Human antibodies in Mexico and Brazil neutralizing tick-borne flaviviruses.

Flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV) are spread by mosquitoes and cause human disease and mortality in tropical areas. In contrast, Powassan virus (POWV), which causes severe neurologic illness, is a flavivirus transmitted by ticks in temperate regions of the Northern hemisphere. We find serologic neutralizing activity against POWV in individuals living in Mexico and Brazil. Monoclonal antibodies P002 and P003, which were derived from a resident of Mexico (where POWV is not reported), neutralize POWV lineage I by recognizing an epitope on the virus envelope domain III (EDIII) that is shared with a broad range of tick- and mosquito-borne flaviviruses. Our findings raise the possibility that POWV, or a flavivirus closely related to it, infects humans in the tropics.

Analytical Ultracentrifugation Detects Quaternary Rearrangements and Antibody-Induced Conformational Selection of the SARS-CoV-2 Spike Trimer.

Analytical ultracentrifugation (AUC) analysis shows that the SARS-CoV-2 trimeric Spike (S) protein adopts different quaternary conformations in solution. The relative abundance of the "open" and "close" conformations is temperature-dependent, and samples with different storage temperature history have different open/close distributions. Neutralizing antibodies (NAbs) targeting the S receptor binding domain (RBD) do not alter the conformer populations; by contrast, a NAb targeting a cryptic conformational epitope skews the Spike trimer toward an open conformation. The results highlight AUC, which is typically applied for molecular mass determination of biomolecules as a powerful tool for detecting functionally relevant quaternary protein conformations.

A predictive decision support system for coronavirus disease 2019 response management and medical logistic planning.

Objective: Coronavirus disease 2019 demonstrated the inconsistencies in adequately responding to biological threats on a global scale due to a lack of powerful tools for assessing various factors in the formation of the epidemic situation and its forecasting. Decision support systems have a role in overcoming the challenges in health monitoring systems in light of current or future epidemic outbreaks. This paper focuses on some applied examples of logistic planning, a key service of the Earth Cognitive System for Coronavirus Disease 2019 project, here presented, evidencing the added value of artificial intelligence algorithms towards predictive hypotheses in tackling health emergencies. Methods: Earth Cognitive System for Coronavirus Disease 2019 is a decision support system designed to support healthcare institutions in monitoring, management and forecasting activities through artificial intelligence, social media analytics, geospatial analysis and satellite imaging. The monitoring, management and prediction of medical equipment logistic needs rely on machine learning to predict the regional risk classification colour codes, the emergency rooms attendances, and the forecast of regional medical supplies, synergically enhancing geospatial and temporal dimensions. Results: The overall performance of the regional risk colour code classifier yielded a high value of the macro-average F1-score (0.82) and an accuracy of 85%. The prediction of the emergency rooms attendances for the Lazio region yielded a very low root mean square error (<11 patients) and a high positive correlation with the actual values for the major hospitals of the Lazio region which admit about 90% of the region's patients. The prediction of the medicinal purchases for the regions of Lazio and Piemonte has yielded a low root mean squared percentage error of 16%. Conclusions: Accurate forecasting of the evolution of new cases and drug utilisation enables the resulting excess demand throughout the supply chain to be managed more effectively. Forecasting during a pandemic becomes essential for effective government decision-making, managing supply chain resources, and for informing tough policy decisions.

Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course.

Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.

Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein.

Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization, and, similar to fp.006 and hr2.016, protects mice expressing human angiotensin-converting enzyme 2 against infection when present as a bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae, including SARS-CoV-2 variants.

Human neutralizing antibodies to cold linear epitopes and to subdomain 1 of SARS-CoV-2.

Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera , including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice when present as bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae , including SARS-CoV-2 variants. One sentence summary: Broadly cross-reactive antibodies that protect from SARS-CoV-2 variants are revealed by virus coldspot-driven discovery.

Anti-chemokine antibodies after SARS-CoV-2 infection correlate with favorable disease course.

Infection by SARS-CoV-2 leads to diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse COVID-19 outcomes. Instead, we discovered that antibodies against specific chemokines are omnipresent after COVID-19, associated with favorable disease, and predictive of lack of long COVID symptoms at one year post infection. Anti-chemokine antibodies are present also in HIV-1 infection and autoimmune disorders, but they target different chemokines than those in COVID-19. Monoclonal antibodies derived from COVID- 19 convalescents that bind to the chemokine N-loop impair cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising anti-chemokine antibodies associated with favorable COVID-19 may be beneficial by modulating the inflammatory response and thus bear therapeutic potential. One-Sentence Summary: Naturally arising anti-chemokine antibodies associate with favorable COVID-19 and predict lack of long COVID.

A Geospatial Artificial Intelligence and satellite-based earth observation cognitive system in response to COVID-19.

The pandemic emergency caused by the spread of COVID-19 has stressed the importance of promptly identifying new epidemic clusters and patterns, to ensure the implementation of local risk containment measures and provide the needed healthcare to the population. In this framework, artificial intelligence, GIS, geospatial analysis and space assets can play a crucial role. Social media analytics can be used to trigger Earth Observation (EO) satellite acquisitions over potential new areas of human aggregation. Similarly, EO satellites can be used jointly with social media analytics to systematically monitor well-known areas of aggregation (green urban areas, public markets, etc.). The information that can be obtained from the Earth Cognitive System 4 COVID-19 (ECO4CO) are both predictive, aiming to identify possible new clusters of outbreaks, and at the same time supervisorial, by monitoring infrastructures (i.e. traffic jams, parking lots) or specific categories (i.e. teenagers, doctors, teachers, etc.). In this perspective, the technologies described in this paper will allow us to detect critical areas where individuals can be involved in risky aggregation clusters. The ECO4CO data lake will be integrated with ad hoc data obtained by health care structures to understand trends and dynamics, to assess criticalities with respect to medical response and supplies, and to test possibilities useful to tackle potential future emergencies. The System will also provide geographical information on the spread of the infection which will allow an appropriate context-specific public health response to the epidemic. This project has been co-funded by the European Space Agency under its Business Applications programme.

Climate change and anthropogenic food manipulation interact in shifting the distribution of a large herbivore at its altitudinal range limit.

Ungulates in alpine ecosystems are constrained by winter harshness through resource limitation and direct mortality from weather extremes. However, little empirical evidence has definitively established how current climate change and other anthropogenic modifications of resource availability affect ungulate winter distribution, especially at their range limits. Here, we used a combination of historical (1997-2002) and contemporary (2012-2015) Eurasian roe deer (Capreolus capreolus) relocation datasets that span changes in snowpack characteristics and two levels of supplemental feeding to compare and forecast probability of space use at the species' altitudinal range limit. Scarcer snow cover in the contemporary period interacted with the augmented feeding site distribution to increase the elevation of winter range limits, and we predict this trend will continue under climate change. Moreover, roe deer have shifted from historically using feeding sites primarily under deep snow conditions to contemporarily using them under a wider range of snow conditions as their availability has increased. Combined with scarcer snow cover during December, January, and April, this trend has reduced inter-annual variability in space use patterns in these months. These spatial responses to climate- and artificial resource-provisioning shifts evidence the importance of these changing factors in shaping large herbivore spatial distribution and, consequently, ecosystem dynamics.

Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease.

Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC50s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI-EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.

Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice.

Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-191,2. A bispecific IgG1-like molecule (CoV-X2) has been developed on the basis of C121 and C135, two antibodies derived from donors who had recovered from COVID-193. Here we show that CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable spike binding to the cellular receptor of the virus, angiotensin-converting enzyme 2 (ACE2). Furthermore, CoV-X2 neutralizes wild-type SARS-CoV-2 and its variants of concern, as well as escape mutants generated by the parental monoclonal antibodies. We also found that in a mouse model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, the simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, and combines the advantages of antibody cocktails with those of single-molecule approaches.

