to the ball, however, it is slightly decreased when arriving at it. Next, we studied how the angle of the speed with the direction to the ball is related to the distance to the ball and the game phases. We observed that, during the defensive phase, goalkeepers are the players that run more parallel to the ball, while forwards are the ones running more directly to the ball position. Importantly, this behavior changes dramatically during the attacking phase. Finally, we show how the proposed methodology can be used to analyze the speed-angle patterns of specific players to understand better how they move on the pitch according to the distance to the ball.

The LTAR-integrated grazing land common experiment at the Texas Gulf.

Extreme weather and climate events have become more frequent and directly affect the ecological structure and function of integrated grazing lands. While the Great Plains have experienced a long history of regular disturbances from drought and floods, grazing, and fires, the increased frequency and magnitude of these disturbances can reduce ecological resilience, largely depending on management practices. Alternative strategies designed to adaptively manage grazing land resources based on the ecology of the system should increase the resistance and resilience to disturbances when compared to prevailing practices. Determining the ecologic and economic value of alternative strategies will require long-term evaluations across large spatial scales. The Long-Term Agroecosystem Research Network has been established to evaluate the differences between alternative and prevailing practices among 18 strategically located sites and across decadal time scales throughout the continental United States. A key integrated grazing land site within this network is the Texas Gulf located at the Riesel Watersheds in the Blackland Prairie of Central Texas. At this study site, the differences between alternative and prevailing grazing management strategies are now being evaluated. The alternative strategy was designed using a combination of knowledge of the site and species ecology with modern-day tools and technologies. Alternatively, the prevailing practice implements a conventional year-round continuous grazing system with heavy reliance on hay and supplemental protein during winter. Results will provide grazing land managers with economically viable adaptive management choices for increasing ecological resilience following extreme and frequent disturbance events.

Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation.

The multifunctional RNA-binding protein hnRNPL is implicated in antibody class switching but its broader function in B cells is unknown. Here, we show that hnRNPL is essential for B cell activation, germinal center formation, and antibody responses. Upon activation, hnRNPL-deficient B cells show proliferation defects and increased apoptosis. Comparative analysis of RNA-seq data from activated B cells and another eight hnRNPL-depleted cell types reveals common effects on MYC and E2F transcriptional programs required for proliferation. Notably, while individual gene expression changes are cell type specific, several alternative splicing events affecting histone modifiers like KDM6A and SIRT1, are conserved across cell types. Moreover, hnRNPL-deficient B cells show global changes in H3K27me3 and H3K9ac. Epigenetic dysregulation after hnRNPL loss could underlie differential gene expression and upregulation of lncRNAs, and explain common and cell type-specific phenotypes, such as dysfunctional mitochondria and ROS overproduction in mouse B cells. Thus, hnRNPL is essential for the resting-to-activated B cell transition by regulating transcriptional programs and metabolism, at least in part through the alternative splicing of several histone modifiers.

Microscopic Origin of the Entropy of Astrophysical Black Holes.

We construct an infinite family of microstates for black holes in Minkowski spacetime which have effective semiclassical descriptions in terms of collapsing dust shells in the black hole interior. Quantum mechanical wormholes cause these states to have exponentially small, but universal, overlaps. We show that these overlaps imply that the microstates span a Hilbert space of log dimension equal to the event horizon area divided by four times the Newton constant, explaining the statistical origin of the Bekenstein-Hawking entropy.

APOBEC2 safeguards skeletal muscle cell fate through binding chromatin and regulating transcription of non-muscle genes during myoblast differentiation.

The apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide (APOBEC) family is composed of nucleic acid editors with roles ranging from antibody diversification to RNA editing. APOBEC2, a member of this family with an evolutionarily conserved nucleic acid-binding cytidine deaminase domain, has neither an established substrate nor function. Using a cellular model of muscle differentiation where APOBEC2 is inducibly expressed, we confirmed that APOBEC2 does not have the attributed molecular functions of the APOBEC family, such as RNA editing, DNA demethylation, and DNA mutation. Instead, we found that during muscle differentiation APOBEC2 occupied a specific motif within promoter regions; its removal from those regions resulted in transcriptional changes. Mechanistically, these changes reflect the direct interaction of APOBEC2 with histone deacetylase (HDAC) transcriptional corepressor complexes. We also found that APOBEC2 could bind DNA directly, in a sequence-specific fashion, suggesting that it functions as a recruiter of HDAC to specific genes whose promoters it occupies. These genes are normally suppressed during muscle cell differentiation, and their suppression may contribute to the safeguarding of muscle cell fate. Altogether, our results reveal a unique role for APOBEC2 within the APOBEC family.

