Intracellular Delivery of Therapeutic Biomolecules through Versatile Polymer Nanotechnology

Advancing pharmaceutical technology has made it possible to treat diseases once considered ‘undruggable.’ Access to these new pharmaceutical targets is possible thanks to the advent of protein and nucleic acid therapeutics. Responses to the COVID-19 pandemic, as well as cutting-edge treatments for cancer and multiple sclerosis have centered on these biologic therapies, promising even greater value in the future. However, their utility is limited at a cellular level by inability to cross the plasma membrane. Nanocarrier technologies encapsulate therapeutics and facilitate uptake into the cell but are often trapped and degraded in endosomes. Arginine-functionalized gold nanoparticles (Arg-NPs) provide efficient, direct cytosolic delivery of various co-engineered proteins, including protein-based CRISPR/Cas9 gene editing machinery. Guanidinium-functionalized poly(oxanorbornene)imide (PONI-Guan) polymers replicate key features of Arg-NPs to provide cytosolic delivery of a range of proteins and nucleic acids under physiologically relevant conditions. My work demonstrated the incredible versatility of PONI-Guan nanocarriers, investigating their capacity for long-term storage through lyophilization, incorporation of a multi-component non-covalent delivery complex, and their ability to transfect both small and larger nucleic acids with high efficiency. My work also helped to demonstrate tropism of PONI-Guan nanoassemblies to inflamed lung tissue, providing a powerful approach to treating inflammatory diseases in the lung. This thesis demonstrates a highly versatile, modular polymer platform for the efficient cytosolic delivery of proteins and nucleic acids under physiological conditions and in a wide range of cell types, revealing a powerful direction for translatability in the treatment of pulmonary inflammation

The Edge-Connectivity of Vertex-Transitive Hypergraphs

A graph or hypergraph is said to be vertex-transitive if its automorphism group acts transitively upon its vertices. A classic theorem of Mader asserts that every connected vertex-transitive graph is maximally edge-connected. We generalise this result to hypergraphs and show that every connected linear uniform vertex-transitive hypergraph is maximally edge-connected. We also show that if we relax either the linear or uniform conditions in this generalisation, then we can construct examples of vertex-transitive hypergraphs which are not maximally edge-connected.Comment: 8 page

Existential Closure in Line Graphs

A graph $G$ is $n$-existentially closed if, for all disjoint sets of vertices $A$ and $B$ with $|A\cup B|=n$, there is a vertex $z$ not in $A\cup B$ adjacent to each vertex of $A$ and to no vertex of $B$. In this paper, we investigate $n$-existentially closed line graphs. In particular, we present necessary conditions for the existence of such graphs as well as constructions for finding infinite families of such graphs. We also prove that there are exactly two $2$-existentially closed planar line graphs. We then consider the existential closure of the line graphs of hypergraphs and present constructions for $2$-existentially closed line graphs of hypergraphs.Comment: 13 pages, 2 figure

Wound Debridement with 25 kHz Ultrasound

Several methods of wound debridement are described in the literature and are available to health care providers who specialize in wound management. Methods include the use of sharp surgical instruments; mechanical methods, such as whirlpool and pulsed lavage with suction; proteolytic and collagenolytic enzymes; autolysis; and sterile fly larvae (maggots). The use of surgical debridement is generally considered the most efficient method when performed by a skilled physician, who may in one session use his or her discretion to excise some viable tissue along with necrotic tissue in the wound. Sharp debridement performed in a clinical setting is a less aggressive procedure performed by physicians and other qualified health care practitioners. This method selectively removes eschar and slough as well as adherent fibrin, the latter with significant difficulty and time consumption. Frequently, sharp, selective removal of nonviable tissue is limited in efficacy owing to only partial removal of fibrin and/or intolerable pain experienced by the patient. The other debridement methods mentioned are primarily intended for selective removal of eschar, slough, and fibrin, of which fibrin may require several days to a few weeks for complete removal. The purpose of this article is to describe a new type of debridement that uses ultrasound technology to remove necrotic tissue. In the authors\u27 preliminary experience, this method appears to have the potential to be a breakthrough for wound cleansing and debridement of adherent fibrin

Engineering the Interface between Inorganic Nanoparticles and Biological Systems through Ligand Design

Nanoparticles (NPs) provide multipurpose platforms for a wide range of biological applications. These applications are enabled through molecular design of surface coverages, modulating NP interactions with biosystems. In this review, we highlight approaches to functionalize nanoparticles with “small” organic ligands (Mw \u3c 1000), providing insight into how organic synthesis can be used to engineer NPs for nanobiology and nanomedicine

Effects of a regenerating matrix on the survival of birds in tropical forest fragments

Background Vast areas of lowland neotropical forest have regenerated after initially being cleared for agricultural purposes. The ecological value of regenerating second growth to forest-dwelling birds may largely depend on the age of the forest, associated vegetative structure, and when it is capable of sustaining avian demographics similar to those found in pristine forest. Methods To determine the influence of second growth age on bird demography, we estimated the annual survival of six central Amazonian bird species residing in pristine forest, a single 100 and a single 10 ha forest fragment, taking into consideration age of the surrounding matrix (i.e. regenerating forest adjacent to each fragment) as an explanatory variable. Results Study species exhibited three responses: arboreal, flocking and ant-following insectivores (Willisornis poecilinotus, Thamnomanes ardesiacus and Pithys albifrons) showed declines in survival associated with fragmentation followed by an increase in survival after 5 years of matrix regeneration. Conversely, Percnostola rufifrons, a gap-specialist, showed elevated survival in response to fragmentation followed by a decline after 5 years of regeneration. Lastly, facultative flocking and frugivore species (Glyphorynchus spirurus and Dixiphia pipra, respectively) showed no response to adjacent clearing and subsequent regeneration. Conclusions Our results in association with previous studies confirm that the value of regenerating forest surrounding habitat patches is dependent on two factors: ecological guild of the species in question and second growth age. Given the rapid increase in survival following succession, we suggest that the ecological value of young tropical forest should not be based solely on a contemporary snapshot, but rather, on the future value of mature second growth as well

