Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identified two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generated a bispecific antibody. Lead antibodies showed strong inhibitory activity against historical SARS-CoV-2 and several emerging variants of concern. We solved several cryo-EM structures at ~3 Angstrom resolution of these neutralizing antibodies in complex with prefusion spike trimer ectodomain, and revealed distinct epitopes, binding patterns, and conformations. The lead clones also showed potent efficacy in vivo against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We also generated and characterized a humanized antibody to facilitate translation and drug development. The humanized clone also has strong potency against both the original virus and the B.1.617.2 Delta variant. These mAbs expand the repertoire of therapeutics against SARS-CoV-2 and emerging variants.

Deleterious Role of Th9 Cells in Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Immune disorders play an important role in IPF pathogenesis. Here, we show that Th9 cells differentiate and activate in the lung tissue of patients with IPF and bleomycin (BLM)-induced lung fibrosis mice. Moreover, we found that Th9 cells promote pulmonary fibrosis in two ways. On the one hand, Th9 cells promote fibroblast differentiation, activation, and collagen secretion by secreting IL-9. On the other hand, they promote differentiation of Th0 cells into Th2 cells by secreting IL-4. Th9 cells and Th2 cells can promote each other, accelerating the Th1/Th2 imbalance and eventually forming a positive feedback of pulmonary fibrosis. In addition, we found that neutralizing IL-9 in both preventive and therapeutic settings ameliorates bleomycin-induced pulmonary fibrosis. Furthermore, we identified several critical signaling pathways involved in the effect of neutralizing IL-9 on pulmonary fibrosis by proteomics study. From an immunological perspective, we elucidated the novel role and underlying mechanism of Th9 cells in pulmonary fibrosis. Our study suggested that Th9-based immunotherapy may be employed as a treatment strategy for IPF.

COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models

Effective treatments against Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Monoclonal antibodies have shown promising results in patients. Here, we evaluate the in vivo prophylactic and therapeutic effect of COVA1-18, a neutralizing antibody highly potent against the B.1.1.7 isolate. In both prophylactic and therapeutic settings, SARS-CoV-2 remains undetectable in the lungs of treated hACE2 mice. Therapeutic treatment also causes a reduction in viral loads in the lungs of Syrian hamsters. When administered at 10 mg kg-1 one day prior to a high dose SARS-CoV-2 challenge in cynomolgus macaques, COVA1-18 shows very strong antiviral activity in the upper respiratory compartments. Using a mathematical model, we estimate that COVA1-18 reduces viral infectivity by more than 95% in these compartments, preventing lymphopenia and extensive lung lesions. Our findings demonstrate that COVA1-18 has a strong antiviral activity in three preclinical models and could be a valuable candidate for further clinical evaluation.

Exploring the Question: “Does Empathy Work in the Same Way in Online and In-Person Therapeutic Settings?”

Providing remote psychotherapy using technology is a growing practice, especially since the outbreak of the COVID-19 pandemic. Even if in numerous studies video conferencing psychotherapy (VCP) was found to be clinically effective, some doubts continue to exist about how the psychotherapeutic alliance works in the online setting, and the characteristics of the empathic process are still poorly understood. This is an exploratory study aimed at analyzing the degree of empathy between the psychotherapist and client pair, and the degree of support perceived by the client who shall be referred to as the patient interchangeably in this study, comparing the sessions in person with those online, during the current pandemic, in order to discriminate the impact of empathy in the digital setting. The sample analyzed was composed of 23 patients with different severity of pathology engaged in online and in-person therapeutic sessions with five psychotherapists of different theoretical leanings. The scores of the support and empathy scale, obtained by both members of the psychotherapeutic couple in the two settings, were analyzed and compared. The test used belongs to an Italian adaptation of the Empathic Understanding (EU) of the Relationship Inventory. What emerged from comparing the scores was interesting: Unlike the psychotherapists, the patients perceived their therapists as significantly more empathic and supportive in the remote setting. These are rather important data, because the literature documents that client empathic perception measures represent a more accurate measure of the empathic relationship and, in general, can predict a good treatment outcome. Although these results need further investigation, they represent an important contribution in filling the scientific gap in the understanding of digital empathy. Also, this study provides new insights for future research on the characteristics and impact empathy has on the practice of remote psychotherapy.

Use of a small molecule integrin activator as a systemically administered vaccine adjuvant in controlling Chagas disease

The development of suitable safe adjuvants to enhance appropriate antigen-driven immune responses remains a challenge. Here we describe the adjuvant properties of a small molecule activator of the integrins αLβ2 and α4β1, named 7HP349, which can be safely delivered systemically independent of antigen. 7HP349 directly activates integrin cell adhesion receptors crucial for the generation of an immune response. When delivered systemically in a model of Chagas disease following immunization with a DNA subunit vaccine encoding candidate T. cruzi antigens, TcG2 and TcG4, 7HP349 enhanced the vaccine efficacy in both prophylactic and therapeutic settings. In a prophylactic setting, mice immunized with 7HP349 adjuvanted vaccine exhibited significantly improved control of acute parasite burden in cardiac and skeletal muscle as compared to vaccination alone. When administered with vaccine therapeutically, parasite burden was again decreased, with the greatest adjuvant effect of 7HP349 being noted in skeletal muscle. In both settings, adjuvantation with 7HP349 was effective in decreasing pathological inflammatory infiltrate, improving the integrity of tissue, and controlling tissue fibrosis in the heart and skeletal muscle of acutely and chronically infected Chagas mice. The positive effects correlated with increased splenic frequencies of CD8+T effector cells and an increase in the production of IFN-γ and cytolytic molecules (perforin and granzyme) by the CD4+ and CD8+ effector and central memory subsets in response to challenge infection. This demonstrates that 7HP349 can serve as a systemically administered adjuvant to enhance T cell-mediated immune responses to vaccines. This approach could be applied to numerous vaccines with no reformulation of existing stockpiles.

