•The lockdown in spring 2020 affected the gender division of labor and childcare.•Italian households experienced a greater involvement of fathers in childcare.•Fathers’ involvement is accompanied by ...an improve in children's emotional wellbeing.•The quality of children's home learning does not depend on which parent is overseeing.•Fathers had a positive mediating effects on children's use of time.
The lockdown imposed during the spring of 2020 as a result of the COVID-19 pandemic upset families lives, in addition to the health consequences of the virus, forcing parents to completely reorganize their labor, domestic work and childcare time. At the same time, school closures forced children to rearrange their lives and learning processes: in Italy, schools and nurseries were closed for four months, and the incidence and quality of distance learning activities was heterogeneous across education levels and among schools. Using real-time survey data on families with under-16 children collected in April 2020, which include information on parents’ market and household work, and their perception of their children's wellbeing, we estimate how the lockdown has affected children's use of time, their emotional status and their home learning, and whether the reallocation of intrahousehold responsibilities during the lockdown played a role in this process. Changes in the parental division of household tasks and childcare, mostly induced by the labor market restrictions imposed during the lockdown, point to a greater involvement of fathers in childcare and homeschooling activities. This positive variation in fathers’ involvement is accompanied by an increase in children's emotional wellbeing and by a reduction in TV and passive screen time. On the other hand, the quality of children's home learning does not appear to depend on which parent is overseeing their work, but rather on the type of distance learning activities proposed by their teachers.
Vaccine-induced high-avidity IgA can protect against bacterial enteropathogens by directly neutralizing virulence factors or by poorly defined mechanisms that physically impede bacterial interactions ...with the gut tissues ('immune exclusion'). IgA-mediated cross-linking clumps bacteria in the gut lumen and is critical for protection against infection by non-typhoidal Salmonella enterica subspecies enterica serovar Typhimurium (S. Typhimurium). However, classical agglutination, which was thought to drive this process, is efficient only at high pathogen densities (≥10
non-motile bacteria per gram). In typical infections, much lower densities (10
-10
colony-forming units per gram) of rapidly dividing bacteria are present in the gut lumen. Here we show that a different physical process drives formation of clumps in vivo: IgA-mediated cross-linking enchains daughter cells, preventing their separation after division, and clumping is therefore dependent on growth. Enchained growth is effective at all realistic pathogen densities, and accelerates pathogen clearance from the gut lumen. Furthermore, IgA enchains plasmid-donor and -recipient clones into separate clumps, impeding conjugative plasmid transfer in vivo. Enchained growth is therefore a mechanism by which IgA can disarm and clear potentially invasive species from the intestinal lumen without requiring high pathogen densities, inflammation or bacterial killing. Furthermore, our results reveal an untapped potential for oral vaccines in combating the spread of antimicrobial resistance.
The neutralizing antibody response to influenza virus is dominated by antibodies that bind to the globular head of haemagglutinin, which undergoes a continuous antigenic drift, necessitating the ...re-formulation of influenza vaccines on an annual basis. Recently, several laboratories have described a new class of rare influenza-neutralizing antibodies that target a conserved site in the haemagglutinin stem. Most of these antibodies use the heavy-chain variable region VH1-69 gene, and structural data demonstrate that they bind to the haemagglutinin stem through conserved heavy-chain complementarity determining region (HCDR) residues. However, the VH1-69 antibodies are highly mutated and are produced by some but not all individuals, suggesting that several somatic mutations may be required for their development. To address this, here we characterize 197 anti-stem antibodies from a single donor, reconstruct the developmental pathways of several VH1-69 clones and identify two key elements that are required for the initial development of most VH1-69 antibodies: a polymorphic germline-encoded phenylalanine at position 54 and a conserved tyrosine at position 98 in HCDR3. Strikingly, in most cases a single proline to alanine mutation at position 52a in HCDR2 is sufficient to confer high affinity binding to the selecting H1 antigen, consistent with rapid affinity maturation. Surprisingly, additional favourable mutations continue to accumulate, increasing the breadth of reactivity and making both the initial mutations and phenylalanine at position 54 functionally redundant. These results define VH1-69 allele polymorphism, rearrangement of the VDJ gene segments and single somatic mutations as the three requirements for generating broadly neutralizing VH1-69 antibodies and reveal an unexpected redundancy in the affinity maturation process.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Anti–citrullinated protein antibodies (ACPAs) are a hallmark of seropositive rheumatoid arthritis (RA). Yet, the precise disease‐relevant autoantigens that are targeted by ACPAs remains a ...matter of debate. This study utilized patient‐derived monoclonal ACPAs, rather than serum autoantibody analysis, to characterize the multireactivity to different protein modifications and to reveal autoantibody subsets in patients with RA.
