A dynamic subpopulation of CRISPR-Cas overexpressers allows Streptococcus pyogenes to rapidly respond to phage.

Many CRISPR-Cas (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein) systems, which provide bacteria with adaptive immunity against phages, are transcriptionally repressed in their native hosts. How CRISPR-Cas expression is induced as needed, for example, during a bacteriophage infection, remains poorly understood. In Streptococcus pyogenes, a non-canonical guide RNA tracr-L directs Cas9 to autorepress its own promoter. Here we describe a dynamic subpopulation of cells harbouring single mutations that disrupt Cas9 binding and cause CRISPR-Cas overexpression. Cas9 actively expands this population by elevating mutation rates at the tracr-L target site. Overexpressers show higher rates of memory formation, stronger potency of old memories and a larger memory storage capacity relative to wild-type cells, which are surprisingly vulnerable to phage infection. However, in the absence of phage, CRISPR-Cas overexpression reduces fitness. We propose that CRISPR-Cas overexpressers are critical players in phage defence, enabling bacterial populations to mount rapid transcriptional responses to phage without requiring transient changes in any one cell.

State-of-the-art diagnosis of autoimmune blistering diseases.

Autoimmune blistering disorders (AIBDs) are a heterogeneous group of approximately a dozen entities comprising pemphigus and pemphigoid disorders and dermatitis herpetiformis. The exact diagnosis of AIBDs is critical for both prognosis and treatment and is based on the clinical appearance combined with the detection of tissue-bound and circulating autoantibodies. While blisters and erosions on the skin and/or inspectable mucosal surfaces are typical, lesions may be highly variable with erythematous, urticarial, prurigo-like, or eczematous manifestations. While direct immunofluorescence microscopy (IFM) of a perilesional biopsy is still the diagnostic gold standard, the molecular identification of the major target antigens opened novel therapeutic avenues. At present, most AIBDs can be diagnosed by the detection of autoantigen-specific serum antibodies by enzyme-linked immunosorbent assay (ELISA) or indirect IFM when the clinical picture is known. This is achieved by easily available and highly specific and sensitive assays employing recombinant immunodominant fragments of the major target antigens, i.e., desmoglein 1 (for pemphigus foliaceus), desmoglein 3 (for pemphigus vulgaris), envoplakin (for paraneoplastic pemphigus), BP180/type XVII collagen (for bullous pemphigoid, pemphigoid gestationis, and mucous membrane pemphigoid), laminin 332 (for mucous membrane pemphigoid), laminin ß4 (for anti-p200 pemphigoid), type VII collagen (for epidermolysis bullosa acquisita and mucous membrane pemphigoid), and transglutaminase 3 (for dermatitis herpetiformis). Indirect IFM on tissue substrates and in-house ELISA and immunoblot tests are required to detect autoantibodies in some AIBD patients including those with linear IgA disease. Here, a straightforward modern approach to diagnosing AIBDs is presented including diagnostic criteria according to national and international guidelines supplemented by long-term in-house expertise.

Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

BACKGROUND: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. METHODS AND FINDINGS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. TRIAL REGISTRATION: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Cardiovascular and renal outcomes of glucagon-like peptide 1 receptor agonists among patients with and without type 2 diabetes mellitus: A meta-analysis of randomized placebo-controlled trials.

Background: Multiple cardiovascular outcomes trials (CVOTs) have shown the efficacy of GLP-1RAs in reducing major adverse cardiovascular events (MACEs) for high-risk patients. However, some CVOTs failed to demonstrate cardiovascular benefits. Objectives: We analyzed the impact of GLP-1RA on cardiovascular and renal outcomes in patients with or without T2DM, with subgroup analysis based on sex, estimated glomerular filtration rate (eGFR), body mass index (BMI), and history of cardiovascular disease (CVD). Methods: A comprehensive database search for placebo-controlled RCTs on GLP-1RA treatment was conducted until April 2024. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with log odds ratios and 95 % confidence intervals (CIs). Results: A total of 13 CVOTs comprising 83,258 patients were included. GLP-1RAs significantly reduced MACE (OR 0.86, 95 % CI: 0.80 to 0.94, p < 0.01) all-cause mortality OR 0.87, 95 % CI: 0.82 to 0.93, p < 0.001, CV mortality (OR 0.87, 95 % CI: 0.81 to 0.94, p < 0.001), stroke (fatal: OR 0.74, 95 % CI: 0.56 to 0.96, p = 0.03; non-fatal: OR 0.87, 95 % CI: 0.79 to 0.96, p = 0.005), coronary revascularization (OR 0.86, 95 % CI: 0.74 to 0.99, p = 0.023), and composite kidney outcome (OR 0.76, 95 % CI: 0.67 to 0.85, p < 0.001. GLP-1RA significantly reduced MACE in both sexes. Furthermore, GLP-1RA reduced MACE regardless of CVD history, BMI, and eGFR level. Conclusion: Significant reductions in MACE, overall and CV mortality, stroke, coronary revascularization, and composite kidney outcome with GLP-1RA treatment were noted across all subgroups.

