Trellis Bioscience (United States)

The U.S. Department of the Navy (DoN) has made several investments into mobile troposcatter communications to support resilient communications. The Navy today relies on satellite communications (SATCOM) and High Frequency (HF) communications for beyond line-of-sight (BLOS) communications. This paper presents the results from several measurement campaigns which include a static terrestrial link, an on-the-move terrestrial vehicular link, and a maritime on-the-move ship-to-shore link. All of these rapid prototyping experimentation activities demonstrate that links over 100-miles are viable using troposcatter as a transmission modality. To the authors knowledge, the reported results represent the longest distance maritime on-the-move troposcatter link which has been demonstrated to date.

Bacterial biofilms on orthopedic implants are resistant to the host immune response and to traditional systemic antibiotics. Novel therapies are needed to improve patient outcomes. TRL1068 is a human monoclonal antibody (mAb) against a biofilm anchoring protein. For assessment of this agent in an orthopedic implant infection model, efficacy was measured by reduction in bacterial burden of Staphylococcus aureus, the most common pathogen for prosthetic joint infections (PJI). Systemic treatment with the biofilm disrupting mAb TRL1068 in conjunction with vancomycin eradicated S. aureus from steel pins implanted in the spine for 26 of 27 mice, significantly more than for vancomycin alone. The mechanism of action was elucidated by two microscopy studies. First, TRL1068 was localized to biofilm using a fluorescent antibody tag. Second, a qualitative effect on biofilm structure was observed using scanning electron microscopy (SEM) to examine steel pins that had been treated in vivo. SEM images of implants retrieved from control mice showed abundant three-dimensional biofilms, whereas those from mice treated with TRL1068 did not. Clinical Significance: TRL1068 binds at high affinity to S. aureus biofilms, thereby disrupting the three-dimensional structure and significantly reducing implant CFUs in a well-characterized orthopedic model for which prior tested agents have shown only partial efficacy. TRL1068 represents a promising systemic treatment for orthopedic implant infection.

The development of therapeutics for cytomegalovirus (CMV) infections, while progressing, has not matched the pace of new treatments of human immunodeficiency virus (HIV) infections; nevertheless, recent developments in the treatment of CMV infections have resulted in improved human health and perhaps will encourage the development of new therapeutic approaches. First, the deployment of ganciclovir and valganciclovir for both the prevention and treatment of CMV infections and disease in transplant recipients has been further improved with the licensure of the efficacious and less toxic letermovir. Regardless, late-onset CMV disease, specifically pneumonia, remains problematic. Second, the treatment of congenital CMV infections with valganciclovir has beneficially improved both hearing and neurologic outcomes, both fundamental advances for these children. In these pediatric studies, viral load was decreased but not eliminated. Thus, an important lesson learned from studies in both populations is the need for new antiviral agents and the necessity for combination therapies as has been shown to be beneficial in the treatment of HIV infections, among others. The development of monoclonal antibodies, sirtuins, and cyclopropovir may provide new treatment options.

We have previously described a native human monoclonal antibody, TRL1068, that disrupts bacterial biofilms by extracting from the biofilm matrix key scaffolding proteins in the DNABII family, which are present in both gram positive and gram negative bacterial species. The antibiotic resistant sessile bacteria released from the biofilm then revert to the antibiotic sensitive planktonic state. Qualitative resensitization to antibiotics has been demonstrated in three rodent models of acute infections. We report here the surprising discovery that antibodies against the target family were found in all twenty healthy humans surveyed, albeit at a low level requiring a sensitive single B-cell assay for detection. We have cloned 21 such antibodies. Aside from TRL1068, only one (TRL1330) has all the biochemical properties believed necessary for pharmacological efficacy (broad spectrum epitope specificity and high affinity). We suggest that the other anti-DNABII antibodies, while not necessarily curative, reflect an immune response at some point in the donor’s history to these components of biofilms. Such an immune response could reflect exposure to bacterial reservoirs that have been previously described in chronic non-healing wounds, periodontal disease, chronic obstructive pulmonary disease, colorectal cancer, rheumatoid arthritis, and atherosclerotic artery explants. The detection of anti-DNABII antibodies in all twenty surveyed donors with no active infection suggests that bacterial biofilm reservoirs may be present periodically in most healthy individuals. Biofilms routinely shed bacteria, creating a continuous low level inflammatory stimulus. Since chronic subclinical inflammation is thought to contribute to most aging-related diseases, suppression of bacterial biofilm has potential value in delaying age-related pathology.

