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Skull growth involves the expansion of both the flat calvarial bones of the skull and the fibrous marginal zones, termed sutures, between them. This process depends on co‐ordinated proliferation of mesenchymal‐derived progenitor cells within the sutures, and their differentiation to osteoblasts which produce the bone matrix required to expand the size of the bony plates. Defects lead to premature closure of these sutures, termed craniosynostosis, resulting in heterogeneous head shape differences due to restricted growth of one or more sutures. The impact on the individual depends on how many and which sutures are affected and the severity of the effect. Several genetic loci are responsible, including a wide range of variants in the gene for the interleukin 11 receptor (IL11RA, OMIM#600939). Recent work from Kespohl and colleagues provides new insights into how some of these variants influence IL‐11R function; we discuss their influences on IL‐11R structure and IL‐11 function as a stimulus of osteoblast differentiation. [ABSTRACT FROM AUTHOR]

Hypertension is a widely prevalent disease and uncontrolled hypertension predisposes affected individuals to severe adverse effects. Though the importance of controlling hypertension is clear, the multitude of therapeutic regimens and patient factors that affect the success of blood pressure control makes it difficult to predict the likelihood to predict whether a patient's blood pressure will be controlled. This project endeavors to investigate whether machine learning can accurately predict the control of a patient's hypertension within 12 months of a clinical encounter. To build the machine learning model, a retrospective review of the electronic medical records of 350,008 patients 18 years of age and older between January 1, 2015 and June 1, 2022 was performed to form model training and testing cohorts. The data included in the model included medication combinations, patient laboratory values, vital sign measurements, comorbidities, healthcare encounters, and demographic information. The mean age of the patient population was 65.6 years with 161,283 (46.1%) men and 275,001 (78.6%) white. A sliding time window of data was used to both prohibit data leakage from training sets to test sets and to maximize model performance. This sliding window resulted in using the study data to create 287 predictive models each using 2 years of training data and one week of testing data for a total study duration of five and a half years. Model performance was combined across all models. The primary outcome, prediction of blood pressure control within 12 months demonstrated an area under the curve of 0.76 (95% confidence interval; 0.75–0.76), sensitivity of 61.52% (61.0–62.03%), specificity of 75.69% (75.25–76.13%), positive predictive value of 67.75% (67.51–67.99%), and negative predictive value of 70.49% (70.32–70.66%). An AUC of 0.756 is considered to be moderately good for machine learning models. While the accuracy of this model is promising, it is impossible to state with certainty the clinical relevancy of any clinical support ML model without deploying it in a clinical setting and studying its impact on health outcomes. By also incorporating uncertainty analysis for every prediction, the authors believe that this approach offers the best-known solution to predicting hypertension control and that machine learning may be able to improve the accuracy of hypertension control predictions using patient information already available in the electronic health record. This method can serve as a foundation with further research to strengthen the model accuracy and to help determine clinical relevance. [ABSTRACT FROM AUTHOR]

Infections caused by malaria parasites place an enormous burden on the world's poorest communities. Breakthrough drugs with novel mechanisms of action are urgently needed. As an organism that undergoes rapid growth and division, the malaria parasite Plasmodium falciparum is highly reliant on protein synthesis, which in turn requires aminoacyl-tRNA synthetases (aaRSs) to charge tRNAs with their corresponding amino acid. Protein translation is required at all stages of the parasite life cycle; thus, aaRS inhibitors have the potential for whole-of-life-cycle antimalarial activity. This review focuses on efforts to identify potent plasmodium-specific aaRS inhibitors using phenotypic screening, target validation, and structure-guided drug design. Recent work reveals that aaRSs are susceptible targets for a class of AMP-mimicking nucleoside sulfamates that target the enzymes via a novel reaction hijacking mechanism. This finding opens up the possibility of generating bespoke inhibitors of different aaRSs, providing new drug leads. [ABSTRACT FROM AUTHOR]

Recent work of Griffin, Ono, Rolen, and Zagier shows that the Jensen polynomials for the Riemann xi function converge to the Hermite polynomials under a suitable normalization. We generalize this result, proving that the normalized Jensen polynomials for a large class of genus zero or one entire functions converge either to the Hermite polynomials, or to a class of polynomials which can be written as a confluent hypergeometric function. [ABSTRACT FROM AUTHOR]

