On-target restoration of a split T cell-engaging antibody for precision immunotherapy

T cell-engaging immunotherapies are changing the landscape of current cancer care. However, suitable target antigens are scarce, restricting these strategies to very few tumor types. Here, we report on a T cell-engaging antibody derivative that comes in two complementary halves and addresses antigen combinations instead of single molecules. Each half, now coined hemibody, contains an antigen-specific single-chain variable fragment (scFv) fused to either the variable light (V-L) or variable heavy (V-H) chain domain of an anti-CD3 antibody. When the two hemibodies simultaneously bind their respective antigens on a single cell, they align and reconstitute the original CD3-binding site to engage T cells. Employing preclinical models for aggressive leukemia and breast cancer, we show that by the combinatorial nature of this approach, T lymphocytes exclusively eliminate dual antigen-positive cells while sparing single positive bystanders. This allows for precision targeting of cancers not amenable to current immunotherapies

Hexactinellid Sponge Reefs on the Canadian Continental Shelf: A Unique "Living Fossil"

Globally unique hexactinellid (siliceous) sponge reefs, found in deep (200 m), glacially scoured troughs of the western Canadian continental shelf, have been explored by a manned submersible. Submersible observations and geophysical data allow examination of the physical and biological processes that have shaped the sponge reefs, which began to form about 9 thousand years (k.y.) ago. The mounds (bioherms) and sheet-like accumulations (biostromes) cover a low-angle, non-depositional, iceberg-scoured seafloor, relict since the déglaciation of the region. Biohermal structures are up to 19 m in height, and are covered with hexactinosan sponges up to 1.5 m tall, creating abenthic habitat that discontinously covers roughly 700 km2. Similar to extinct siliceous sponge reefs, mud mounds, and reef mounds that were widespread during the Mesozoic, the modern reefs are like a"living fossil" and provide a unique modern analogue. Fishing activities, especially trawling or bottom dragging, have damaged the slow-growing reefs insome areas. Résumé Uniques au monde, les récifs d'épongés d'hexactinellides (siliceux) qui se trouvent à 200 m de profondeur dans des fosses d'abrasion glaciaires du plateau continental de l'Ouest du Canada, ont été explorés à partir de sous-marins habités. Les observations sous-marines et les données de géophysique permettent d'étudier les mécanismes physiques et biologiques qui ont présidé à l'édification des récifs d'épongés qui ont commencé à se former aux environs de 9 ka  P. Ces édifices récifaux en amas (biohermes), et en couches (biostromes) recouvrent un fond marin légèrement incliné par l'abrasion d'icebergs post-glaciaires. Ces biohermes ont jusqu'à 19 m de hauteur et sont recouverts d'une couche de 1,5 m de hauteur d'épongés hexactinellidiennes, forment un habitat couvrant de manière discontinue une surface de 700 km2. Semblables à ces récifs d'épongés très répandus au Mésozoïques, amas boueux et amas récifaux, les récifs modernes sont de véritables fossiles vivants, et sont à ce titre forts utiles pour la compréhension de leurs contreparties fossiles. Par endroits, les activités de pêche industrielle, particulièrement le chalutage ou le dragage de fond ont endommagé ces édifices récifales à croissantes lentes

Characterization on organic matrix proteins enclosed in high Mg-calcite crystals of the coralline sponge Spirastrella (Acanthochaetetes) wellsi

Protein components found in freeze-dried specimens of the coralline sponge Spirastrella (Acanthochaetetes) wellsi were separated and characterized . Proteins extracted from skeleton crystals (matrix proteins) contained high concentrations of glycin (16 %) as weil as enhanced amounts of asparagin/aspartic acid (11 %) and glutamin/glutamic acid (10 %). At least 10 proteins could be separated by SDSPAGE. Six of them, with molecular weights between 30 and 45 kDa, may be considered as distinct matrix proteins. The bulk of total soluble proteins as weil as all soluble matrix proteins are acidic with pH values below 5. Our results indicate that at least in one stage crystal growth is matrix mediated, i.e. controlled by the sponge

Hey Alexa, Please Help Us Solve This Problem! How Interactions with Smart Personal Assistants Improve Group Performance

Despite a growing body of research about the design and use of Smart Personal Assistants, such as Google’s Assistant or Amazon’s Alexa, existing work has mainly focused on their use as task support for individual users in rather simple problem scenarios. Little is known about their ability to improve collaboration among multiple users in more complex problem settings. Using a mixed-method approach, we investigate the value of Smart Personal Assistants as facilitators by directly comparing 40 groups of three who either interact with a Smart Personal Assistant or a scripted human facilitator in a complex problem-solving scenario. The results indicate that groups interacting with Smart Personal Assistant facilitators show significantly better task outcomes and higher degrees of collaboration quality. A conversation analysis approach further analyzes differences in human SPA communication. Our work contributes to computer-supported cooperative work research and emphasizes the value of conversation analysis approaches in HCI research

Kidney Injury by Variants in the <i>COL4A5</i> Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases