The limestone spheroids of 'Ubeidiya: intentional imposition of symmetric geometry by early hominins?

Spheroids are one of the least understood lithic items yet are one of the most enduring, spanning from the Oldowan to the Middle Palaeolithic. Why and how they were made remains highly debated. We seek to address whether spheroids represent unintentional by-products of percussive tasks or if they were intentionally knapped tools with specific manufacturing goals. We apply novel three-dimensional analysis methods, including spherical harmonics and surface curvature, to 150 limestone spheroids from 'Ubeidiya (ca 1.4 Ma), presently the earliest Acheulean occurrence outside of Africa, to bring a new perspective to these enigmatic artefacts. We reconstruct the spheroid reduction sequence based on trends in their scar facets and geometry, finding that the spheroid makers at 'Ubeidiya followed a premeditated reduction strategy. During their manufacture, the spheroids do not become smoother, but they become markedly more spherical. They approach an ideal sphere, a feat that likely required skilful knapping and a preconceived goal. Acheulean bifaces are currently thought to represent the earliest evidence of hominins imposing a premeditated, symmetrical shape on stone. The intentional production of sphere-like objects at 'Ubeidiya similarly shows evidence of Acheulean hominins desiring and achieving intentional geometry and symmetry in stone.

Batata-doce em dietas para juvenis de tilápia em substituição parcial ao farelo de milho: uma análise econômica e de variáveis zootécnicas / Sweet potato in diets for tilapia juveniles in partial replacement to corn bran: An economic analysis and zootechnical variables

Objetivou-se avaliar o desempenho e a viabilidade econômica da substituição parcial do farelo de milho pela farinha de batata-doce, para averiguar se é viável ou não a inclusão nas rações para tilápia. O experimento teve duração de 30 dias entre os meses de maio e junho de 2021 em delineamento experimental inteiramente casualizado com 4 tratamentos e 5 repetições. Entre os 4 tratamentos propostos, 3 eram compostos por diferentes níveis de substituição do farelo de milho pela farinha de batata-doce nas rações experimentais (0,0%; 5,0% e 10,0%) e um composto pela ração comercial (tratamento controle). Ao todo foram utilizados 300 peixes com peso inicial aproximado de 9,10 ± 1,48 g, sendo a unidade experimental representada por 15 peixes em um aquário de 100 litros. Foi constatado que o farelo de milho pode ser substituído pela farinha de batata-doce até o nível mais alto avaliado, que foi de 10% de substituição na ração experimental para tilápia, pois superou a ração comercial, apresentando menor custo e sem afetar o desempenho dos animais.

The objective was to evaluate the performance and economic viability of partial replacement of corn bran by sweet potato flour, in order to determine whether or not its inclusion in tilapia diets is feasible. The experiment lasted 30 days between May and June 2021 in a completely randomized experimental design with 4 treatments and 5 replications. Among the 4 proposed treatments, 3 consisted of different levels of replacement of corn bran by sweet potato flour in the experimental diets (0.0%; 5.0% and 10.0%) and one consisted of the commercial diet (control treatment). A total of 300 fish with an approximate initial weight of 9.10 ± 1.48 g were used, with the experimental unit represented by 15 fish in a 100-liter aquarium. It was found that corn bran can be replaced by sweet potato flour up to the highest level evaluated, which was 10% replacement in the experimental feed for tilapia, as it surpassed the commercial feed, with lower cost and without affecting performance. of the animals.

Environmental identification of arbuscular mycorrhizal fungi using the LSU rDNA gene region: an expanded database and improved pipeline.