The classical AGM produces wonderful infinite sequences of arithmetic and geometric means with common limit. For finite fields F q , with q ≡ 3 (mod 4) , we introduce a finite field analogue AGM F q that spawns directed finite graphs instead of infinite sequences. The compilation of these graphs reminds one of a jellyfish swarm, as the 3D renderings of the connected components resemble jellyfish (i.e., tentacles connected to a bell head). These swarms turn out to be more than the stuff of child's play; they are taxonomical devices in number theory. Each jellyfish is an isogeny graph of elliptic curves with isomorphic groups of F q -points, which can be used to prove that each swarm has at least (1 / 2 − ε) q jellyfish. This interpretation also gives a description of the class numbers of Gauss, Hurwitz, and Kronecker which is akin to counting types of spots on jellyfish. [ABSTRACT FROM AUTHOR]

In the wake of the era of Trump and Brexit, legacies and values of European Enlightenment seem under threat as never before. Cosmopolitanism in particular, generally understood as an Enlightenment virtue, has come to be associated with a sort of rootlessness, and has not, as generally understood, valued local affiliation. For David Goodhart, writing in 2017, this characteristic has resulted in a polarisation between "anywheres" (liberal middleclass cosmopolitans) and "somewheres" (broadly speaking, conservative working-class voters who have strong attachments to their nation and places of origin). An Irish Tory monarchist who sought in his poem The Deserted Village (1770) to defend rural communities from the ravages of economic modernity, Oliver Goldsmith (1728-74) was also in other key works a cosmopolitan commentator who compared countries in order to warn Britain against the dangers of economic liberalism, as he did in The Traveller, or a Prospect of Society (1764). Thus, he could be thought of as a more conservative cosmopolitan than many of his British and French peers; as such his particular enlightenment legacy is his example of a middle ground between the "anywheres" and "somewheres" of Goodhart's thesis. [ABSTRACT FROM AUTHOR]

We explicitly construct the Dirichlet series $$\begin{equation*}L_{\mathrm{Tam}}(s):=\sum_{m=1}^{\infty}\frac{P_{\mathrm{Tam}}(m)}{m^s},\end{equation*}$$ where |$P_{\mathrm{Tam}}(m)$| is the proportion of elliptic curves |$E/\mathbb{Q}$| in short Weierstrass form with Tamagawa product m. Although there are no |$E/\mathbb{Q}$| with everywhere good reduction, we prove that the proportion with trivial Tamagawa product is |$P_{\mathrm{Tam}}(1)={0.5053\dots}$|⁠. As a corollary, we find that |$L_{\mathrm{Tam}}(-1)={1.8193\dots}$| is the average Tamagawa product for elliptic curves over |$\mathbb{Q}$|⁠. We give an application of these results to canonical and Weil heights. [ABSTRACT FROM AUTHOR]

In this note we obtain effective lower bounds for the canonical heights of non-torsion points on E(Q) by making use of suitable elliptic curve ideal class pairings ΨE,−D : E(Q) × E−D(Q) &#8594 CL(−D). In terms of the class number H(−D) and TE(−D), a logarithmic function in D, we prove h(P) > |Etor(Q)|2/(H(−D)+ |Etor(Q)|)2 ⋅ TE(−D). [ABSTRACT FROM AUTHOR]

For positive rank r elliptic curves E (Q) , we employ ideal class pairings E (Q) × E − D (Q) → CL (− D) , for quadratic twists E − D (Q) with a suitable "small y -height" rational point, to obtain explicit class number lower bounds that improve on earlier work by the authors. For the curves E (a) : y 2 = x 3 − a , with rank r (a) , this gives h (− D) ≥ 1 10 ⋅ | E tor (Q) | R Q (E) ⋅ π r (a) 2 2 r (a) Γ (r (a) 2 + 1) ⋅ log ⁡ (D) r (a) 2 log ⁡ log ⁡ D , representing a general improvement to the classical lower bound of Goldfeld, Gross and Zagier when r (a) ≥ 3. We prove that the number of twists E − D (a) (Q) with such a suitable point (resp. with such a point and rank ≥2 under the Parity Conjecture) is ≫ a , ε X 1 2 − ε. We give infinitely many cases where r (a) ≥ 6. These results can be viewed as an analogue of the classical estimate of Gouvêa and Mazur for the number of rank ≥2 quadratic twists, where in addition we obtain "log-power" improvements to the Goldfeld-Gross-Zagier class number lower bound. [ABSTRACT FROM AUTHOR]

