RESP2: An uncertainty aware multi-target multi-property optimization AI pipeline for antibody discovery.

Discovery of therapeutic antibodies against infectious disease pathogens presents distinct challenges. Ideal candidates must possess not only the properties required for any therapeutic antibody (e.g.

The long-term expansion and recession of human populations.

Over the last 12,000 y, human populations have expanded and transformed critical earth systems. Yet, a key unresolved question in the environmental and social sciences remains: Why did human populations grow and, sometimes, decline in the first place? Our research builds on 20 y of archaeological research studying the deep time dynamics of human populations to propose an explanation for the long-term growth and stability of human populations. Innovations in the productive capacity of populations fuels exponential-like growth over thousands of years; however, innovations saturate over time and, often, may leave populations vulnerable to large recessions in their well-being and population density.

The RESP AI model accelerates the identification of tight-binding antibodies.

High-affinity antibodies are often identified through directed evolution, which may require many iterations of mutagenesis and selection to find an optimal candidate. Deep learning techniques hold the potential to accelerate this process but the existing methods cannot provide the confidence interval or uncertainty needed to assess the reliability of the predictions. Here we present a pipeline called RESP for efficient identification of high affinity antibodies.

Engineering human JMJD2A tudor domains for an improved understanding of histone peptide recognition.

JMJD2A is a histone lysine demethylase which recognizes and demethylates H3K9me3 and H3K36me3 residues and is overexpressed in various cancers. It utilizes a tandem tudor domain to facilitate its own recruitment to histone sites, recognizing various di- and tri-methyl lysine residues with moderate affinity. In this study, we successfully engineered the tudor domain of JMJD2A to specifically bind to H4K20me3 with a 20-fold increase of affinity and improved selectivity.

Engineering a Histone Reader Protein by Combining Directed Evolution, Sequencing, and Neural Network Based Ordinal Regression.

Directed evolution is a powerful approach for engineering proteins with enhanced affinity or specificity for a ligand of interest but typically requires many rounds of screening/library mutagenesis to obtain mutants with desired properties. Furthermore, mutant libraries generally only cover a small fraction of the available sequence space. Here, for the first time, we use ordinal regression to model protein sequence data generated through successive rounds of sorting and amplification of a protein-ligand system.

Should I stay or should I go? The emergence of partitioned land use among human foragers.

Taking inspiration from the archaeology of the Texas Coastal Plain (TCP), we develop an ecological theory of population distribution among mobile hunter-gatherers. This theory proposes that, due to the heterogeneity of resources in space and time, foragers create networks of habitats that they access through residential cycling and shared knowledge. The degree of cycling that individuals exhibit in creating networks of habitats, encoded through social relationships, depends on the relative scarcity of resources and fluctuations in those resources.

Deciphering and engineering chromodomain-methyllysine peptide recognition.

Posttranslational modifications (PTMs) play critical roles in regulating protein functions and mediating protein-protein interactions. An important PTM is lysine methylation that orchestrates chromatin modifications and regulates functions of non-histone proteins. Methyllysine peptides are bound by modular domains, of which chromodomains are representative.

Differential orientation and conformation of surface-bound keratinocyte growth factor on (hydroxyethyl)methacrylate, (hydroxyethyl)methacrylate/methyl methacrylate, and (hydroxyethyl)methacrylate/methacrylic acid hydrogel copolymers.

The development of hydrogels for protein delivery requires protein-hydrogel interactions that cause minimal disruption of the protein's biological activity. Biological activity can be influenced by factors such as orientational accessibility for receptor binding and conformational changes, and these factors can be influenced by the hydrogel surface chemistry. (Hydroxyethyl)methacrylate (HEMA) hydrogels are of interest as drug delivery vehicles for keratinocyte growth factor (KGF) which is known to promote re-epithelialization in wound healing.

Discovery and Mechanism of Highly Efficient Cyclic Cell-Penetrating Peptides.

Previous cell-penetrating peptides (CPPs) generally have low cytosolic delivery efficiencies, because of inefficient endosomal escape. In this study, a family of small, amphipathic cyclic peptides was found to be highly efficient CPPs, with cytosolic delivery efficiencies of up to 120% (compared to 2.0% for Tat).