Arbuscular mycorrhizal fungi (AMF; Glomeromycota) are difficult to culture; therefore, establishing a robust amplicon-based approach to taxa identification is imperative to describe AMF diversity. Further, due to low and biased sampling of AMF taxa, molecular databases do not represent the breadth of AMF diversity, making database matching approaches suboptimal. Therefore, a full description of AMF diversity requires a tool to determine sequence-based placement in the Glomeromycota clade. Nonetheless, commonly used gene regions, including the SSU and ITS, do not enable reliable phylogenetic placement. Here, we present an improved database and pipeline for the phylogenetic determination of AMF using amplicons from the large subunit (LSU) rRNA gene. We improve our database and backbone tree by including additional outgroup sequences. We also improve an existing bioinformatics pipeline by aligning forward and reverse reads separately, using a universal alignment for all tree building, and implementing a BLAST screening prior to tree building to remove non-homologous sequences. Finally, we present a script to extract AMF belonging to 11 major families as well as an amplicon sequencing variant (ASV) version of our pipeline. We test the utility of the pipeline by testing the placement of known AMF, known non-AMF, and Acaulospora sp. spore sequences. This work represents the most comprehensive database and pipeline for phylogenetic placement of AMF LSU amplicon sequences within the Glomeromycota clade.

High-Throughput Screening to Identify Small Molecules That Selectively Inhibit APOL1 Protein Level in Podocytes.

High-throughput phenotypic screening is a key driver for the identification of novel chemical matter in drug discovery for challenging targets, especially for those with an unclear mechanism of pathology. For toxic or gain-of-function proteins, small-molecule suppressors are a targeting/therapeutic strategy that has been successfully applied. As with other high-throughput screens, the screening strategy and proper assays are critical for successfully identifying selective suppressors of the target of interest. We executed a small-molecule suppressor screen to identify compounds that specifically reduce apolipoprotein L1 (APOL1) protein levels, a genetically validated target associated with increased risk of chronic kidney disease. To enable this study, we developed homogeneous time-resolved fluorescence (HTRF) assays to measure intracellular APOL1 and apolipoprotein L2 (APOL2) protein levels and miniaturized them to 1536-well format. The APOL1 HTRF assay served as the primary assay, and the APOL2 and a commercially available p53 HTRF assay were applied as counterscreens. Cell viability was also measured with CellTiter-Glo to assess the cytotoxicity of compounds. From a 310,000-compound screening library, we identified 1490 confirmed primary hits with 12 different profiles. One hundred fifty-three hits selectively reduced APOL1 in 786-O, a renal cell adenocarcinoma cell line. Thirty-one of these selective suppressors also reduced APOL1 levels in conditionally immortalized human podocytes. The activity and specificity of seven resynthesized compounds were validated in both 786-O and podocytes.

Subspheroids in the lithic assemblage of Barranco León (Spain): Recognizing the late Oldowan in Europe.

The lithic assemblage of Barranco León (BL), attributed to the Oldowan techno-complex, contributes valuable information to reconstruct behavioral patterning of the first hominins to disperse into Western Europe. This archaic stone tool assemblage comprises two, very different groups of tools, made from distinct raw materials. On the one hand, a small-sized toolkit knapped from Jurassic flint, comprising intensively exploited cores and small-sized flakes and fragments and, on the other hand, a large-sized limestone toolkit that is mainly linked to percussive activities. In recent years, the limestone macro-tools have been the center of particular attention, leading to a re-evaluation of their role in the assemblage. Main results bring to light strict hominin selective processes, mainly concerning the quality of the limestone and the morphology of the cobbles, in relation to their use-patterning. In addition to the variety of traces of percussion identified on the limestone tools, recurrences have recently been documented in their positioning and in the morphology of the active surfaces. Coupled with experimental work, this data has contributed to formulating hypothesis about the range of uses for these tools, beyond stone knapping and butchery, for activities such as: wood-working or tendon and meat tenderizing. The abundance of hammerstones, as well as the presence of heavy-duty scrapers, are special features recognized for the limestone component of the Barranco León assemblage. This paper presents, for the first time, another characteristic of the assemblage: the presence of polyhedral and, especially, subspheroid morphologies, virtually unknown in the European context for this timeframe. We present an analysis of these tools, combining qualitative evaluation of the raw materials, diacritical study, 3D geometric morphometric analysis of facet angles and an evaluation of the type and position of percussive traces; opening up the discussion of the late Oldowan beyond the African context.

SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53.