Source Citation: Major Extremity Trauma Research Consortium (METRC); O'Toole RV, Stein DM, O'Hara NN, et al. Aspirin or low-molecular-weight heparin for thromboprophylaxis after a fracture. N Engl J Med. 2023;388:203-213. 36652352 Clinical Impact Ratings: Hospitalists: GIM/FP/GP: Hematology: [ABSTRACT FROM AUTHOR]

We investigate ξ (s) = 1 2 s (s − 1) π − s 2 Γ (s 2) ζ (s) , where ζ (s) is the Riemann zeta function. The Riemann hypothesis (RH) asserts that if ξ (s) = 0 , then Re (s) = 1 2. Pólya proved that RH is equivalent to the hyperbolicity of the Jensen polynomials J d , n (X) constructed from certain Taylor coefficients of ξ (s). For each d ≥ 1 , recent work proves that J d , n (X) is hyperbolic for sufficiently large n. In this paper, we make this result effective. Moreover, we show how the low-lying zeros of the derivatives ξ (n) (s) influence the hyperbolicity of J d , n (X). [ABSTRACT FROM AUTHOR]

Research examining physiological responses to trauma cues in PTSD has identified a subset of "nonresponders" showing suppressed physiological reactivity. The defense cascade model posits that individuals respond to stressors by progressing through a series of defensive reactions, with nonresponders having advanced to a shutdown response. It remains unclear whether dissociation is at the end of a continuum of passive behavior, indicating full shutdown, or if it comprises a distinct response. The present study aimed to address this uncertainty, using EFA to compare a two-factor (active, passive) and three-factor (active, passive, dissociative) model of defensive responding. Eighty-nine female physical and sexual assault survivors reported their peritraumatic reactions within 1 month of their assault, which were entered into the EFA. The three-factor model was superior, suggesting dissociation is a distinct category of peritraumatic coping. Peritraumatic use of both passive and dissociative coping strategies were each significantly associated with ongoing use of passive coping and increased PTSD symptoms 1-month posttrauma; surprisingly, the use of passive peritraumatic coping strategies was a better indicator than peritraumatic dissociation. The inclusion of depression as a covariate removed the association of passive (but not dissociative) coping with PTSD symptom severity. Active coping use was not significantly associated with any outcome, suggesting that the presence of shutdown responses is more informative than the presence or absence of any active coping. These findings highlight the importance of differentiating peritraumatic coping responses and the need for increased attention to the comparatively neglected topic of passive coping. [ABSTRACT FROM AUTHOR]

Insomnia is a common symptom of posttraumatic stress disorder (PTSD) that is resistant to first-line cognitive behavioral interventions. However, research suggests that, among individuals with PTSD, self-reported sleep impairment is typically more severe than what is objectively observed, a phenomenon termed sleep state misperception. Relatively little research has examined which individuals with PTSD are most likely to exhibit sleep state misperception. This study explored clinical predictors of sleep state misperception in a sample of 43 women with PTSD and clinically significant sleep impairment. During a baseline assessment, participants' PTSD symptoms were assessed using a clinical interview and their sleep was assessed using the Pittsburgh Sleep Quality Index (PSQI). Objective sleep, self-reported sleep, and PTSD symptoms were then assessed over a 1-week period using actigraphy and daily diaries. Consistent with previous research, women in the study exhibited total sleep time (TST), sleep efficiency (SE), and sleep onset latency (SOL) sleep state misperception. For TST and SE, but not SOL, discrepancies between actigraphy and the PSQI were associated with each clinician-rated PTSD symptom cluster, whereas discrepancies between actigraphy and daily diary were only associated with clinician-rated reexperiencing symptoms. The only self-reported PTSD symptom that was uniquely associated with sleep state misperception was nightmares. This association was no longer significant after controlling for sleep-related anxiety. Results suggest that women with more severe reexperiencing symptoms of PTSD, particularly nightmares, may be more likely to exhibit TST and SE sleep state misperception, perhaps due to associated sleep-related anxiety. [ABSTRACT FROM AUTHOR]

