High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells

T follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Even though Tfh-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high-affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. Indeed, we found by epitope mapping and BCR sequencing that Tfh cells focused the B cell response and therefore, in the absence of Tfh cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation

Manipulation of Costimulatory Molecules by Intracellular Pathogens: Veni, Vidi, Vici!!

Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the “code of conduct” of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens

High-affinity, neutralizing antibodies to SARS-CoV-2 can be made in the absence of T follicular helper cells [preprint]

T follicular helper (Tfh) cells are the conventional drivers of protective, germinal center (GC)-based antiviral antibody responses. However, loss of Tfh cells and GCs has been observed in patients with severe COVID-19. As T cell-B cell interactions and immunoglobulin class switching still occur in these patients, non-canonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both Tfh-dependent and -independent antibodies were induced against SARS-CoV-2 as well as influenza A virus. Tfh-independent responses were mediated by a population we call lymph node (LN)-Th1 cells, which remain in the LN and interact with B cells outside of GCs to promote high-affinity but broad-spectrum antibodies. Strikingly, antibodies generated in the presence and absence of Tfh cells displayed similar neutralization potency against homologous SARS-CoV-2 as well as the B.1.351 variant of concern. These data support a new paradigm for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GCs and even compensate for GCs damaged by viral inflammation

Magnetocaloric properties, exchange bias, and critical behavior of Ge substituted Ni50Mn36Sn14 Heusler alloys

The effect of Ge substitution on the magnetic, magnetocaloric, and exchange bias properties of Heusler alloy system Ni50Mn36Sn14-xGex (x = 1, 2) has been investigated. With the increase of Ge content, the cell volume decreases due to the smaller Ge radius and the martensitic transition temperature increases, while the Curie temperature of the austenite phase shows a small decrease. Metamagnetic behavior is observed in the low temperature magnetization isotherms for x = 1, whereas it is less pronounced in x = 2. The maximum magnetic entropy changes associated with the martensitic transition are 7.8 J/kg K and 2.3 J/kg K for x = 1 and 2, respectively, for a field change of 5 T. Relative cooling power is found to be more in the vicinity of the Curie temperature of the austenite phase, compared to that at the martensitic transition temperature in both x = 1 and 2. At low temperatures, both the samples exhibit exchange bias effect, with x = 2 showing higher value of exchange bias field. This is ascribed to the coexistence of ferromagnetic and antiferromagnetic interactions in these alloys. Further, the critical behavior of the austenite phase of both the alloys is studied and the values of the critical exponents are found to be different from the mean field values, which is attributed to the magnetic inhomogeneity originated due to Ge substitution. (C) 2015 AIP Publishing LLC

Tuning the structural and magnetocaloric properties of Gd5Si2Ge2 with Nd substitution

Structural and magnetocaloric properties of Nd substituted Gd5-xNdxSi2Ge2 with x = 0.05, 0.1, and 0.2 have been investigated. The composition with x = 0.05 crystallizes in monoclinic Gd5Si2Ge2 structure with P112(1)/a space group and undergoes a first order phase transition with a Curie temperature of 275 K. With increase in Nd content to x = 0.1, the compound is found to stabilize in orthorhombic Gd5Si4 phase with Pnma space group. The compounds with x = 0.1 and 0.2 undergoes a second order magnetic transition at 300K and 293 K, respectively. Temperature variation of maximum entropy change for Gd5-xNdxSi2Ge2 alloys with x = 0.05, 0.1, and 0.2 are 7.9, 3.7, and 3.2 J/kg K, respectively, for a field change of 20 kOe, and 12.8, 7.6, and 7.2 J/kg K, respectively, for 50 kOe. A large relative cooling power of 295, 205, and 188 J/kg are obtained for x = 0.05, 0.1, and 0.2, respectively, fulfilling the required criteria for a potential magnetic refrigerant in the room temperature regime. (C) 2015 AIP Publishing LLC

