On the String Consensus Problem and the Manhattan Sequence Consensus Problem

In the Manhattan Sequence Consensus problem (MSC problem) we are given $k$ integer sequences, each of length $l$, and we are to find an integer sequence $x$ of length $l$ (called a consensus sequence), such that the maximum Manhattan distance of $x$ from each of the input sequences is minimized. For binary sequences Manhattan distance coincides with Hamming distance, hence in this case the string consensus problem (also called string center problem or closest string problem) is a special case of MSC. Our main result is a practically efficient $O(l)$-time algorithm solving MSC for $k\le 5$ sequences. Practicality of our algorithms has been verified experimentally. It improves upon the quadratic algorithm by Amir et al.\ (SPIRE 2012) for string consensus problem for $k=5$ binary strings. Similarly as in Amir's algorithm we use a column-based framework. We replace the implied general integer linear programming by its easy special cases, due to combinatorial properties of the MSC for $k\le 5$. We also show that for a general parameter $k$ any instance can be reduced in linear time to a kernel of size $k!$, so the problem is fixed-parameter tractable. Nevertheless, for $k\ge 4$ this is still too large for any naive solution to be feasible in practice.Comment: accepted to SPIRE 201

Targeted Mutagenesis of a Therapeutic Human Monoclonal IgG1 Antibody Prevents Gelation at High Concentrations

A common challenge encountered during development of high concentration monoclonal antibody formulations is preventing self-association. Depending on the antibody and its formulation, self-association can be seen as aggregation, precipitation, opalescence or phase separation. Here we report on an unusual manifestation of self-association, formation of a semi-solid gel or “gelation”. Therapeutic monoclonal antibody C4 was isolated from human B cells based on its strong potency in neutralizing bacterial toxin in animal models. The purified antibody possessed the unusual property of forming a firm, opaque white gel when it was formulated at concentrations \u3e40 mg/mL and the temperature wa

Structure-based Design of Broadly Neutralizing HCV Antibody and Vaccine

Hepatitis C virus (HCV) chronically infects nearly 200 million people worldwide. Antibodies have the potential to prevent establishment of chronic HCV infection in individuals exposed to the virus. Several broadly neutralizing monoclonal antibodies capable of binding HCV surface glycoproteins have been identified, including HCV1 identified by MassBiologics at UMMS, which targets a highly conserved linear epitope. We utilized the recently solved structure of the HCV1-bound epitope to identify regions of the antibody that could be modified to potentially improve binding to a mutation (N415K) which facilitates escape from neutralization. Based on systematic in silico mutagenesis of HCV1 residues in the Rosetta protein modeling program, a number of single or double antibody mutants were selected for in vitro evaluation. The mutated antibodies were synthesized and their ability to neutralize HCV pseudoviruses expressing either wild-type epitope sequence or the N415K variant was evaluated. Antibodies with mutations on the heavy chain, R65Q and V50L, demonstrated improved neutralizing activity against the N415K escape mutant without impacting their ability to neutralize wild type virus. We also sought to design a novel HCV vaccine that could focus the response to a small conserved neutralizing epitope of the virus defined by HCV1. The HCV1 epitope structure was used to search a large dataset of known protein structures from the Protein Data Bank, resulting in designs of scaffolds that were predicted to stably accommodate the epitope. These epitope-presenting scaffold proteins have been made and will be screened in animal studies to determine their potential as vaccine candidates for HCV prevention

Confronting a post-pandemic new-normal—threats and opportunities to trust-based relationships in natural resource science and management

Natural resource governance is inherently complex owing to the socio-ecological systems in which it is embedded. Working arrangements have been fundamentally transformed throughout the COVID-19 pandemic with potential negative impacts on trust-based social networks foundational to resource management and transboundary governance. To inform development of a post-pandemic new-normal in resource management, we examined trust relationships using the Laurentian Great Lakes of North America as a case study. 82.9% (n = 97/117) of Great Lakes fishery managers and scientists surveyed indicated that virtual engagement was effective for maintaining well-established relationships during the pandemic; however, 76.7% (n = 89/116) of respondents indicated in-person engagement to be more effective than virtual engagement for building and maintaining trust. Despite some shortcomings, virtual or remote engagement presents opportunities, such as: (1) care and nurturing of well-established long-term relationships; (2) short-term (1–3 years) trust maintenance; (3) peer-peer or mentor-mentee coordination; (4) supplemental communications; (5) producer-push knowledge dissemination; and, if done thoughtfully, (6) enhancing diversity, equity, and inclusion. Without change, pre-pandemic trust-based relationships foundational to cooperative, multinational, resource management are under threat

Not just another genome

Sequence analysis of the Daphnia pulex genome holds some surprises that could not have been anticipated from what was learned so far from other arthropod genomes. It establishes Daphnia as an eco-genetical model organism par excellence

Arachidonic acid metabolism by canine tracheal epithelial cells. Product formation and relationship to chloride secretion.