Methods
Twelve human monoclonal ACPAs (positive by the second‐generation cyclic citrullinated peptide test) were generated from 6 RA patients, and a head‐to‐head comparison of their reactivities was performed. For profiling, we used a complementary DNA–based protein array (Engine GmbH) and 3 peptide‐screening platforms with RA autoantigens (Thermo Fisher Scientific), citrullinated and carbamylated peptides (NimbleGen/Roche), or histone‐derived peptides with different posttranslational modifications (JPT Histone Code), covering >207,000 peptides (>7,800 gene products).
Results
The fine‐specificity profiles of the investigated ACPAs varied, but all of the monoclonal ACPAs displayed multireactivity to a large number of citrullinated peptides/proteins, each characterized by specific binding properties. ACPA subsets could be defined by clone‐distinct consensus binding motifs (e.g., Cit–Gly, Gly–Cit, or Arg–Cit–Asp), with the most common ACPA recognition being that of a Gly in the +1 flanking position, but with additional amino acid preferences. For ACPA protein recognition, we observed a preference for citrullinated RNA‐binding proteins with high Arg/Gly content. Six of the 12 ACPA clones also bound acetylated lysine (KAc) or homocitrulline peptide motifs, displaying a similar affinity or higher apparent affinity than that for citrullinated peptides.
Conclusion
ACPAs and anti–modified protein autoantibodies represent overlapping facets of RA autoimmunity and bind to a wide variety of modified proteins, extending well beyond the historically recognized set of RA autoantigens. So far, KAc reactivity has been detected only in the context of anti–carbamylated and anti–citrullinated peptide autoantibody responses, postulating the existence of hierarchies of autoreactivity in RA. Future investigations of ACPA fine specificities and functionality should take into consideration the presence of consensus Cit/Carb/KAc motifs and the multireactivity of these autoantibodies in patients with RA.
In systemic light chain amyloidosis (AL), pathogenic monoclonal immunoglobulin light chains (LC) form toxic aggregates and amyloid fibrils in target organs. Prompt diagnosis is crucial to avoid ...permanent organ damage, but delayed diagnosis is common because symptoms usually appear only after strong organ involvement. Here we present LICTOR, a machine learning approach predicting LC toxicity in AL, based on the distribution of somatic mutations acquired during clonal selection. LICTOR achieves a specificity and a sensitivity of 0.82 and 0.76, respectively, with an area under the receiver operating characteristic curve (AUC) of 0.87. Tested on an independent set of 12 LCs sequences with known clinical phenotypes, LICTOR achieves a prediction accuracy of 83%. Furthermore, we are able to abolish the toxic phenotype of an LC by in silico reverting two germline-specific somatic mutations identified by LICTOR, and by experimentally assessing the loss of in vivo toxicity in a Caenorhabditis elegans model. Therefore, LICTOR represents a promising strategy for AL diagnosis and reducing high mortality rates in AL.
Plasmodium falciparum antigens expressed on the surface of infected erythrocytes are important targets of naturally acquired immunity against malaria, but their high number and variability provide ...the pathogen with a powerful means of escape from host antibodies. Although broadly reactive antibodies against these antigens could be useful as therapeutics and in vaccine design, their identification has proven elusive. Here we report the isolation of human monoclonal antibodies that recognize erythrocytes infected by different P. falciparum isolates and opsonize these cells by binding to members of the RIFIN family. These antibodies acquired broad reactivity through a novel mechanism of insertion of a large DNA fragment between the V and DJ segments. The insert, which is both necessary and sufficient for binding to RIFINs, encodes the entire 98 amino acid collagen-binding domain of LAIR1, an immunoglobulin superfamily inhibitory receptor encoded on chromosome 19. In each of the two donors studied, the antibodies are produced by a single expanded B-cell clone and carry distinct somatic mutations in the LAIR1 domain that abolish binding to collagen and increase binding to infected erythrocytes. These findings illustrate, with a biologically relevant example, a novel mechanism of antibody diversification by interchromosomal DNA transposition and demonstrate the existence of conserved epitopes that may be suitable candidates for the development of a malaria vaccine.