Emotional engagement when recollecting a trauma memory is considered a key element of effective trauma-focused therapy. Research has shown that reduced physiological reactivity during trauma recall is associated with worse treatment outcomes for posttraumatic stress disorder (PTSD), but this has yet to be examined in a cognitively oriented treatment. This study examined whether pretreatment heart rate (HR) reactivity during trauma recall predicts PTSD symptom improvement and treatment dropout during Cognitive Processing Therapy (CPT) for PTSD. Participants were 142 women with PTSD secondary to interpersonal violence enrolled in one of two clinicals trials. HR reactivity reflected the mean increase in HR after listening to two 30-s scripts of the trauma memory prior to treatment. Linear mixed-effects models showed the effect of HR reactivity on change in total PTSD symptoms was not significant, but lower HR reactivity predicted less improvement in reexperiencing and avoidance and was associated with increased dropout. Findings suggest pretreatment physiological reactivity to the trauma memory may be a prognostic indicator of some elements of treatment response in CPT. Results tentatively support the importance of emotional activation during trauma recall in cognitive treatment of PTSD, though more research is needed to clarify how low HR reactivity impacts treatment. • Women with PTSD (n = 142) received 12 sessions of cognitive processing therapy (CPT). • Prior to treatment, heart rate reactivity (HRR) during trauma recall was measured. • Lower HRR predicted less improvement in reexperiencing and avoidance during CPT. • Lower HRR also predicted greater study and treatment dropout. • No association between pretreatment HRR and total PTSD symptom change was found. [ABSTRACT FROM AUTHOR]

Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder. SEPHS1 is in the selenocysteine biosynthetic pathway. We report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Our findings provide insight into the molecular pathogenesis of this neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

Tripartite ATP-independent periplasmic (TRAP) transporters are secondary-active transporters that receive their substrates via a soluble-binding protein to move bioorganic acids across bacterial or archaeal cell membranes. Recent cryo-electron microscopy (cryo-EM) structures of TRAP transporters provide a broad framework to understand how they work, but the mechanistic details of transport are not yet defined. Here we report the cryo-EM structure of the Haemophilus influenzae N-acetylneuraminate TRAP transporter (HiSiaQM) at 2.99 Å resolution (extending to 2.2 Å at the core), revealing new features. The improved resolution (the previous HiSiaQM structure is 4.7 Å resolution) permits accurate assignment of two Na+ sites and the architecture of the substrate-binding site, consistent with mutagenic and functional data. Moreover, rather than a monomer, the HiSiaQM structure is a homodimer. We observe lipids at the dimer interface, as well as a lipid trapped within the fusion that links the SiaQ and SiaM subunits. We show that the affinity (KD) for the complex between the soluble HiSiaP protein and HiSiaQM is in the micromolar range and that a related SiaP can bind HiSiaQM. This work provides key data that enhances our understanding of the 'elevator-with-an-operator' mechanism of TRAP transporters. [ABSTRACT FROM AUTHOR]

The production of advanced biofuels represents a near-term opportunity to decarbonize the heavy vehicle transportation sector. However, important barriers must be overcome and successful deployment of these technologies will require (i) catalyst and process development to reduce cost and improve carbon utilization and (ii) industry-relevant validation of operability to de-risk scale-up. Herein, we seek to address these challenges for an integrated two-step process involving catalytic fast pyrolysis (CFP) followed by co-hydrotreating of bio-oil with refinery streams. Technoeconomic and lifecycle analysis based on the data presented herein reveal the potential to generate low-carbon transportation fuels and chemical co-products with a modelled selling price of $2.83 gasoline gallon equivalent (2016$) and a 78% reduction in greenhouse gas emissions compared to fossil-based pathways. The feedstock for this research was a blend of 50 wt% loblolly pine and 50 wt% waste forest residues, and the CFP step was performed using an ex situ fixed bed of Pt/TiO2 with co-fed H2 at atmospheric pressure. Compared to previous state-of-technology benchmarks, advancements in catalyst design and synthesis methodology enabled a four-fold reduction in Pt loading and a 400% increase in time on stream without negatively impacting upgrading performance. Additionally, a first-of-its-kind integrated assessment of waste gas adsorption showed near quantitative recovery of acetone and 2-butanone, which collectively represent approximately 5% of the biomass carbon. The valorization of these co-products opens opportunities to support decarbonization of the chemical sector while simultaneously improving the overall process carbon efficiency to >40%. After condensation, the CFP-oil was co-hydrotreated with straight run diesel (10 : 90 vol%) to achieve 95% biogenic carbon incorporation. The oxygen content of the hydrotreated oil was below detection limits, and the diesel fraction exhibited a cetane number and cloud point suitable for a finished fuel. This manuscript concludes by highlighting remaining research needs associated with improving thermal management during catalyst regeneration, mitigating catalyst deactivation due to inorganic deposition, and demonstrating the durability of biomass feeding systems when operated in hydrogen-rich environments. [ABSTRACT FROM AUTHOR]