Bispecific antibody neutralizes circulating SARS-CoV-2 variants, prevents escape and protects mice from disease.

Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19) 1,2 . We developed a bispecific, IgG1-like molecule (CoV-X2) based on two antibodies derived from COVID-19 convalescent donors, C121 and C135 3 . CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 neutralizes SARS-CoV-2 and its variants of concern, as well as the escape mutants generated by the parental monoclonals. In a novel animal model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.

Convergent antibody responses to SARS-CoV-2 in convalescent individuals.

During the coronavirus disease-2019 (COVID-19) pandemic, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has led to the infection of millions of people and has claimed hundreds of thousands of lives. The entry of the virus into cells depends on the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2. Although there is currently no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21-5. Here we report on 149 COVID-19-convalescent individuals. Plasma samples collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titres; titres were less than 50 in 33% of samples, below 1,000 in 79% of samples and only 1% of samples had titres above 5,000. Antibody sequencing revealed the expansion of clones of RBD-specific memory B cells that expressed closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on the RBD neutralized the virus with half-maximal inhibitory concentrations (IC50 values) as low as 2 ng ml-1. In conclusion, most convalescent plasma samples obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals.

During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21-5. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal neutralizing titers ranging from undetectable in 33% to below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody cloning revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

Neuropsychology as a profession in Italy.

The purpose of this study was to analyze the characteristics of individuals working in the field of neuropsychology in Italy, as part of a larger study examining the practice of neuropsychology across various countries. They were asked about their background, professional training, current work situation, types of assessment, preferred diagnostic procedures, as well as the rehabilitation techniques, their targeted populations, teaching responsibilities, and research activities. A total of 154 professionals completed an online survey from April 28, 2016 through June 30, 2016. The majority of participants were women, with a mean age of 42.6 years. Participants reported working for the National Health System, in private practice, or in private rehabilitation facilities. Overall, they reported being very satisfied with their work. Those who identified themselves as neuropsychologists primarily assessed individuals with dementia, stroke, movement disorders, and traumatic brain injury. While the majority of participants declared no problems with the instruments they used, others reported complaints, including but not limited to the financial cost of current neuropsychological tests and the lack of psychometric support. The main perceived obstacles were the lack of willingness to collaborate among professionals, the scarcity of academic training programs, and the lack of clinical training opportunities.

Effects of oral contraceptives and natural menstrual cycling on environmental learning.

BACKGROUND: Endogenous ovarian hormones as well as exogenous oestradiol and progesterone play an important role in cognitive processing. Specifically, these hormones play a role in different aspects of memory, both in terms of storage capacity and temporal duration of the mnemonic track. These hormones also have various effects on different types of memory (i.e., verbal, visuo-spatial, prospective). This study investigated the effects of hormones on topographic memory, a type of memory specifically needed to recall a pathway and to acquire spatial information about locations, distances, and directions. METHODS: We compared 25 naturally cycling women (NCW) in two different cycling phases, the early follicular phase (4th - 5th days) and the mid-luteal phase (20th-21st days), with 26 women taking oral contraceptives (OC) tested in the active pill phase (20th to 21st day of OC cycle) and the inactive pill phase (2nd to 4th day of OC cycle). Both groups performed the Walking Corsi Test to assess topographic memory in their respective cycling phases. Women were instructed to learn an eight-step sequence path and recall the path five minutes later. RESULTS: We found that the two groups differed in terms of learning the 8-step sequence path; OC users were always better (4-5 days vs. 20-21 days) than NCW. No differences emerged in the delayed recall of the same path. CONCLUSIONS: As already observed in other memory domains (i.e., verbal memory, emotional memory), OC users showed an advantage in terms of topographic learning. Our results might be explained by hormonal mechanisms and may suggest the future application of OC in women with topographic disorders or visuo-spatial difficulties.