This study extends the rational addiction theory by introducing an endogenous discounting of future utilities. The discount rate depends on habits accumulating over time because of the repeated ...consumption of an addictive good. The endogeneity of the discount rate affects consumption decisions via a habit-dependent rate of time preference and discloses a patience-dependence trade-off. The existence of a steady state in which habits do not grow and its optimality are proven. The local stability properties of the steady state reveal that the equilibrium can be a saddle node, implying smooth convergence to the steady state, but also a stable or unstable focus, potentially predicting real-world behaviors such as binge drinking or extreme addiction states that may drive to death. The stability of the steady state mostly depends on the habit formation process, suggesting that heterogeneity in habit formation may be a key component to explain heterogeneity in time preferences.
Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse drug reaction, consisting of progressive bone destruction in the maxillofacial region of patients. ONJ can be caused by two ...pharmacological agents: Antiresorptive (including bisphosphonates (BPs) and receptor activator of nuclear factor kappa-B ligand inhibitors) and antiangiogenic. MRONJ pathophysiology is not completely elucidated. There are several suggested hypothesis that could explain its unique localization to the jaws: Inflammation or infection, microtrauma, altered bone remodeling or over suppression of bone resorption, angiogenesis inhibition, soft tissue BPs toxicity, peculiar biofilm of the oral cavity, terminal vascularization of the mandible, suppression of immunity, or Vitamin D deficiency. Dental screening and adequate treatment are fundamental to reduce the risk of osteonecrosis in patients under antiresorptive or antiangiogenic therapy, or before initiating the administration. The treatment of MRONJ is generally difficult and the optimal therapy strategy is still to be established. For this reason, prevention is even more important. It is suggested that a multidisciplinary team approach including a dentist, an oncologist, and a maxillofacial surgeon to evaluate and decide the best therapy for the patient. The choice between a conservative treatment and surgery is not easy, and it should be made on a case by case basis. However, the initial approach should be as conservative as possible. The most important goals of treatment for patients with established MRONJ are primarily the control of infection, bone necrosis progression, and pain. The aim of this paper is to represent the current knowledge about MRONJ, its preventive measures and management strategies.
Pulmonary alveolar proteinosis (PAP) is a severe autoimmune disease caused by autoantibodies that neutralize GM-CSF resulting in impaired function of alveolar macrophages. In this study, we ...characterize 21 GM-CSF autoantibodies from PAP patients and find that somatic mutations critically determine their specificity for the self-antigen. Individual antibodies only partially neutralize GM-CSF activity using an in vitro bioassay, depending on the experimental conditions, while, when injected in mice together with human GM-CSF, they lead to the accumulation of a large pool of circulating GM-CSF that remains partially bioavailable. In contrast, a combination of three non-cross-competing antibodies completely neutralizes GM-CSF activity in vitro by sequestering the cytokine in high-molecular-weight complexes, and in vivo promotes the rapid degradation of GM-CSF-containing immune complexes in an Fc-dependent manner. Taken together, these findings provide a plausible explanation for the severe phenotype of PAP patients and for the safety of treatments based on single anti-GM-CSF monoclonal antibodies.
Human cystic echinococcosis is a chronic, complex and neglected infection. Its clinical management has evolved over decades without adequate evaluation of efficacy. Recent expert opinion recommends ...that uncomplicated inactive cysts of the liver should be left untreated and solely monitored over time ("watch-and-wait" approach). However, clinical data supporting this approach are still scant and published mostly as conference proceedings. In this study, we report our experience with long-term sonographic and serological follow-up of inactive cysts of the liver. From March 1994 to October 2013, 38 patients with 47 liver cysts, diagnosed as inactive without any previous treatment history, were followed with ultrasound and serology at 6-12 months intervals for a period of at least 24 months (median follow-up 51.95 months) in our outpatient clinic. In 97.4% of patients, the cysts remained inactive over time and in only one case was reactivation of the cyst detected. No complications occurred during the time of monitoring. During follow-up, serology tests for CE were negative at diagnosis or became negative in 74.1% and were positive or became positive in 25.9% of cases. Patients with inactive cysts on ultrasound but positive serological tests were also investigated by CT scan (chest and abdomen) to rule out extra-hepatic cyst localization. This study confirms the importance of a stage-specific approach to the management of cystic echinococcosis and supports the use of a monitoring-only approach to inactive, uncomplicated cysts of the liver. It also confirms that serology plays only an ancillary role in the clinical management of these patients, compared to ultrasound and other imaging techniques. The implications of these findings for clinical management and natural history of cystic echinococcosis are discussed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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