Objectives: Post-pneumonectomy syndrome (PPS) is rare and predominantly characterised by dynamic airway obstruction due to mediastinal rotation at any time point following pneumonectomy. The objective of this systematic review was to identify the optimal treatment strategy for PPS based on subjective symptomatic relief, objective radiological imaging, and treatment durability. Methods: A systematic review was performed up to and including February 2022 based on the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" guidelines. All studies that presented the management of symptomatic patients > 16 years of age with radiologically confirmed PPS were included. The primary outcome was the identification of the optimal treatment strategy and the secondary outcome was durability of the treatment. The Oxford Centre for Evidence Based Medicine level was assigned to each study. Results: A total of 330 papers were identified and reviewed; 41 studies met the inclusion criteria. Data including patient demographics, indication for initial pneumonectomy, presenting symptoms, management approach, outcomes, and follow-up were assessed and analysed. Management approaches were divided into three categories: (a) mediastinal repositioning using implant prostheses; (b) endobronchial stenting; (c) other corrective procedures. One hundred and four patients were identified in total and of those, 87 underwent mediastinal repositioning with insertion of a prosthetic implant. Complications included over- or under-filling of the prosthesis (8.5%) and implant leakage (8.9%). Conclusion: Management of PPS using a prosthetic implant to reposition the mediastinum is the treatment of choice. Key adjuncts to optimise surgical approach and minimise complications include pre-operative CT volumetric analysis to guide implant size and intra-operative transoesophageal echocardiography to guide mediastinal repositioning. [ABSTRACT FROM AUTHOR]

To assess whether extra-oesophageal symptoms are predictive of oesophageal malignancy. A prospective, single-centre cross-sectional questionnaire study at a tertiary referral unit for oesophageal cancer using the Comprehensive Reflux Symptoms Scale (CReSS) questionnaire tool. Respondents with oesophageal malignancy were compared with historical cohorts undergoing airway examination or upper gastrointestinal endoscopy and found to have benign diagnoses. We developed a model for predicting oesophageal cancer using linear discriminant analysis and logistic regression, assessed by Monte Carlo cross validation. Respondents with oesophageal malignancy (n = 146; mean age 70.5; male: female, 71:29) were compared with those undergoing airway examination (n = 177) and upper gastrointestinal endoscopy (n = 351), found to have benign diagnoses. No single questionnaire item, or group of co-varying items (factors), reliably discriminated oesophageal cancer from other diagnoses. Individual items which suggested higher risk of oesophageal malignancy included dysphagia (area under the curve (AUC) 0.68), low appetite (AUC 0.66), and early satiety (AUC 0.58). Conversely, throat pain (AUC 0.38), bloating (AUC 0.38) and heartburn (AUC 0.37) were inversely related to cancer risk. A forward stepwise regression analysis including a subset of 12 CReSS questionnaire items together with age and sex derived a model predictive of oesophageal malignancy in this cohort (AUC 0.89). We demonstrate a model comprised of 12 questionnaire items and 2 demographic parameters as a potential predictive tool for oesophageal malignancy diagnosis in this study population. Translating this model for predicting oesophageal malignancy in the general population is a valuable topic for future research. • Oesophageal malignancy remains a diagnostic challenge, often presenting late. • Extra-oesophageal symptoms are not cancer referral criteria in the United Kingdom. • Symptoms can be characterised with the Comprehensive Reflux Symptoms Scale (CReSS). • Extra-oesophageal symptoms may be useful to predict risk of oesophageal malignancy. • This could be used to risk stratify patients for upper gastrointestinal endoscopy. [ABSTRACT FROM AUTHOR]