Early endosomal escape of a cyclic cell-penetrating peptide allows effective cytosolic cargo delivery.

Cyclic heptapeptide cyclo(FΦRRRRQ) (cFΦR4, where Φ is l-2-naphthylalanine) was recently found to be efficiently internalized by mammalian cells. In this study, its mechanism of internalization was investigated by perturbing various endocytic events through the introduction of pharmacologic agents and genetic mutations. The results show that cFΦR4 binds directly to membrane phospholipids, is internalized into human cancer cells through endocytosis, and escapes from early endosomes into the cytoplasm.

Conditional prerequisites for microchannel cytologic analysis on wet mount (fluid-based) biopsies.

Background: Advanced capabilities in genomic sequencing developed in the research sector will soon enter the clinical arena. Issues such as the proportioning of patient specimen material for traditional bright-field microscopic evaluation or dedication for molecular analysis will intensify, particularly in situations of small core biopsies. Microfluidics appears aptly suited as a platform capable of allowing traditional cytologic diagnostics and downstream molecular analysis from the same specimen.

Simultaneous binding of two peptidyl ligands by a SRC homology 2 domain.

Src homology 2 (SH2) domains mediate protein-protein interactions by recognizing phosphotyrosine (pY)-containing sequences of target proteins. In all of the SH2 domain-pY peptide interactions described to date, the SH2 domain binds to a single pY peptide. Here, determination of the cocrystal structure of the N-terminal SH2 domain of phosphatase SHP-2 bound to a class IV peptide (VIpYFVP) revealed a noncanonical 1:2 (protein-peptide) complex.

Distinct ligand specificity of the Tiam1 and Tiam2 PDZ domains.

Guanine nucleotide exchange factor proteins of the Tiam family are activators of the Rho GTPase Rac1 and critical for cell morphology, adhesion, migration, and polarity. These proteins are modular and contain a variety of interaction domains, including a single post-synaptic density-95/discs large/zonula occludens-1 (PDZ) domain. Previous studies suggest that the specificities of the Tiam1 and Tiam2 PDZ domains are distinct.

HDAC6 and Ubp-M BUZ domains recognize specific C-terminal sequences of proteins.

The BUZ/Znf-UBP domain is a protein module found in the cytoplasmic deacetylase HDAC6, E3 ubiquitin ligase BRAP2/IMP, and a subfamily of ubiquitin-specific proteases. Although several BUZ domains have been shown to bind ubiquitin with high affinity by recognizing its C-terminal sequence (RLRGG-COOH), it is currently unknown whether the interaction is sequence-specific or whether the BUZ domains are capable of binding to proteins other than ubiquitin. In this work, the BUZ domains of HDAC6 and Ubp-M were subjected to screening against a one-bead-one-compound (OBOC) peptide library that exhibited random peptide sequences with free C-termini.

Tubulin glutamylation regulates ciliary motility by altering inner dynein arm activity.

How microtubule-associated motor proteins are regulated is not well understood. A potential mechanism for spatial regulation of motor proteins is provided by posttranslational modifications of tubulin subunits that form patterns on microtubules. Glutamylation is a conserved tubulin modification [1] that is enriched in axonemes.

Determining the protein drug release characteristics and cell adhesion to a PLLA or PLGA biodegradable polymer membrane.

Biodegradable polymers are of interest for developing controlled protein drug delivery platforms. In this study, two poly (alpha-hydroxy) esters were formulated with Aerosol-OT, a surfactant stabilizer, to encapsulate the protein keratinocyte growth factor (KGF) for controlled release KGF is involved in a number of crucial biologic processes, most notably epithelial growth and repair. The concentration of KGF that caused a biological response in vitro was determined (optimally 10 ng/mL) and compared with the release of KGF from the two biodegradable polymer membrane formulations.

The diffusion of maize to the southwestern United States and its impact.

Our understanding of the initial period of agriculture in the southwestern United States has been transformed by recent discoveries that establish the presence of maize there by 2100 cal. B.C.

Phase separation at the surface of poly(ethylene oxide)-containing biodegradable poly(L-lactic acid) blends.