Abrogation of p53 function occurs in almost all human cancers, with more than 50% of cancers harboring inactivating mutations in p53 itself. Mutation of p53 is indicative of highly aggressive cancers and poor prognosis. The vast majority of mutations in p53 occur in its core DNA binding domain (DBD) and result in inactivation of p53 by reducing its thermodynamic stability at physiological temperature. Here, we report a small molecule, SCH529074, that binds specifically to the p53 DBD in a saturable manner with an affinity of 1-2 microm. Binding restores wild type function to many oncogenic mutant forms of p53. This small molecule reactivates mutant p53 by acting as a chaperone, in a manner similar to that previously reported for the peptide CDB3. Binding of SCH529074 to the p53 DBD is specifically displaced by an oligonucleotide with a sequence derived from the p53-response element. In addition to reactivating mutant p53, SCH529074 binding inhibits ubiquitination of p53 by HDM2. We have also developed a novel variant of p53 by changing a single amino acid in the core domain of p53 (N268R), which abolishes binding of SCH529074. This amino acid change also inhibits HDM2-mediated ubiquitination of p53. Our novel findings indicate that through its interaction with p53 DBD, SCH529074 restores DNA binding activity to mutant p53 and inhibits HDM2-mediated ubiquitination.

A fully human insulin-like growth factor-I receptor antibody SCH 717454 (Robatumumab) has antitumor activity as a single agent and in combination with cytotoxics in pediatric tumor xenografts.

The insulin-like growth factor-I receptor (IGF-IR) and its ligands (IGF-I and IGF-II) have been implicated in the growth, survival, and metastasis of a broad range of malignancies including pediatric tumors. Blocking the IGF-IR action is a potential cancer treatment. A fully human neutralizing monoclonal antibody, SCH 717454 (19D12, robatumumab), specific to IGF-IR, has shown potent antitumor effects in ovarian cancer in vitro and in vivo. In this study, SCH 717454 was evaluated in several pediatric solid tumors including neuroblastoma, osteosarcoma, and rhabdomyosarcoma. SCH 717454 is shown here to downregulate IGF-IR as well as inhibit IGF-IR and insulin receptor substrate-1 phosphorylation in pediatric tumor cells. IGF-IR and insulin receptor substrate-1 phosphorylation in the tumor cells. In vivo, SCH 717454 exhibits activity as a single agent and significantly inhibited growth of neuroblastoma, osteosarcoma, and rhabdomyosarcoma tumor xenografts. Combination of SCH 717454 with cisplatin or cyclophosphamide enhanced both the degree and the duration of the in vivo antitumor activity compared with single-agent treatments. Furthermore, SCH 717454 treatment markedly reduced Ki-67 expression and blood vessel formation in tumor xenografts, showing that the in vivo activity is derived from its inhibition of tumor cell proliferation and angiogenesis activity.

Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti-IGF-IR antibody.

Insulin-like growth factor-I receptor (IGF-IR) plays an important role in tumor cell growth and survival. On ligand stimulation, IGF-IR, a receptor tyrosine kinase, phosphorylates tyrosine residues on two major substrates, IRS-1 and Shc, which subsequently signal through the Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways. Here, we describe the characterization of a fully human anti-IGF-IR monoclonal antibody 19D12 that inhibits IGF binding and autophosphorylation of both IGF-IR/IGF-IR homodimers and IGF-IR/insulin receptor heterodimers. 19D12 does not recognize insulin receptor homodimers. In addition to inhibiting IGF-IR autophosphorylation, 19D12 also inhibits IRS-1 phosphorylation and activation of the major downstream signaling molecules AKT and extracellular signal-regulated kinase 1/2. Furthermore, the antibody down-regulates the total IGF-IR protein level and can exhibit antibody-dependent cellular cytotoxicity activity against a non-small cell adenocarcinoma cell line in vitro in the presence of isolated human natural killer cells. 19D12 binds tightly to the receptor, with an affinity of 3.8 pmol/L as measured by KinExA. In cell culture, 19D12 inhibits proliferation and soft agar growth of various tumor cell lines. In vivo, 19D12 inhibits the tumor growth of a very aggressive human ovarian tumor xenograft model A2780. These data support the development of this anti-IGF-IR monoclonal antibody as a promising anticancer agent.