Les cellules épithéliales de trachée de chien, sous l'effet de l'ionophore calcique A23187 métabolisent l'acide arachidonique par la prostaglandine H synthase (prostaglandine D2) et des lipoxygénases (leukotriènes B4et C4). La prostaglandine D2stimule la sécrétion de Cl−(inhibition par l'indométhacine). Expériences de marquages, HPLC en phase inversée, spectrographie de masse, chromatographies en phase gazeuse et sur couche mince, essai radioimmunologique, mesures d'Isc

Structure-Based Design of Hepatitis C Virus Vaccines That Elicit Neutralizing Antibody Responses to a Conserved Epitope

Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response; thus, an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412 to 423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope. This resulted in epitope-based immunogens based on a cyclic defensin protein, as well as a bivalent immunogen with two copies of the epitope on the E2 surface. We solved the X-ray structure of a cyclic immunogen in complex with the HCV1 antibody and confirmed preservation of the epitope conformation and the HCV1 interface. Mice vaccinated with our designed immunogens produced robust antibody responses to epitope I, and their serum could neutralize HCV. Notably, the cyclic designs induced greater epitope-specific responses and neutralization than the native peptide epitope. Beyond successfully designing several novel HCV immunogens, this study demonstrates the principle that neutralizing anti-HCV antibodies can be induced by epitope-based, engineered vaccines and provides the basis for further efforts in structure-based design of HCV vaccines. IMPORTANCE: Hepatitis C virus is a leading cause of liver disease and liver cancer, with approximately 3% of the world\u27s population infected. To combat this virus, an effective vaccine would have distinct advantages over current therapeutic options, yet experimental vaccines have not been successful to date, due in part to the virus\u27s high sequence variability leading to immune escape. In this study, we rationally designed several vaccine immunogens based on the structure of a conserved epitope that is the target of broadly neutralizing antibodies. In vivo results in mice indicated that these antigens elicited epitope-specific neutralizing antibodies, with various degrees of potency and breadth. These promising results suggest that a rational design approach can be used to generate an effective vaccine for this virus

Combinations of β-lactam or aminoglycoside antibiotics with plectasin are synergistic against methicillin-sensitive and methicillin-resistant Staphylococcus aureus.

Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and the latter can be difficult to treat. The traditional strategy of novel therapeutic drug development inevitably leads to emergence of resistant strains, rendering the new drugs ineffective. Therefore, rejuvenating the therapeutic potentials of existing antibiotics offers an attractive novel strategy. Plectasin, a defensin antimicrobial peptide, potentiates the activities of other antibiotics such as β-lactams, aminoglycosides and glycopeptides against MSSA and MRSA. We performed in vitro and in vivo investigations to test against genetically diverse clinical isolates of MSSA (n = 101) and MRSA (n = 115). Minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. The effects of combining plectasin with β-lactams, aminoglycosides and glycopeptides were examined using the chequerboard method and time kill curves. A murine neutropenic thigh model and a murine peritoneal infection model were used to test the effect of combination in vivo. Determined by factional inhibitory concentration index (FICI), plectasin in combination with aminoglycosides (gentamicin, neomycin or amikacin) displayed synergistic effects in 76-78% of MSSA and MRSA. A similar synergistic response was observed when plectasin was combined with β-lactams (penicillin, amoxicillin or flucloxacillin) in 87-89% of MSSA and MRSA. Interestingly, no such interaction was observed when plectasin was paired with vancomycin. Time kill analysis also demonstrated significant synergistic activities when plectasin was combined with amoxicillin, gentamicin or neomycin. In the murine models, plectasin at doses as low as 8 mg/kg augmented the activities of amoxicillin and gentamicin in successful treatment of MSSA and MRSA infections. We demonstrated that plectasin strongly rejuvenates the therapeutic potencies of existing antibiotics in vitro and in vivo. This is a novel strategy that can have major clinical implications in our fight against bacterial infections