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Influenza viruses remain a severe threat to human health, causing up to 650,000 deaths annually1,2. Seasonal influenza virus vaccines can prevent infection, but are rendered ineffective by antigenic drift. To provide improved protection from infection, novel influenza virus vaccines that target the conserved epitopes of influenza viruses, specifically those in the hemagglutinin stalk and neuraminidase, are currently being developed3. Antibodies against the hemagglutinin stalk confer protection in animal studies4–6. However, no data exist on natural infections in humans, and these antibodies do not show activity in the hemagglutination inhibition assay, the hemagglutination inhibition titer being the current correlate of protection against influenza virus infection7–9. While previous studies have investigated the protective effect of cellular immune responses and neuraminidase-inhibiting antibodies, additional serological correlates of protection from infection could aid the development of broadly protective or universal influenza virus vaccines10–13. To address this gap, we performed a household transmission study to identify alternative correlates of protection from infection and disease in naturally exposed individuals. Using this study, we determined 50% protective titers and levels for hemagglutination inhibition, full-length hemagglutinin, neuraminidase and hemagglutinin stalk-specific antibodies. Further, we found that hemagglutinin stalk antibodies independently correlated with protection from influenza virus infection.Study of influenza virus transmission in humans provides evidence that hemagglutinin stalk-specific antibodies correlate with protection from infection.

Inhibitory interneurons are integral to sensory processing, yet revealing their cell type-specific roles in sensory circuits remains an ongoing focus. To Investigate the mouse olfactory system, we selectively remove GABAergic transmission from a subset of olfactory bulb interneurons, EPL interneurons (EPL-INs), and assay odor responses from their downstream synaptic partners — tufted cells and mitral cells. Using a combination of in vivo electrophysiological and imaging analyses, we find that inactivating this single node of inhibition leads to differential effects in magnitude, reliability, tuning width, and temporal dynamics between the two principal neurons. Furthermore, tufted and not mitral cell responses to odor mixtures become more linearly predictable without EPL-IN inhibition. Our data suggest that olfactory bulb interneurons, through exerting distinct inhibitory functions onto their different synaptic partners, play a significant role in the processing of odor information. The precise cell-type specific role of inhibitory interneurons in regulating sensory responses in the olfactory bulb is not known. Here, the authors report that removing GABAergic inhibition from one layer differentially affects response dynamics of the two main output cell types and changes odor mixture processing.

An individual’s antibody titers to influenza A strains are a result of the complicated interplay between infection history, cross-reactivity, immune waning, and other factors. It has been challenging to disentangle how population-level patterns of humoral immunity change as a function of age, calendar year, and birth cohort from cross-sectional data alone. We analyzed 1,589 longitudinal sera samples from 260 children across three studies in Nicaragua, 2006–16. Hemagglutination inhibition (HAI) titers were determined against four H3N2 strains, one H1N1 strain, and two H1N1pdm strains. We assessed temporal patterns of HAI titers using an age–period–cohort modeling framework. We found that titers against a given virus depended on calendar year of serum collection and birth cohort but not on age. Titer cohort patterns were better described by participants’ ages relative to year of likely introduction of the virus’s antigenic cluster than by age relative to year of strain introduction or by year of birth. These cohort effects may be driven by a decreasing likelihood of early-life infection after cluster introduction and by more broadly reactive antibodies at a young age. H3N2 and H1N1 viruses had qualitatively distinct cohort patterns, with cohort patterns of titers to specific H3N2 strains reaching their peak in children born 3 years prior to that virus’s antigenic cluster introduction and with titers to H1N1 and H1N1pdm strains peaking for children born 1–2 years prior to cluster introduction but not being dramatically lower for older children. Ultimately, specific patterns of strain circulation and antigenic cluster introduction may drive population-level antibody titer patterns in children.

Despite activity as single agent cancer therapies, Rapamycin (rapa) and its rapalogs may have their greatest effects when combined with other therapeutic modalities. In addition to direct antitumor activity, rapalogs reverse multiple tumor-intrinsic immune evasion mechanisms. These should facilitate tumor-specific T cell activity, but since rapa directly inhibits effector T cells, this potential immune enhancement is lost. We hypothesized that if T cells were rendered resistant to rapa they could capitalize on its downregulation of tumor immune evasion. We therefore modified T cells with a rapa-resistant mutant of mTor, mTorRR, and directed them to B lymphomas by coexpressing a chimeric antigen receptor (CAR) for CD19 (CAR.CD19-28ζ). T cells expressing transgenic mTorRR from a piggyBac transposon maintain mTor signaling, proliferate in the presence of rapa and retain their cytotoxic function and ability to secrete interferon-γ (IFNγ) after stimulation, effector functions that were inhibited by rapa in control T cells. In combination, rapa and rapa-resistant-CAR.CD19-28ζ-expressing T cells produced greater antitumor activity against Burkitt's lymphoma and pre-B ALL cell lines in vitro than CAR.CD19-28ζ T cells or rapa alone. In conclusion, the combination of rapa and rapa-resistant, CAR.CD19-28ζ-expressing T cells may provide a novel therapy for the treatment of B cell malignancies and other cancers.