"You get out of the house, you talk to each other, you laugh And that's fantastic" - a qualitative study about older people's perceptions of social prescribing in mainland Portugal.

BACKGROUND: Social prescribing (SP) is a non-clinical approach, most commonly based in healthcare units, that aims to address non-medical health-related social needs by connecting individuals with community-based services. This qualitative study explores the perception of Portuguese older adults regarding the benefits of SP and their willingness to participate in SP initiatives. METHODS: Three face-to-face focus group sessions were conducted with 23 participants in different cities in Portugal. Open and semi-open questions were used to guide the discussions and thematic analysis was used to analyze the data. RESULTS: The participants recognized the potential benefits of SP for older adults, including diversifying leisure activities, improving mental health, and complementing existing support systems. They highlighted the need for external support, usually in the form of link workers, to facilitate personalized referrals and consider individual characteristics and preferences. While some participants expressed reluctance to engage in SP due to their existing busy schedules and a perceived sense of imposition, others showed openness to having new experiences and recognized the potential value of SP in promoting activity. Barriers to participation, including resistance to change, mobility issues, and family responsibilities, were identified. CONCLUSIONS: The study emphasizes the importance of a person-centered and co-designed approach to SP, involving older adults in the planning and implementation of interventions. The findings provide valuable insights for the development of SP programs tailored to the unique needs and aspirations of older adults in Portugal, ultimately promoting active and healthy aging. Future research should consider the perspectives of family doctors and include a broader representation of older adults from diverse geographic areas.

The social microbiome: The missing mechanism mediating the sociality-fitness nexus?

In many social mammals, early social life and social integration in adulthood largely predict individual health, lifespan, and reproductive success. So far, research has mainly focused on chronic stress as the physiological mediator between social environment and fitness. Here, we propose an alternative, non-exclusive mechanism relying on microbially mediated effects: social relationships with conspecifics in early life and adulthood might strongly contribute to diversifying host microbiomes and to the transmission of beneficial microbes. In turn, more diverse and valuable microbiomes would promote pathogen resistance and optimal health and translate into lifelong fitness benefits. This mechanism relies on recent findings showing that microbiomes are largely transmitted via social routes and play a pervasive role in host development, physiology and susceptibility to pathogens. We suggest that the social transmission of microbes could explain the sociality-fitness nexus to a similar or higher extent than chronic social stress and deserves empirical studies in social mammals.

Accurate species classification of Arctic toothed whale echolocation clicks using one-third octave ratios.

Passive acoustic monitoring has been an effective tool to study cetaceans in remote regions of the Arctic. Here, we advance methods to acoustically identify the only two Arctic toothed whales, the beluga (Delphinapterus leucas) and narwhal (Monodon monoceros), using echolocation clicks. Long-term acoustic recordings collected from moorings in Northwest Greenland were analyzed. Beluga and narwhal echolocation signals were distinguishable using spectrograms where beluga clicks had most energy >30 kHz and narwhal clicks had a sharp lower frequency limit near 20 kHz. Changes in one-third octave levels (TOL) between two pairs of one-third octave bands were compared from over one million click spectra. Narwhal clicks had a steep increase between the 16 and 25 kHz TOL bands that was absent in beluga click spectra. Conversely, beluga clicks had a steep increase between the 25 and 40 kHz TOL bands that was absent in narwhal click spectra. Random Forest classification models built using the 16 to 25 kHz and 25 to 40 kHz TOL ratios accurately predicted the species identity of 100% of acoustic events. Our findings support the use of echolocation TOL ratios in future automated click classifiers for acoustic monitoring of Arctic toothed whales and potentially for other odontocete species.