Studies of microbiota reveal inter-relationships between the microbiomes of the gut and lungs. This relationship may influence the progression of lung disease, particularly in patients with cystic fibrosis (CF), who often experience extraoesophageal reflux (EOR). Despite identifying this relationship, it is not well characterised. Our hypothesis is that the gastric and lung microbiomes in CF are related, with the potential for aerodigestive pathophysiology. We evaluated gastric and sputum bacterial communities by culture and 16S rRNA gene sequencing in 13 CF patients. Impacts of varying levels of bile acids, pepsin and pH on patient isolates of Pseudomonas aeruginosa (Pa) were evaluated. Clonally related strains of Pa and NTM were identified in gastric and sputum samples from patients with symptoms of EOR. Bacterial diversity was more pronounced in sputa compared to gastric juice. Gastric and lung bile and pepsin levels were associated with Pa biofilm formation. Analysis of the aerodigestive microbiomes of CF patients with negative sputa indicates that the gut can be a reservoir of Pa and NTM. This combined with the CF patient's symptoms of reflux and potential aspiration, highlights the possibility of communication between microorganisms of the gut and the lungs. This phenomenon merits further research. [ABSTRACT FROM AUTHOR]

The rabies virus (RABV) phosphoprotein (P protein) is expressed as several isoforms, which differ in nucleocytoplasmic localization and microtubule (MT) association, mediated by several sequences, including nuclear localization (NLS) and export (NES) sequences. This appears to underpin a functional diversity enabling multiple functions in viral replication and modulation of host biology. Mechanisms regulating trafficking are poorly defined, but phosphorylation by protein kinase C (PKC) in the P protein C-terminal domain (PCTD) regulates nuclear trafficking, mediated by PCTD-localized NLS/NES sequences, indicating that phosphorylation contributes to functional diversity. The molecular mechanism underlying the effects of PKC, and potential roles in regulating other hostcell interactions are unresolved. Here, we assess effects of phosphorylation on the P3 isoform, which differs from longer isoforms through an ability to localize to the nucleus and associate with MTs, which are associated with antagonism of interferon (IFN) signaling. We find that phosphomimetic mutation of the PKC site S210 inhibits nuclear accumulation and MT association/bundling. Structural analysis indicated that phosphomimetic mutation induces no significant structural change to the NLS/NES but results in the side chain of N226 switching its interactions from E228, within the NES, to E210. Intriguingly, N226 is the sole substituted residue between the PCTD of the pathogenic IFN-resistant RABV strain Nishigahara and a derivative attenuated IFN-sensitive strain Ni-CE, inhibiting P3 nuclear localization and MT association. Thus, S210 phosphorylation appears to impact on N226/E228 to regulate P protein localization, with N226 mutation in Ni-CE mimicking a constitutively phosphorylated state resulting in IFN sensitivity and attenuation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Atomic layer-deposited TiO 2 onto Pt/Al 2 O 3 enhances production of jet fuel-range alkanes. • Ti cation sites created by reduction of the TiO 2 overcoats at highest examined surface coverage. • Conversion of key intermediate in HDO reaction increased upon creation of new Ti cation sites. The conversion of wet waste-derived volatile fatty acids into jet fuel-range hydrocarbons is a promising route for increasing the production of sustainable aviation fuel; however, the cost and moderate alkane selectivity of Pt-based hydrodeoxygenation catalysts present challenges for commercialization. To address this, we used atomic layer deposition to apply TiO 2 overcoats to Pt/Al 2 O 3 catalysts and create new interface sites that exhibited 8 times higher site time yield of the desirable n-alkane product than uncoated catalyst. Through TPR/TPD, XPS, CO DRIFTS, and DFT calculations, we found that the increased selectivity of the ALD-coated catalyst was due to the creation of O vacancies at the Pt-TiO 2 interface under reducing conditions, resulting in new Ti3+ acid sites near the active metal. Maximum conversion and alkane selectivity during HDO was achieved with an ALD-coated 0.5% wt Pt catalyst, indicating that TiO 2 ALD can be used to maximize the utility of precious-metal catalysts. [ABSTRACT FROM AUTHOR]