In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

Maya Sreeranganathan,1 Saji Uthaman,2 Bruno Sarmento,3–5 Chethampadi Gopi Mohan,1 In-Kyu Park,1 Rangasamy Jayakumar2 1Centre for Nanosciences and Molecular Medicine, Amrita University, Kochi, India; 2Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju, Republic of Korea; 3I3S – Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal, 4INEB – Instituto de Engenharia Biomédica, University of Porto, Porto, Portugal, 5CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra, Portugal Abstract: Epidermal growth factor receptor (EGFR), upregulated in gastric cancer patients, is an oncogene of interest in the development of targeted cancer nanomedicines. This study demonstrates in silico modeling of monoclonal antibody cetuximab (CET MAb)-conjugated docetaxel (DOCT)-loaded poly(γ-glutamic acid) (γ-PGA) nanoparticles (Nps) and evaluates the in vitro/in vivo effects on EGFR-overexpressing gastric cancer cells (MKN-28). Nontargeted DOCT-γ-PGA Nps (NT Nps: 110±40 nm) and targeted CET MAb-DOCT-γ-PGA Nps (T Nps: 200±20 nm) were prepared using ionic gelation followed by 1-Ethyl-3-(3-dimethyl aminopropyl)carbodiimide­– N-Hydoxysuccinimide (EDC­– NSH) chemistry. Increased uptake correlated with enhanced cytotoxicity induced by targeted Nps to EGFR +ve MKN-28 compared with nontargeted Nps as evident from MTT and flow cytometric assays. Nanoformulated DOCT showed a superior pharmacokinetic profile to that of free DOCT in Swiss albino mice, indicating the possibility of improved therapeutic effect in the disease model. Qualitative in vivo imaging showed early and enhanced tumor targeted accumulation of CET MAb-DOCT-γ-PGA Nps in EGFR +ve MKN-28–based gastric cancer xenograft, which exhibited efficient arrest of tumor growth compared with nontargeted Nps and free DOCT. Thus, actively targeted CET MAb-DOCT-γ-PGA Nps could be developed as a substitute to conventional nonspecific chemotherapy, and hence could become a feasible strategy for cancer therapy for EGFR-overexpressing gastric tumors. Keywords: targeted nanoparticles, poly(γ-glutamic acid) nanoparticles, docetaxel, cetuximab, epidermal growth factor receptor, gastric cance

Structural properties, magnetic interactions, magnetocaloric effect and critical behaviour of cobalt doped La0.7Te0.3MnO3

The effect of cobalt doping on the structural, magnetic and magnetocaloric properties of electron-doped manganite La0.7Te0.3Mn1-xCoxO3 (x = 0, 0.1, 0.2, 0.25, 0.3 and 0.5) has been investigated. The parent compound La0.7Te0.3MnO3 crystallizes in a rhombohedral structure with R (3) over barc space group. With the increase in Co concentration to x = 0.2, a structural transition from rhombohedral (R (3) over barc space group) to orthorhombic (Pbnm space group) is observed. X-ray photoelectron spectroscopy (XPS) indicates that the structural transition is due to the disordered distribution of Mn2+/Mn3+ and Co2+/Co3+ ions. All the samples undergo a paramagnetic-ferromagnetic (PM-FM) phase transition. With the increase in Co content to x = 0.1, the unit cell volume increases with a decrease in both Mn-O-Mn bond angle and T-c indicating a weakening of the double exchange interaction. However, with further increase in Co concentration, T-c increases. The presence of competing ferromagnetic and antiferromagnetic interactions leads to a glassy behaviour at low temperatures for low Co doping concentrations. However, for higher Co concentrations, no such behaviour is observed. Arrott plots reveal a second order nature of magnetic transition for all the samples. The magnetic exchange interactions for x = 0.3 and 0.5 follow the mean-field model. Magnetization results show that the magnetocaloric property of the electron-doped manganite is affected by the substitution of Co at Mn sites. Relatively large values of relative cooling power and broad temperature interval of the magnetocaloric effect make the present compounds promising for sub-room temperature magnetic refrigeration applications

Recovery facilitation services in a mental health setting: the Institute of Mental Health and Neurosciences (IMHANS) model

Chronic psychiatric illnesses cause disability. The language of recovery is now widely used globally in mental health policy, services, and research. This concept of recovery is relatively new to Indian mental health settings. The Recovery Facilitation Services initiated at the Institute of Mental Health and Neurosciences (IMHANS), Kozhikode (Calicut), Kerala, South India, follows a framework for service delivery based on sound principles of psychosocial rehabilitation. This paper elaborates on the rationale, the design, financial aspects, challenges encountered, and general observations regarding the effectiveness of the working of this service