Systematic RADaR analysis of responses to the open-ended question in the Culture of Care Barometer survey of a Dutch hospital.

OBJECTIVES: Systematically measuring the work environment of healthcare employees is key to continuously improving the quality of care and addressing staff shortages. In this study, we systematically analyse the responses to the one open-ended question posed in the Dutch version of the Culture of Care Barometer (CoCB-NL) to examine (1) if the responses offered new insights into healthcare employees' perceptions of their work environment and (2) if the original CoCB had any themes missing. DESIGN: Retrospective text analysis using Rigorous and Accelerated Data Reduction technique. SETTING: University hospital in the Netherlands using the CoCB-NL as part of the annual employee survey. PARTICIPANTS: All hospital employees were invited to participate in the study (N=14 671). In total, 2287 employees responded to the open-ended question. RESULTS: 2287 comments were analysed. Comments that contained more than one topic were split according to topic, adding to the total (n=2915). Of this total, 372 comments were excluded because they lacked content or respondents indicated they had nothing to add. Subsequently, 2543 comments were allocated to 33 themes. Most comments (n=2113) addressed the 24 themes related to the close-ended questions in the CoCB-NL. The themes most commented on concerned questions on 'organisational support'. The remaining 430 comments covered nine additional themes that addressed concerns about work environment factors (team connectedness, team effectiveness, corporate vision, administrative burden and performance pressure) and themes (diversity and inclusion, legal frameworks and collective bargaining, resilience and work-life balance, and personal matters). CONCLUSIONS: Analysing responses to the open-ended question in the CoCB-NL led to new insights into relevant elements of the work environment and missing themes in the COCB-NL. Moreover, the analysis revealed important themes that not only require attention from healthcare organisations to ensure adequate improvements in their employees' work environment but should also be considered to further develop the CoCB-NL.

Social prescribing for people living with dementia (PLWD) and their carers: what works, for whom, under what circumstances and why - protocol for a complex intervention systematic review.

INTRODUCTION: Dementia is a complex medical condition that poses significant challenges to healthcare systems and support services. People living with dementia (PLWD) and their carers experience complex needs often exacerbated by social isolation and challenges in accessing support. Social prescribing (SP) seeks to enable PLWD and their carers to access community and voluntary sector resources to support them address such needs. Existing research, however, does not describe what SP interventions are currently in place in dementia care. Little is known about the needs these interventions are designed to address, the reasons that lead PLWD and their carers to participate in them, their effectiveness and the extent to which they could increase positive health outcomes if adopted and how. METHODS AND ANALYSIS: A complex intervention systematic review of SP for PLWD and/or their carers will be conducted using an iterative logic model approach. Six electronic (MEDLINE, EMBASE, PsycINFO, CINAHL, Scopus and Cochrane/CENTRAL) and two grey literature databases (EThOS and CORE) were searched for publications between 1 January 2003 and June 2023, supplemented by handsearching of reference lists of included studies. Study selection, data extraction and risk of bias assessment, using Gough's Weight of Evidence Framework, will be independently performed by two reviewers. A narrative approach will be employed to synthesise and report quantitative and qualitative data. Reporting will be informed by the Preferred Reporting Items for Systematic Review and Meta-Analysis Complex Interventions extension statement and checklist. ETHICS AND DISSEMINATION: No ethical approval is required due to this systematic review operating only with secondary sources. Findings will be disseminated through peer-reviewed publications, conference presentations and meetings with key stakeholders including healthcare professionals, patient and carer groups, community organisations (eg, the Social Prescribing Network and the Evidence Collaborative at the National Academy for Social Prescribing), policymakers and funding bodies. PROSPERO REGISTRATION NUMBER: CRD42023428625.

Mobility, functionality and functional mobility: A review and application for canine veterinary patients.

Mobility is an essential aspect of a dog's daily life. It is defined as the ability to move freely and easily and deviations from an animals' normal mobility capabilities are often an indicator of disease, injury or pain. When a dog's mobility is compromised, often functionality (ability to perform activities of daily living [ADL]), is also impeded, which can diminish an animal's quality of life. Given this, it is necessary to understand the extent to which conditions impact a dog's physiological ability to move around their environment to carry out ADL, a concept termed functional mobility. In contrast to human medicine, validated measures of canine functional mobility are currently limited. The aim of this review is to summarise the extent to which canine mobility and functionality are associated with various diseases and how mobility and functional mobility are currently assessed within veterinary medicine. Future work should focus on developing a standardised method of assessing functional mobility in dogs, which can contextualise how a wide range of conditions impact a dog's daily life. However, for a true functional mobility assessment to be developed, a greater understanding of what activities dogs do on a daily basis and movements underpinning these activities must first be established.