Selective map-following navigation deficit: A new case of developmental topographical disorientation.

INTRODUCTION: Developmental topographical disorientation (DTD) is a lifelong condition in which affected individuals are selectively impaired in navigating space. Although it seems that DTD is widespread in the population, only a few cases have been studied from both a behavioral and a neuroimaging point of view. Here, we report a new case of DTD, never described previously, of a young woman (C.F.) showing a specific deficit in translating allocentrically coded information into egocentrically guided navigation, in presence of spared ability of constructing such representations. METHOD: A series of behavioral experiments was performed together with a resting-state functional magnetic resonance imaging (fMRI). RESULTS: We demonstrated that C.F. was fully effective in learning and following routes and in building up cognitive maps as well as in recognizing landmarks. C.F.'s navigational skills, instead, dropped drastically in the map-following task when she was required to use a map to navigate in a novel environment. The rs-fMRI experiment demonstrated aberrant functional connectivity between regions within the default-mode network (DMN), and in particular between medial prefrontal cortex and posterior cingulate, medial parietal, and temporal cortices. DISCUSSION: Our results would suggest that, at least in C.F., dysfunctional coactivation of core DMN regions would interfere with the ability to exploit cognitive maps for real-life navigation even when these maps can be correctly built.

Does the cerebellum contribute to human navigation by processing sequential information?

OBJECTIVE: Several authors have proposed that the cerebellum has an important role in functions of higher order as a general mode of sequence detection, independently from the nature of the information. The aim of this study was to verify whether the cerebellum mediates the processing of navigational sequential information and to determine whether it is influenced by the modality of the stimuli presentation. METHOD: We tested 12 cerebellar patients and 12 healthy age-matched participants in 2 comparable navigational tasks (Walking Corsi Test and the Magic Carpet) requiring to memorizing a sequence of spatial locations. The 2 tasks differ each other for the modality of stimuli presentation: in the Walking Corsi Test the sequence is shown by an examiner that walks on the carpet, whereas in the Magic Carpet it is shown by a computer that lights up the tiles in the sequence. We hypothesize that different mental processes are implicated between the Walking Corsi Test and the Magic Carpet. Indeed, whereas watching the examiner, who performs the sequence on the carpet, allows the patient to simulate the action mentally in the Walking Corsi Test, such simulation cannot be triggered in the Magic Carpet. RESULTS: Our results showed that cerebellar patients obtained scores significantly lower than control participants only in the Magic Carpet. CONCLUSIONS: We interpreted the patients' performance as a specific deficit in detecting and ordering single independent stimuli as a sequence, when the maintenance of stimulus-response associations is more demanding. (PsycINFO Database Record

Cognitive-behavioural phenotype in a group of girls from 1.2 to 12 years old with the Incontinentia Pigmenti syndrome: Recommendations for clinical management.

Incontinentia Pigmenti (IP, OMIM#308300) is a rare X-linked genomic disorder (about 1,400 cases) that affects the neuroectodermal tissue and Central Nervous System (CNS). The objective of this study was to describe the cognitive-behavioural profile in children in order to plan a clinical intervention to improve their quality of life. A total of 14 girls (age range: from 1 year and 2 months to 12 years and 10 months) with IP and the IKBKG/NEMO gene deletion were submitted to a cognitive assessment including intelligence scales, language and visuo-spatial competence tests, learning ability tests, and a behavioural assessment. Five girls had severe to mild intellectual deficiencies and the remaining nine had a normal neurodevelopment. Four girls were of school age and two of these showed no intellectual disability, but had specific disabilities in calculation and arithmetic reasoning. This is the first description of the cognitive-behavioural profile in relation to developmental age. We stress the importance of an early assessment of learning abilities in individuals with IP without intellectual deficiencies to prevent the onset of any such deficit.