A Self-Adaptive Automatic Incident Detection System for Road Surveillance Based on Deep Learning.

We present an automatic road incident detector characterised by a low computational complexity for easy implementation in affordable devices, automatic adaptability to changes in scenery and road conditions, and automatic detection of the most common incidents (vehicles with abnormal speed, pedestrians or objects falling on the road, vehicles stopped on the shoulder, and detection of kamikaze vehicles). To achieve these goals, different tasks have been addressed: lane segmentation, identification of traffic directions, and elimination of unnecessary objects in the foreground. The proposed system has been tested on a collection of videos recorded in real scenarios with real traffic, including areas with different lighting. Self-adaptability (plug and play) to different scenarios has been tested using videos with significant scene changes. The achieved system can process a minimum of 80 video frames within the camera's field of view, covering a distance of 400 m, all within a span of 12 s. This capability ensures that vehicles travelling at speeds of 120 km/h are seamlessly detected with more than enough margin. Additionally, our analysis has revealed a substantial improvement in incident detection with respect to previous approaches. Specifically, an increase in accuracy of 2-5% in automatic mode and 2-7% in semi-automatic mode. The proposed classifier module only needs 2.3 MBytes of GPU to carry out the inference, thus allowing implementation in low-cost devices.

B-cell intrinsic regulation of antibody mediated immunity by histone H2A deubiquitinase BAP1.

Introduction: BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, through its direct catalytic activity on the repressive epigenetic mark histone H2AK119ub, as well as on several other substrates. BAP1 is also a highly important tumor suppressor, expressed and functional across many cell types and tissues. In recent work, we demonstrated a cell intrinsic role of BAP1 in the B cell lineage development in murine bone marrow, however the role of BAP1 in the regulation of B cell mediated humoral immune response has not been previously explored. Methods and results: In the current study, we demonstrate that a B-cell intrinsic loss of BAP1 in activated B cells in the Bap1 fl/fl Cγ1-cre murine model results in a severe defect in antibody production, with altered dynamics of germinal centre B cell, memory B cell, and plasma cell numbers. At the cellular and molecular level, BAP1 was dispensable for B cell immunoglobulin class switching but resulted in an impaired proliferation of activated B cells, with genome-wide dysregulation in histone H2AK119ub levels and gene expression. Conclusion and discussion: In summary, our study establishes the B-cell intrinsic role of BAP1 in antibody mediated immune response and indicates its central role in the regulation of the genome-wide landscapes of histone H2AK119ub and downstream transcriptional programs of B cell activation and humoral immunity.

The recruitment of TRiC chaperonin in rotavirus viroplasms correlates with virus replication.

Rotavirus (RV) replication takes place in the viroplasms, cytosolic inclusions that allow the synthesis of virus genome segments and their encapsidation in the core shell, followed by the addition of the second layer of the virion. The viroplasms are composed of several viral proteins, including NSP5, which serves as the main building block. Microtubules, lipid droplets, and miRNA-7 are among the host components recruited in viroplasms. We investigated the interaction between RV proteins and host components of the viroplasms by performing a pull-down assay of lysates from RV-infected cells expressing NSP5-BiolD2. Subsequent tandem mass spectrometry identified all eight subunits of the tailless complex polypeptide I ring complex (TRiC), a cellular chaperonin responsible for folding at least 10% of the cytosolic proteins. Our confirmed findings reveal that TRiC is brought into viroplasms and wraps around newly formed double-layered particles. Chemical inhibition of TRiC and silencing of its subunits drastically reduced virus progeny production. Through direct RNA sequencing, we show that TRiC is critical for RV replication by controlling dsRNA genome segment synthesis, particularly negative-sense single-stranded RNA. Importantly, cryo-electron microscopy analysis shows that TRiC inhibition results in defective virus particles lacking genome segments and polymerase complex (VP1/VP3). Moreover, TRiC associates with VP2 and NSP5 but not with VP1. Also, VP2 is shown to be essential for recruiting TRiC in viroplasms and preserving their globular morphology. This study highlights the essential role of TRiC in viroplasm formation and in facilitating virion assembly during the RV life cycle. IMPORTANCE: The replication of rotavirus takes place in cytosolic inclusions termed viroplasms. In these inclusions, the distinct 11 double-stranded RNA genome segments are co-packaged to complete a genome in newly generated virus particles. In this study, we show for the first time that the tailless complex polypeptide I ring complex (TRiC), a cellular chaperonin responsible for the folding of at least 10% of the cytosolic proteins, is a component of viroplasms and is required for the synthesis of the viral negative-sense single-stranded RNA. Specifically, TRiC associates with NSP5 and VP2, the cofactor involved in RNA replication. Our study adds a new component to the current model of rotavirus replication, where TRiC is recruited to viroplasms to assist replication.