• Catalytic Fast Pyrolysis (CFP) of woody biomass to produce hydrocarbon fuels. • Petroleum refinery co-hydroprocessing of CFP bio-intermediates. • Impact of chemical coproducts on economics and sustainability. • Impact of the source of hydrogen on sustainability. In this work we present model results for a scaled-up conceptual process informed by bench scale biomass catalytic fast pyrolysis (CFP) and hydrotreating experimental data. This process uses a Pt/TiO 2 catalyst during CFP, which produces a partially deoxygenated organic biocrude intermediate that is then hydroprocessed to a hydrocarbon fuel blendstock; the catalyst also enables high yields of acetone and methyl-ethyl-ketone (MEK) coproducts. Two options for hydroprocessing were modeled: (A) co-hydrotreating at a petroleum refinery using hydrogen sourced from steam reforming of natural gas and (B) standalone hydrotreating at a biorefinery using hydrogen sourced from CFP off gases. The results revealed that Case A was economically advantageous with a modeled minimum fuel selling price (MFSP) of $2.83/GGE or gallon gasoline equivalent (in 2016 US dollars), while the additional cost of standalone hydrotreating facilities in Case B increased the MFSP to $3.13/GGE. Conversely, greenhouse gas (GHG) emissions were lower for Case B (3.9 g CO 2 e/MJ) compared to Case A (21.5 g CO 2 e/MJ) due to the use of biogenic (Case B) and fossil-derived (Case A) hydrogen. In a third option (Case C), the requirements for separation and purification of acetone and MEK were removed from the refinery co-processing scenario (Case A) to evaluate the impacts of this process simplification. Elimination of these coproducts increased the MFSP to $3.21/GGE and GHG emissions to 35 g CO 2 e/MJ. These comparisons based on our detailed conceptual models provide economic and sustainability guidance regarding processing choices for future biorefineries. While refinery coprocessing using existing equipment and the production of relatively valuable coproducts can benefit the economics, the hydrogen-source and biogenic coproducts can have significant impacts on the sustainability of the process, and feasibility to use CFP off-gases or other renewable sources for hydrogen production can help lower GHG emissions. [ABSTRACT FROM AUTHOR]

[Display omitted] • Small heat-shock proteins populate a monomer–dimer-oligomer equilibrium. • The alpha-crystallin domain binds at fibril ends to inhibit elongation. • Chaperone-activity is inhibited by disulfide crosslinking at the dimer interface. • Monomers of the alpha-crystallin domain are proposed to interact with fibril ends. Small heat-shock proteins (sHSPs) are ubiquitously expressed molecular chaperones present in all kingdoms of life that inhibit protein misfolding and aggregation. Despite their importance in proteostasis, the structure–function relationships of sHSPs remain elusive. Human sHSPs are characterised by a central, highly conserved α-crystallin domain (ACD) and variable-length N- and C-terminal regions. The ACD forms antiparallel homodimers via an extended β-strand, creating a shared β-sheet at the dimer interface. The N- and C-terminal regions mediate formation of higher order oligomers that are thought to act as storage forms for chaperone-active dimers. We investigated the interactions of the ACD of two human sHSPs, αB-crystallin (αB-C) and Hsp27, with apolipoprotein C-II amyloid fibrils using analytical ultracentrifugation and nuclear magnetic resonance spectroscopy. The ACD was found to interact transiently with amyloid fibrils to inhibit fibril elongation and naturally occurring fibril end-to-end joining. This interaction was sensitive to the concentration of fibril ends indicating a 'fibril-capping' interaction. Furthermore, resonances arising from the ACD monomer were attenuated to a greater extent than those of the ACD dimer in the presence of fibrils, suggesting that the monomer may bind fibrils. This hypothesis was supported by mutagenesis studies in which disulfide cross-linked ACD dimers formed by both αB-C and Hsp27 were less effective at inhibiting amyloid fibril elongation and fibril end-to-end joining than ACD constructs lacking disulfide cross-linking. Our results indicate that sHSP monomers inhibit amyloid fibril elongation, highlighting the importance of the dynamic oligomeric nature of sHSPs for client binding. [ABSTRACT FROM AUTHOR]