Effects of a regenerating matrix on the survival of birds in tropical forest fragments

Background: Vast areas of lowland neotropical forest have regenerated after initially being cleared for agricultural purposes. The ecological value of regenerating second growth to forest-dwelling birds may largely depend on the age of the forest, associated vegetative structure, and when it is capable of sustaining avian demographics similar to those found in pristine forest. Methods: To determine the influence of second growth age on bird demography, we estimated the annual survival of six central Amazonian bird species residing in pristine forest, a single 100 and a single 10 ha forest fragment, taking into consideration age of the surrounding matrix (i.e. regenerating forest adjacent to each fragment) as an explanatory variable. Results: Study species exhibited three responses: arboreal, flocking and ant-following insectivores (Willisornis poecilinotus, Thamnomanes ardesiacus and Pithys albifrons) showed declines in survival associated with fragmentation followed by an increase in survival after 5 years of matrix regeneration. Conversely, Percnostola rufifrons, a gap-specialist, showed elevated survival in response to fragmentation followed by a decline after 5 years of regeneration. Lastly, facultative flocking and frugivore species (Glyphorynchus spirurus and Dixiphia pipra, respectively) showed no response to adjacent clearing and subsequent regeneration. Conclusions: Our results in association with previous studies confirm that the value of regenerating forest surrounding habitat patches is dependent on two factors: ecological guild of the species in question and second growth age. Given the rapid increase in survival following succession, we suggest that the ecological value of young tropical forest should not be based solely on a contemporary snapshot, but rather, on the future value of mature second growth as well. © 2020 The Author(s)

Cactaceae at Caryophyllales.org- A dynamic online species-level taxonomic backbone for the family

This data paper presents a largely phylogeny-based online taxonomic backbone for the Cactaceae compiled from literature and online sources using the tools of the EDIT Platform for Cybertaxonomy. The data will form a contribution of the Caryophyllales Network for the World Flora Online and serve as the base for further integration of research results from the systematic research community. The final aim is to treat all effectively published scientific names in the family. The checklist includes 150 accepted genera, 1851 accepted species, 91 hybrids, 746 infraspecific taxa (458 heterotypic, 288 with autonyms), 17,932 synonyms of accepted taxa, 16 definitely excluded names, 389 names of uncertain application, 672 unresolved names and 454 names belonging to (probably artificial) named hybrids, totalling 22,275 names. The process of compiling this database is described and further editorial rules for the compilation of the taxonomic backbone for the Caryophyllales Network are proposed. A checklist depicting the current state of the taxonomic backbone is provided as supplemental material. All results are also available online on the website of the Caryophyllales Network and will be constantly updated and expanded in the future. Citation: Korotkova N., Aquino D., Arias S., Eggli U., Franck A., Gómez-Hinostrosa C., Guerrero P. C., Hernández H. M., Kohlbecker A., Köhler M., Luther K., Majure L. C., Müller A., Metzing D., Nyffeler R., Sánchez D., Schlumpberger B. & Berendsohn W. G. 2021: Cactaceae at Caryophyllales.org- A dynamic online species-level taxonomic backbone for the family.-Willdenowia 51: 251-270. Version of record first published online on 31 August 2021 ahead of inclusion in August 2021 issue. Data published through: Http://caryophyllales.org/cactaceae/Checklis

Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of Teduglutide in Pediatric Short Bowel Syndrome

Objective To determine safety and pharmacodynamics/efficacy of teduglutide in children with intestinal failure associated with short bowel syndrome (SBS-IF). Study design This 12-week, open-label study enrolled patients aged 1-17 years with SBS-IF who required parenteral nutrition (PN) and showed minimal or no advance in enteral nutrition (EN) feeds. Patients enrolled sequentially into 3 teduglutide cohorts (0.0125 mg/kg/d [n = 8], 0.025 mg/kg/d [n = 14], 0.05 mg/kg/d [n = 15]) or received standard of care (SOC, n = 5). Descriptive summary statistics were used. Results All patients experienced ≥1 treatment-emergent adverse event; most were mild or moderate. No serious teduglutide-related treatment-emergent adverse events occurred. Between baseline and week 12, prescribed PN volume and calories (kcal/kg/d) changed by a median of −41% and −45%, respectively, with 0.025 mg/kg/d teduglutide and by −25% and −52% with 0.05 mg/kg/d teduglutide. In contrast, PN volume and calories changed by 0% and −6%, respectively, with 0.0125 mg/kg/d teduglutide and by 0% and −1% with SOC. Per patient diary data, EN volume increased by a median of 22%, 32%, and 40% in the 0.0125, 0.025, and 0.05 mg/kg/d cohorts, respectively, and by 11% with SOC. Four patients achieved independence from PN, 3 in the 0.05 mg/kg/d cohort and 1 in the 0.025 mg/kg/d cohort. Study limitations included its short-term, open-label design, and small sample size. Conclusions Teduglutide was well tolerated in pediatric patients with SBS-IF. Teduglutide 0.025 or 0.05 mg/kg/d was associated with trends toward reductions in PN requirements and advancements in EN feeding in children with SBS-IF