The surface chemistry and in-depth distribution of the composition of a poly(ethylene oxide) (PEO)-containing biodegradable poly(L-lactic acid) (PLLA) blend matrix system have been investigated using X-ray photoelectron spectroscopy (XPS). This study reports detailed quantitative compositional information using a novel numerical method for determining depth profiles. The PEO system studied is an amphiphilic Pluronic P104 surfactant, PEO-b-poly(propylene oxide) (PPO)-b-PEO.

Guest aggregation within poly(L-lactic acid)/pluronic P104 thin films.

Rhodamine 6G (R6G) doped thin films composed of poly(L-lactic acid) (PLLA) and Pluronic P104 were spin cast onto glass microscope slides and characterized by ultraviolet-visible, steady-state, and time-resolved fluorescence spectroscopy. The results show that R6G aggregation within the film increases as the R6G concentration and P104 loading increases. These results suggest an approach for studying drug distributions (monomers, aggregates) within biodegradable polymer formulations.

[Laparoscopic cholecystectomy in an overnight admission].

Objective: to determine the feasibility and desirability of laparoscopic cholecystectomy (LC) in an overnight versus a several day admission.

Background: Although LC is performed in U.S.

Targeted gene disruption of dynein heavy chain 7 of Tetrahymena thermophila results in altered ciliary waveform and reduced swim speed.

Tetrahymena thermophila swims by the coordinated beating of hundreds of cilia that cover its body. It has been proposed that the outer arm dyneins of the ciliary axoneme control beat frequency, whereas the inner arm dyneins control waveform. To test the role of one of these inner arms, dynein heavy chain 7 protein (Dyh7p), a knockout mutant was generated by targeted biolistic transformation of the vegetative macronucleus.

Fibroblast growth factor receptor signaling affects development and function of dopamine neurons - inhibition results in a schizophrenia-like syndrome in transgenic mice.

Developing and mature midbrain dopamine (DA) neurons express fibroblast growth factor (FGF) receptor-1 (FGFR1). To determine the role of FGFR1 signaling in the development of DA neurons, we generated transgenic mice expressing a dominant negative mutant [FGFR1(TK-)] from the catecholaminergic, neuron-specific tyrosine hydroxylase (TH) gene promoter. In homozygous th(tk-)/th(tk-) mice, significant reductions in the size of TH-immunoreactive neurons were found in the substantia nigra compacta (SNc) and the ventral tegmental area (VTA) at postnatal days 0 and 360.

Effects of clozapine and 2,5-dimethoxy-4-methylamphetamine [DOM] on 5-HT2A receptor expression in discrete brain areas.

Activation of 5-HT2A receptors has been shown to be an essential component of the discriminative stimulus effects of indoleamine and phenethylamine hallucinogens. The objective of the present study was to determine the neuroanatomical location of the 5HT2A receptors which may be responsible for the stimulus effects of the phenethylamine hallucinogen [-]2,5-dimethoxy-4-methylamphetamine (DOM). It was hypothesized that brain areas containing altered 5-HT2A receptor expression in the context of a similar alteration in DOM-induced stimulus control might be important in mediating the stimulus effects of DOM.

Disruption of genes encoding predicted inner arm dynein heavy chains causes motility phenotypes in Tetrahymena.

The multi-dynein hypothesis [Asai, 1995: Cell Motil Cytoskeleton 32:129-132] states: (1) there are many different dynein HC isoforms; (2) each isoform is encoded by a different gene; (3) different isoforms have different functions. Many studies provide evidence in support of the first two statements [Piperno et al., 1990: J Cell Biol 110:379-389; Kagami and Kamiya, 1992: J Cell Sci 103:653-664; Gibbons, 1995: Cell Motil Cytoskeleton 32:136-144; Porter et al.

Keratinocyte growth factor and autocrine repair in airway epithelium.

Background: Delayed or nonreepithelialization of the large conducting airway (ie, trachea and bronchus) is a clinically recognized but poorly understood result of airway trauma. This delay results in granulation tissue formation and scarring, which impairs mucocilliary transport and can critically compromise gas exchange. Keratinocyte growth factor (KGF) is a known epithelial cell mitogen that is derived from mesenchymal cells.