Political Ideology Direction of Policy Agendas and Maternal Mortality Outcomes in the U.S., 1915-2007.

OBJECTIVES: The causes for persistently high and increasing maternal mortality rates in the United States have been elusive. METHODS: We use the shift in the ideological direction of the Republican and the Democratic parties in the 1960s, to test the hypothesis that fluctuations in overall and race-specific maternal mortality rates (MMR) follow the power shifts between the parties before and after the Political Realignment (PR) of the 1960s. RESULTS: Using time-series data analysis methods, we find that, net of trend, overall and race-specific MMRs were higher under Democratic administrations than Republican ones before the PR (1915-1965)-i.e., when the Democratic Party was a protector of the Jim Crow system. This pattern, however, changed after the PR (1966-2007), with Republican administrations underperforming Democratic ones-i.e., during the period when the Republican Party shifted toward a more economically and socially conservative agenda. The pre-post PR partisan shifts in MMRs were larger for Black (9.5%, p < . 01 ) relative to White mothers (7.4%, p < . 05 ) during the study period. CONCLUSIONS FOR PRACTICE: These findings imply that parties and the ideological direction of their agendas substantively affect the social determinants of maternal health and produce politized health outcomes.

Multiscale Heterogeneous Polymer Composites for High Stiffness 4D Printed Electrically Controllable Multifunctional Structures.

4D printing is an emerging field where 3D printing techniques are used to pattern stimuli-responsive materials to create morphing structures, with time serving as the fourth dimension. However, current materials utilized for 4D printing are typically soft, exhibiting an elastic modulus (E) range of 10-4 to 10 MPa during shape change. This restricts the scalability, actuation stress, and load-bearing capabilities of the resulting structures. To overcome these limitations, multiscale heterogeneous polymer composites are introduced as a novel category of stiff, thermally responsive 4D printed materials. These inks exhibit an E that is four orders of magnitude greater than that of existing 4D printed materials and offer tunable electrical conductivities for simultaneous Joule heating actuation and self-sensing capabilities. Utilizing electrically controllable bilayers as building blocks, a flat geometry that morphs into a 3D self-standing lifting robot is designed and printed, setting new records for weight-normalized load lifted and actuation stress when compared to other 3D printed actuators. Furthermore, this ink palette is employed to create and print planar lattice structures that transform into various self-supporting complex 3D shapes. Finally these inks are integrated into a 4D printed electrically controlled multigait crawling robotic lattice structure that can carry 144 times its own weight.

RPA guides UNG to uracil in ssDNA to facilitate antibody class switching and repair of mutagenic uracil at the replication fork.

Activation-induced cytidine deaminase (AID) interacts with replication protein A (RPA), the major ssDNA-binding protein, to promote deamination of cytosine to uracil in transcribed immunoglobulin (Ig) genes. Uracil-DNA glycosylase (UNG) acts in concert with AID during Ig diversification. In addition, UNG preserves genome integrity by base-excision repair (BER) in the overall genome. How UNG is regulated to support both mutagenic processing and error-free repair remains unknown. UNG is expressed as two isoforms, UNG1 and UNG2, which both contain an RPA-binding helix that facilitates uracil excision from RPA-coated ssDNA. However, the impact of this interaction in antibody diversification and genome maintenance has not been investigated. Here, we generated B-cell clones with targeted mutations in the UNG RPA-binding motif, and analysed class switch recombination (CSR), mutation frequency (5' Ig Sµ), and genomic uracil in clones representing seven Ung genotypes. We show that the UNG:RPA interaction plays a crucial role in both CSR and repair of AID-induced uracil at the Ig loci. By contrast, the interaction had no significant impact on total genomic uracil levels. Thus, RPA coordinates UNG during CSR and pre-replicative repair of mutagenic uracil in ssDNA but is not essential in post-replicative and canonical BER of uracil in dsDNA.