Depicting emotions for a male or for a female audience: Do children adapt the content of their drawings to the audience gender?

When depicting emotions, children have been shown to alter the content of their drawings (e.g., number and types of expressive cues) depending on the characteristics of the audience (i.e., age, familiarity, and authority). However, no study has yet investigated the influence of the audience gender on children’s depiction of emotions in their drawings. This study examined whether drawing for a male versus for a female audience have an impact on the number and type of emotional information children use to depict sadness, anger, and fear. Children aged 7 ( N = 92) and 9 ( N = 126) were asked to draw a figure and then to produce three drawings of a person, to depict three emotions (sadness, anger, fear). Children were randomly assigned to one of the three conditions: they were instructed either to draw with no explicit mention of an audience (control condition) or to draw so that the depicted emotion would be recognized by a male (male audience condition) or by a female (female audience condition). A content analysis was conducted on children’s drawings, revealing the use of seven types of graphic cues for each emotion. We found numerous differences between the three conditions relative to the type of cues used by children to depict emotions, particularly for anger and fear and particularly at the age of 7. Overall, children used facial cues more frequently for a female audience and contextual cues more frequently for a male audience. These results are discussed in terms of their implications in clinical, educational, and therapeutic settings.

A gaming system with haptic feedback to improve upper extremity function: A prospective case series

BACKGROUND: Video games can be used to motivate repetitive movements in paediatric rehabilitation. Most upper limb videogaming therapies do not however include haptic feedback which can limit their impact. OBJECTIVE: To explore the effectiveness of interactive computer play with haptic feedback for improving arm function in children with cerebral palsy (CP). METHODS: Eleven children with hemiplegic CP attended 12 therapist-guided sessions in which they used a gaming station composed of the Novint Falcon, custom-built handles, physical supports for the child’s arm, games, and an application to manage and calibrate therapeutic settings. Outcome measures included Quality of Upper Extremity Skills Test (QUEST) and Canadian Occupational Performance Measure (COPM). The study protocol is registered on clinicaltrials.gov (NCT04298411). RESULTS: Participants completed a mean of 3858 wrist extensions and 6665 elbow/shoulder movements during the therapist-guided sessions. Clinically important improvements were observed on the dissociated and grasp dimensions on the QUEST and the performance and satisfaction scales of the COPM (all p< 0.05). CONCLUSION: This study suggests that computer play with haptic feedback could be a useful and playful option to help improve the hand/arm capacities of children with CP and warrants further study. The opportunities and challenges of using low-cost, mainstream gaming software and hardware for therapeutic applications are discussed.

Measurement of Shared Social Identity in Singing Groups for People With Aphasia

Community groups are commonly used as a mode of delivery of interventions for promoting health and well-being. Research has demonstrated that developing a sense of shared social identity with other group members is a key mechanism through which the health benefits of group membership are realized. However, there is little understanding of how shared social identity emerges within these therapeutic settings. Understanding the emergence of shared social identity may help researchers optimize interventions and improve health outcomes. Group-based singing activities encourage coordination and a shared experience, and are a potential platform for the development of shared social identity. We use the “Singing for People with Aphasia” (SPA) group intervention to explore whether group cohesiveness, as a behavioral proxy for shared social identity, can be observed and tracked across the intervention. Video recordings of group sessions from three separate programmes were rated according to the degree of cohesiveness exhibited by the group. For all treatment groups, the final group session evidenced reliably higher levels of cohesiveness than the first session (t values ranged from 4.27 to 7.07; all p values &lt; 0.003). As well as providing confidence in the design and fidelity of this group-based singing intervention in terms of its capacity to build shared social identity, this evaluation highlighted the value of observational methods for the analysis of shared social identity in the context of group-based singing interventions.

Challenges in translational research: MDMA in the laboratory versus therapeutic settings

Despite substantial progress in the use of mind-altering drugs to treat psychiatric disorders, the psychological processes through which these drugs change mood or behavior are poorly understood. Controlled laboratory studies with well-defined psychological constructs are valuable to understand how these drugs manifest their therapeutic benefit. However, there are substantial methodological differences between clinical studies investigating therapeutic outcome and laboratory studies investigating the processes that might underlie the therapeutic effects. Here, we examine some of these differences using the example of 3,4-methylenedioxymethamphetamine (MDMA). We review differences in expectancies, social and physical context, participant characteristics, pharmacological factors, and outcome measures in studies with participants who do or do not have psychiatric diagnoses. We describe the challenges and opportunities in translating findings from laboratory studies to the clinic and identify ways to bridge the gap between these approaches.