Anti-CRISPR proteins trigger a burst of CRISPR-Cas9 expression that enhances phage defense.

CRISPR-Cas immune systems provide bacteria with adaptive immunity against bacteriophages, but they are often transcriptionally repressed to mitigate auto-immunity. In some cases, CRISPR-Cas expression increases in response to a phage infection, but the mechanisms of induction are largely unknown, and it is unclear whether induction occurs strongly and quickly enough to benefit the bacterial host. In S. pyogenes, Cas9 is both an immune effector and auto-repressor of CRISPR-Cas expression. Here, we show that phage-encoded anti-CRISPR proteins relieve Cas9 auto-repression and trigger a rapid increase in CRISPR-Cas levels during a single phage infective cycle. As a result, fewer cells succumb to lysis, leading to a striking survival benefit after multiple rounds of infection. CRISPR-Cas induction also reduces lysogeny, thereby limiting a route for horizontal gene transfer. Altogether, we show that Cas9 is not only a CRISPR-Cas effector and repressor but also a phage sensor that can mount an anti-anti-CRISPR transcriptional response.

Developing a framework of concerns from people living with frailty, for the Measure Yourself Concerns and Wellbeing (MYCaW) person-centred outcome measure.

INTRODUCTION: Measure Yourself Concerns and Wellbeing is a validated person-centred outcome measure, piloted as a core monitoring tool to understand what matters to people living with frailty in Gloucestershire. This paper describes the acceptability of MYCaW used in this setting, and the development of a framework for analysing personalised concerns from people living with frailty. METHODS: MYCaW was implemented in the Complex Care at Home service and South Cotswold Frailty Service from November 2020 onwards. MYCaW was completed at the person's first meeting with a community matron and then 3 months later. Nineteen staff completed an anonymous survey to provide feedback on the acceptability of the tool. A framework of concerns bespoke to people living with frailty was created via iterative rounds of independent coding of 989 concerns from 526 people. The inter-rater reliability of the framework was determined by using the Cronbach alpha test. RESULTS: MYCaW was simple to use and helped health professionals' discussions to be patient focused. A pictorial scale accompanying the Numerical Rating Scale was developed and tested to help people engage with scoring their concerns and well-being more easily. A framework of concerns from people living with frailty was produced with five main supercategories: Mental and Emotional Concerns; Physical Concerns; Healthcare and Service Provision Concerns, Concerns with General Health and Well-being and Practical Concerns. Inter-rater reliability was kappa=0.905. CONCLUSIONS: MYCaW was acceptable as a core monitoring tool for people living with frailty and enabled a systematic approach to opening 'What Matters to Me' conversations. The personalised data generated valuable insights into how the frailty services positively impacted the outcomes for people living with frailty. The coding framework demonstrated a wide range of concerns-many linked to inequalities and not identified on existing outcome measures recommended for people living with frailty.

Infant Whole-Cell Versus Acellular Pertussis Vaccination in 1997 to 1999 and Risk of Childhood Hospitalization for Food-Induced Anaphylaxis: Linked Administrative Databases Cohort Study.