The extracellular matrix of epithelial tumors undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How matrix integrity is maintained in the face of dynamic biophysical forces is largely undefined. Here we investigated the role of fibulin-2, a matrix glycoprotein that functions biomechanically as an inter-molecular clasp and thereby facilitates supra-molecular assembly. Fibulin-2 was abundant in the extracellular matrix of human lung adenocarcinomas and was highly expressed in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma from co-expression of mutant K-ras and p53. Loss-of-function experiments in tumor cells revealed that fibulin-2 was required for tumor cells to grow and metastasize in syngeneic mice, a surprising finding given that other intra-tumoral cell types are known to secrete fibulin-2. However, tumor cells grew and metastasized equally well in Fbln2-null and -wild-type littermates, implying that malignant progression was dependent specifically upon tumor cell-derived fibulin-2, which could not be offset by other cellular sources of fibulin-2. Fibulin-2 deficiency impaired the ability of tumor cells to migrate and invade in Boyden chambers, to create a stiff extracellular matrix in mice, to cross-link secreted collagen, and to adhere to collagen. We conclude that fibulin-2 is a driver of malignant progression in lung adenocarcinoma and plays an unexpected role in collagen cross-linking and tumor cell adherence to collagen.

Haemophilus influenzae (Hi) colonizes the human respiratory tract and is an important pathogen associated with chronic obstructive pulmonary disease (COPD). Bacterial factors that interact with the human host may be important in the pathogenesis of COPD. These factors, however, have not been well defined. The overall goal of this study was to identify bacterial genetic elements with increased prevalence among H. influenzae strains isolated from patients with COPD compared to those isolated from the pharynges of healthy individuals. Four nontypeable H. influenzae (NTHi) strains, two isolated from the airways of patients with COPD and two from a healthy individual, were subjected to whole genome sequencing using 454 FLX Titanium technology. COPD strain-specific genetic islands greater than 500 bp in size were identified by in silico subtraction. Open reading frames residing within these islands include known Hi virulence genes such as lic2b, hgbA, iga, hmw1 and hmw2, as well as genes encoding urease and other enzymes involving metabolic pathways. The distributions of seven selected genetic islands were assessed among a panel of 421 NTHi strains of both disease and commensal origins using a Library-on-a-Slide high throughput dot blot DNA hybridization procedure. Four of the seven islands screened, containing genes that encode a methyltransferase, a dehydrogenase, a urease synthesis enzyme, and a set of unknown short ORFs, respectively, were more prevalent in COPD strains than in colonizing strains with prevalence ratios ranging from 1.21 to 2.85 (p ≤ 0.0002). Surprisingly, none of these sequences show increased prevalence among NTHi isolated from the airways of patients with cystic fibrosis. Our data suggest that specific bacterial genes, many involved in metabolic functions, are associated with the ability of NTHi strains to survive in the lower airways of patients with COPD.

Immunosuppression of tumour-infiltrating lymphocytes (TIL) is a common feature of advanced cancer, but its biological basis has remained obscure. We demonstrate here a molecular link between epithelial-to-mesenchymal transition (EMT) and CD8 + TIL immunosuppression, two key drivers of cancer progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumour cells, leading to CD8 + T-cell immunosuppression and metastasis. These findings are supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets. In addition to revealing a link between EMT and T-cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists. Tumour-infiltrating lymphocytes (TILs) can be suppressed by the tumour, but how this occurs is not clear. Here the authors show that the miR-200 family, which suppresses epithelial–mesenchymal transition, also targets tumour cell PD-L1 and thereby intratumoral immunosuppression and metastasis.

This paper implements Teaching-Learning based optimization (TLBO) to obtain optimized value of spring stiffness for better ride comfort. Further, this optimized value is then used in a semi-active quarter car setup to remove any discrepancies due to non-optimized spring. This paper also introduces a novel approach to control the Semi-active suspension parameter (damping coefficient) for a better performance. For controlling semi-active parameters, PID controller has been used. PID controller output is fed to the quarter car setup as a damping coefficient. Thus changing the damping coefficient dynamically as the disturbance occurs, and thus improving the ride comfort. The sprung mass acceleration and rattle space of semi-active quarter car has been compared with sprung mass acceleration and rattle space of passive quarter car model to show the difference in results and thereby, results and conclusions are drawn.

Thrombocytopenia can be seen in about 20-25% of patients with bacterial infective endocarditis (IE). Platelets have a major role in the pathogenesis of endocarditis, and they are also sensitive monitors of systemic host response to bacteremia. Thrombocytopenia on presentation of patients with IE identifies higher risk groups and carries higher mortality risk. The presence of thrombocytopenia is an independent prognosticator of poor outcomes in IE. We present a case of a 40-year-old male with the history of injection drug use who was diagnosed with IE and was found to have severe thrombocytopenia on admission was treated with intravenous antibiotics, which dramatically improved his platelet counts as well without any need for plasmapheresis or platelet transfusions.

Tobacco use, and thus tobacco-related morbidity, is elevated amongst patients with behavioral health treatment needs. Consequently, it is important that centers providing health care to this group mandate providers’ use of tobacco screenings to inform the need for tobacco use disorder intervention. This study examined the prevalence of mandated tobacco screenings in 80 centers providing health care to Texans with behavioral health needs, examined key factors that could enhance screening conduct, and delineated providers’ perceived barriers to tobacco use intervention provision. The results indicated that 80% of surveyed centers mandated tobacco use screenings; those that did were significantly more likely than those that did not to have a hard stop for tobacco use status in health records and were marginally more likely to make training on tobacco screening available to providers. The most widespread barriers to tobacco use disorder care provision were relative perceived importance of competing diagnoses, lack of community resources to refer patients, perceived lack of time, lack of provider knowledge or confidence, and belief that patients do not comply with cessation treatment. Overall, the results suggest that there are opportunities for centers providing care to Texans with behavioral health needs to bolster their tobacco screening and intervention capacity to better address tobacco-related health disparities in this group. Health care centers can support their providers to intervene in tobacco use by mandating screenings, streamlining clinical workflows with hard stops in patient records, and educating providers about the importance of treating tobacco with brief evidence-based intervention strategies while providing accurate information about patients’ interest in quitting and providers’ potential impacts on a successful quit attempt.