The concept of patient blood management (PBM) was introduced by the World Health Organization in 2011 and is defined as a "patient-focused, evidence-based and systematic approach for optimizing the management of patients and transfusion of blood products to ensure high quality and effective patient care". Patient blood management is a multimodal approach based on three pillars: optimization of blood mass, minimization of blood loss and optimization of patient tolerance to anaemia. Antifibrinolytics play a major role in cardiac surgery, where the risk of perioperative bleeding is high and affects a majority of patients, by effectively reducing bleeding, transfusions, re-operations, as well as their associated morbidity and mortality. They represent an essential part of the pharmacological arsenal of patient blood management. However, despite the trend towards high-level PBM practices, currently very few European countries have national PBM guidelines and these guidelines, taken as a whole, are heterogeneous in form and content. In particular, the use of antifibrinolytics in cardiac surgery is often not discussed in detail beyond general prophylactic use and any recommendations lack detail including choice of drug, dosing, and mode of administration. Thus, the implementation of PBM programs in Europe is still challenging. In 2021, the WHO published a new document highlighting the urgent need to close the gap in PBM awareness and implementation and announced their upcoming initiative to develop specific PBM implementation guidelines. This review aims first, to summarize the role played by fibrinolysis in haemostatic disorders; second, to give an overview of the current available guidelines in Europe detailing PBM implementation in cardiac surgery; and third, to analyse the place and use of antifibrinolytics in these guidelines. [ABSTRACT FROM AUTHOR]

Interleukin-11 (IL-11) is a cytokine that has been strongly implicated in the pathogenesis of fibrotic diseases and solid malignancies. Elevated IL-11 expression is also associated with several non-malignant inflammatory diseases where its function remains less well-characterized. Here, we summarize current literature surrounding the contribution of IL-11 to the pathogenesis of autoimmune inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, diabetes and systemic sclerosis, as well as other chronic inflammatory conditions such as periodontitis, asthma, chronic obstructive pulmonary disease, psoriasis and colitis. [ABSTRACT FROM AUTHOR]

[Display omitted] • H2 relaxin has distinct and unique binding sites for RXFP1 and RXFP2. • Both the LDLa module and linker of RXFP1 and RXFP2 are essential for activation. • A conserved motif in the linker adopts different structures in RXFP1 and RXFP2. • These differences lead to distinct mechanisms for relaxin-induced activation. Our poor understanding of the mechanism by which the peptide-hormone H2 relaxin activates its G protein coupled receptor, RXFP1 and the related receptor RXFP2, has hindered progress in its therapeutic development. Both receptors possess large ectodomains, which bind H2 relaxin, and contain an N-terminal LDLa module that is essential for receptor signaling and postulated to be a tethered agonist. Here, we show that a conserved motif (GDxxGWxxxF), C-terminal to the LDLa module, is critical for receptor activity. Importantly, this motif adopts different structures in RXFP1 and RXFP2, suggesting distinct activation mechanisms. For RXFP1, the motif is flexible, weakly associates with the LDLa module, and requires H2 relaxin binding to stabilize an active conformation. Conversely, the GDxxGWxxxF motif in RXFP2 is more closely associated with the LDLa module, forming an essential binding interface for H2 relaxin. These differences in the activation mechanism will aid drug development targeting these receptors. [ABSTRACT FROM AUTHOR]

Study Objective: To describe and compare patient blood management (PBM) practices in cardiac surgery in nine European countries and identify the main risk factors for bleeding or transfusion according to the surveyed centres.Design: We set up an online survey to evaluate PBM practices in two clinical scenarios, risk factors for bleeding or transfusion, and previous experience with antifibrinolytics.Setting: This survey was completed by European anesthesiologists in 2019.Patients: No patients were included in the survey.Intervention: None.Measurements: We evaluated the degree of implementation of PBM practices in patients undergoing cardiac surgery.Main Results: Ninety-eight of 177 responses (38%) were complete with variable response rates by country. In a non-emergent situation, no respondents would transfuse red cells preoperatively in an anaemic patient, while cell salvage (89%) and antifibrinolytics (82%) would almost always be used. Optimization of Hemoglobin level (36%) and use of off-pump techniques (34%), minimally invasive surgery (25%) and relatively recently-developed CPB technologies such as mini-bypass (32%) and autologous priming (38%), varied greatly across countries. In an emergent clinical situation, topical haemostatic agents would frequently be used (61%). Tranexamic acid (72%) and aprotinin (20%) were the main antifibrinolytics used, with method of administration and dose varying markedly across countries. Five factors were considered to increase risk of bleeding or transfusion by at least 90% of respondents: pre-operative anaemia, prior cardiac surgery, clopidogrel 5 days or less before surgery, use of other P2Y12 inhibitors at any point, and thrombocytopenia <100.109 platelets/mm3.Conclusion: PBM guidelines are not universally implemented in European cardiac surgery centres or countries, resulting in discrepancies in techniques and products used for a given clinical situation. [ABSTRACT FROM AUTHOR]