BACKGROUND: Evidence suggests that children who had received an initial priming dose of whole-cell pertussis (wP) vaccine, rather than acellular pertussis (aP) vaccine, had a lower risk of developing IgE-mediated food allergy, the most common cause of anaphylaxis-related hospital presentations of childhood. OBJECTIVE: To assess the association between wP versus aP vaccination in infancy and subsequent hospital presentations for anaphylaxis. METHODS: This study was preregistered under PMID 34874968. Perinatal records for a cohort of New South Wales-born children (1997-1999) receiving their first dose of pertussis-containing vaccine before age 4 months were probabilistically linked to hospital and immunization records. We used adjusted Cox models to estimate hazard ratios (aHRs) and 95% CIs for anaphylaxis-coded hospitalizations. RESULTS: There were 218,093 New South Wales-born children who received a first dose of wP or aP before age 4 months. Among these children, 86 experienced at least one hospitalization for food-induced anaphylaxis at age 5-15 years (range of events per patient, one to three). The person-time of follow-up was 1,476,969 years, and 665,519 years for children vaccinated with wP as a first dose (wP-1 children) and aP as a first dose (aP-1 children), respectively. The incidence rates for first hospitalization for food anaphylaxis were 3.5 (95% CI, 2.6-4.6) and 5.1 (95% CI, 3.5-7.1) per 100,000 child-years among wP-1 children and aP-1 children, respectively (aHR for wP vs aP = 0.47; 95% CI, 0.26-0.83). For first admission for venom anaphylaxis, the incidence rate was 4.9 (95% CI, 3.9-6.2) per 100,000 child-years among wP-1 children and 5.1 (95% CI, 3.5-7.1) per 100,000 child-years among aP-1 children (aHR for wP vs aP = 0.92; 95% CI, 0.53-1.60), and for all-cause anaphylaxis, the incidence rate was 10.6 (95% CI, 9.0-12.4) per 100,000 child-years among wP-1 children and 12.8 (95% CI, 10.2-15.8) per 100,000 child-years among aP-1 children (aHR for wP vs aP = 0.92; 95% CI, 0.53-1.60). CONCLUSION: Vaccination with wP in infancy was associated with a lower risk of hospitalizations for food-induced anaphylaxis (and therefore severe IgE-mediated food allergy) occurring in childhood.

Cross-Sectional Survey of Public Perception of Commercial Greyhound Racing in New Zealand.

The commercial greyhound racing industry in New Zealand is struggling with an eroding social license and 'on-notice' status. Multiple independent reviews of the industry have identified ongoing issues of animal welfare during and between races, euthanasia decisions, poor data tracking, a lack of transparency and problems with rehoming dogs, resulting in New Zealand animal advocacy agencies and the general public questioning the continuation of greyhound racing. The current paper assessed the New Zealand public's awareness and familiarity with commercial greyhound racing, identified current levels of public support or opposition for racing, and provided context in terms of engagement with greyhound racing using a comprehensive survey of a robust sample of New Zealanders. The results confirm that the social license of the greyhound industry is under challenge with most respondents expressing disagreement with or lack of knowledge of current industry practices and indicating they would vote in support of a ban. There is scope for increasing public acceptability by addressing welfare issues, increasing awareness of positive industry practices, and encouraging transparency of the greyhound racing agency. However, as greyhound racing is on the decline worldwide, calls are likely to continue for a phase-out of commercial greyhound racing.

Ulnar shape of extant primates: Functional signals and covariation with triquetrum shape.

OBJECTIVES: In this study, we investigated the shape differences of the distal ulna in a phylogenetic context among a broad range of primate taxa. Furthermore, we evaluated covariation between ulnar and triquetrum shape and a possible association between ulnar shape and locomotor behavior. MATERIALS AND METHODS: We applied 3D geometric morphometrics on a large dataset comprising the distal ulna of 124 anthropoid primate specimens belonging to 12 different genera. For each species, a mean shape was calculated using 11 Procrustes-aligned surface landmarks on the distal ulna. These mean shapes are used in a bgPCA, pPCA, and PACA and 3D morphs were used to visualize more subtle differences between taxa. A p2B-PLS analysis was performed to test the covariance between distal ulnar and triquetrum shape. RESULTS: The results show that more closely related species exhibit a similar distal ulnar shape. Overall, extant hominid ulnae show a shape shift compared to those of extant monkeys and hylobatids. This includes a shortening of the ulnar styloid process and dorspalmarly widening of the ulnar head, shape characteristics that are independent of phylogeny. Within the hominids, Pongo pygmaeus seem to possess the most plesiomorphic distal ulnar shape, while Gorilla and Homo sapiens display the most derived distal ulna. Cercopithecoids, hylobatids, and P. pygmaeus are characterized by a relatively deep ECU groove, which is a shape trait dependent of phylogeny. Although there was no significant covariation between distal ulnar shape and triquetrum shape, the shape differences of the distal ulna between the different primate taxa reveal a possible link with locomotor behavior. CONCLUSIONS: The comparative analyses of this study reveal different shape trends in a phylogenetic context. Highly arboreal primates, such as hylobatids and Ateles fusciceps, show a distal ulnar morphology that appears to be adapted to tensile and torsional forces. In primates that use their wrist under more compressive conditions, such as quadrupedal cercopithecoids and great apes, the distal ulnar morphology seems to reflect increased compressive forces. In modern humans, the distal ulnar shape can be associated to enhanced manipulative skills and power grips. There was no significant covariation between distal ulnar shape and triquetrum shape, probably due to the variation in the amount of contact between the triquetrum and ulna. In combination with future research on wrist mobility in diverse primate taxa, the results of this study will allow us to establish form-function relationships of the primate wrist and contribute towards an evidence-based interpretation of fossil remains.