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Many serious bacterial infections are difficult to treat due to biofilm formation, which provides physical protection and induces a sessile phenotype refractory to antibiotic treatment compared to the planktonic state. A key structural component of biofilm is extracellular DNA, which is held in place by secreted bacterial proteins from the DNABII family: integration host factor (IHF) and histone-like (HU) proteins. A native human monoclonal antibody, TRL1068, has been discovered using single B-lymphocyte screening technology. It has low-picomolar affinity against DNABII homologs from important Gram-positive and Gram-negative bacterial pathogens. The disruption of established biofilm was observedin vitroat an antibody concentration of 1.2 μg/ml over 12 h. The effect of TRL1068in vivowas evaluated in a murine tissue cage infection model in which a biofilm is formed by infection with methicillin-resistantStaphylococcus aureus(MRSA; ATCC 43300). Treatment of the established biofilm by combination therapy of TRL1068 (15 mg/kg of body weight, intraperitoneal [i.p.] administration) with daptomycin (50 mg/kg, i.p.) significantly reduced adherent bacterial count compared to that after daptomycin treatment alone, accompanied by significant reduction in planktonic bacterial numbers. The quantification of TRL1068 in sample matrices showed substantial penetration of TRL1068 from serum into the cage interior. TRL1068 is a clinical candidate for combination treatment with standard-of-care antibiotics to overcome the drug-refractory state associated with biofilm formation, with potential utility for a broad spectrum of difficult-to-treat bacterial infections.

A wideband HF NVIS measurement campaign in Southern California collected 7 terabytes of channel sounding across 2–12 MHz from 72 days of data collection between October 2014 and February 2015. This massive dataset demonstrates that the traditional HF NVIS channel models are ill-suited to describe the observed HF NVIS propagation phenomena. In particular, it is observed that the HF NVIS channel is often non-stationary over a few minutes; with taps rapidly shifting in delay, exhibiting abrupt changes in phase characteristics, and periodic variations in magnitude—all having significant implications on modem design, e.g. block length, preamble length and repetition rate, interleaving size, and modulation type. To this end, this study summarizes the empirical findings of the delay and Doppler characteristics, as well as the non-traditional fading modes, of wideband HF NVIS channels.

We consider a cooperative data exchange problem with the goal of generating a secret key. Specifically, we investigate the number of public transmissions required for a set of clients to agree on a secret key with probability one, subject to the constraint that it remains private from an eavesdropper. Although the problems are closely related, we prove that secret key generation with fewest linear transmissions is NP-hard, while it is known that the analogous problem in traditional cooperative data exchange can be solved in polynomial time. In doing this, we completely characterize the best-possible performance of linear coding schemes, and also prove that linear codes can be strictly suboptimal.

The mitigation of in-band interference from co-located emitters is an increasingly important problem in commercial and military wireless communications systems design. In this work, we present a co-located interference mitigation approach that is targeted for scenarios in which the interfering signal is received at an extremely high power and the delay between the received (over-the-air) and reference (wired) copies of the interferer is not negligible. Such scenarios are common in military applications (e.g., simultaneous jamming and communications). The proposed Joint Analog and Digital Interference Cancellation (JADIC) system is self-configuring and can provide over 100 dB of suppression of wideband and narrowband jammers.