Integrated Conversion of Lignocellulosic Biomass to Bio-Based Amphiphiles using a Functionalization-Defunctionalization Approach.

Concerns over the sustainability and end-of-life properties of fossil-derived surfactants have driven interest in bio-based alternatives. Lignocellulosic biomass with its polar functional groups is an obvious feedstock for surfactant production but its use is limited by process complexity and low yield. Here, we present a simple two-step approach to prepare bio-based amphiphiles directly from hemicellulose and lignin at high yields (29 % w/w based on the total raw biomass and >80 % w/w of these two fractions). Acetal functionalization of xylan and lignin with fatty aldehydes during fractionation introduced hydrophobic segments and subsequent defunctionalization by hydrogenolysis of the xylose derivatives or acidic hydrolysis of the lignin derivatives produced amphiphiles. The resulting biodegradable xylose acetals and/or ethers, and lignin-based amphiphilic polymers both largely retained their original natural structures, but exhibited competitive or superior surface activity in water/oil systems compared to common bio-based surfactants.

Laryngeal graft after total laryngectomy in humans: A SWiM analysis.

Evaluation of the results of laryngeal transplantation (LT) in humans. Analysis of 3 bibliographic databases with the keywords "larynx, transplantation, autograft". In total, 626 abstracts were read and 25 articles selected. The main objective was to analyze the characteristics of laryngeal transplant patients. The accessory objectives comprised analysis of operative technique, immunosuppressive treatment and results. Four articles were selected for analysis. Two patients were transplanted after total laryngectomy for laryngeal carcinoma and 2 after laryngeal trauma. Three of the 4 patients had true transplantation with arterial, venous and neural microanastomosis. Two patients were decannulated and the tracheostomy tube was maintained in the other 2. Three of the 4 patients had good-quality phonation and could feed without a gastric tube. One patient died of carcinoma progression and 1 patient had to be explanted 14 years after transplantation. The number of LTs reported is too small for scientific determination of the place of this intervention in laryngology. The published results could, at first sight, suggest that the future of LT is uncertain. However, several elements, also suggest that otolaryngologists should continue to take an interest in this technique.

SARS-CoV-2 NSP14 MTase activity is critical for inducing canonical NF-κB activation.

Upon SARS-CoV-2 infection, patients with severe forms of COVID-19 often suffer from a dysregulated immune response and hyperinflammation. Aberrant expression of cytokines and chemokines is associated with strong activation of the immunoregulatory transcription factor NF-κB, which can be directly induced by the SARS-CoV-2 protein NSP14. Here, we use NSP14 mutants and generated cells with host factor knockouts (KOs) in the NF-κB signaling pathways to characterize the molecular mechanism of NSP14-induced NF-κB activation. We demonstrate that full-length NSP14 requires methyltransferase (MTase) activity to drive NF-κB induction. NSP14 WT, but not an MTase-defective mutant, is poorly expressed and inherent post-translational instability is mediated by proteasomal degradation. Binding of SARS-CoV-2 NSP10 or addition of the co-factor S-adenosylmethionine (SAM) stabilizes NSP14 and augments its potential to activate NF-κB. Using CRISPR/Cas9-engineered KO cells, we demonstrate that NSP14 stimulation of canonical NF-κB activation relies on NF-κB factor p65/RELA downstream of the NEMO/IKK complex, while c-Rel or non-canonical RelB are not required to induce NF-κB transcriptional activity. However, NSP14 overexpression is unable to induce canonical IκB kinase ß (IKKß)/NF-κB signaling and in co-immunoprecipitation assays we do not detect stable associations between NSP14 and NEMO or p65, suggesting that NSP14 activates NF-κB indirectly through its methyltransferase activity. Taken together, our data provide a framework how NSP14 can augment basal NF-κB activation, which may enhance cytokine expression in SARS-CoV-2 infected cells.