Original Fragment Research Articles

Computational fragment screening of dimeric SARS-CoV-2 main protease.

During the coronavirus pandemic the lack of antiviral therapeutics drove intense interest in rapid drug discovery by the scientific, and medical communities. The Voelz lab took part in the COVID Moonshot initiative, which focused on virtually screening small drug-like fragments as leads for inhibitors of the main protease (Mpro) of SARS-CoV-2, identified using high throughput crystallographic techniques. The Voelz lab performed absolute binding free energy calculations on the [email protected] distributed computing platform to massively parallelize the molecular dynamic (MD) simulations. Crystallographic fragment-based screening techniques can be time consuming, costly, and dependent on the availability of protein crystals. Could fragment based drug discovery be performed completely in silico? To address this question, we aim to perform simulations to virtually screen the original fragment library used in the COVID Moonshot, and assess the accuracy of the predictions. The GROMACS simulation package was used to construct a simulation topology of the apo form of dimeric Mpro from its crystal structure. The correct protonation states of titratable residues were taken from published experimental results. As a first step, we prepared and performed a set of simulations of Mpro in solution, each with one of 11 drug fragments selected from the crystallographic fragment screen, all of which are known to co-crystallize with Mpro experimentally. The simulations are analyzed to determine where the drug fragments like to bind to the Mpro receptor. These results are compared results to the experimental co-crystal structures to determine how accurately MD simulations can predict the known binding pose of small drug like fragments.

Extending multi-layer energy-based fragment method for excited-state calculations of large covalently bonded fragment systems.

Recently, we developed a low-scaling Multi-Layer Energy-Based Fragment (MLEBF) method for accurate excited-state calculations and nonadiabatic dynamics simulations of nonbonded fragment systems. In this work, we extend the MLEBF method to treat covalently bonded fragment ones. The main idea is cutting a target system into many fragments according to chemical properties. Fragments with dangling bonds are first saturated by chemical groups; then, saturated fragments, together with the original fragments without dangling bonds, are grouped into different layers. The accurate total energy expression is formulated with the many-body energy expansion theory, in combination with the inclusion-exclusion principle that is used to delete the contribution of chemical groups introduced to saturate dangling bonds. Specifically, in a two-layer MLEBF model, the photochemically active and inert layers are calculated with high-level and efficient electronic structure methods, respectively. Intralayer and interlayer energies can be truncated at the two- or three-body interaction level. Subsequently, through several systems, including neutral and charged covalently bonded fragment systems, we demonstrate that MLEBF can provide accurate ground- and excited-state energies and gradients. Finally, we realize the structure, conical intersection, and path optimizations by combining our MLEBF program with commercial and free packages, e.g., ASE and SciPy. These developments make MLEBF a practical and reliable tool for studying complex photochemical and photophysical processes of large nonbonded and bonded fragment systems.

Multi-Analytical Investigations of the Medieval Turkish Bath from Golești Open Air Museum

The Golești Manor ensemble consists of architectural monuments dating back to the 17th, 18th, and 19th centuries, with ephemeral architecture roots from Phanariot times but also some pre- Brancovan influences. The Turkish steam bath is placed in the northeast of the enclosure, and it is thought to have been built by Stroe Leurdeanu. Although there are still original fragments of the old plaster that have been preserved, the Turkish bath has undergone several restorations through time, some of them poorly documented. Hyperspectral imaging (HSI) combined with LIBS were used in order to analyze the bricks and the mortars, evaluate their preservation state, map the original elements, and document and classify the interventions previously made. Based on the supervised classifications, several areas of interest were selected for LIBS elemental analysis, and multivariate data analysis was conducted in order to discriminate similar composition materials and to map the interventions and the original. By analyzing the variability of the spectral profiles, different algorithms were applied to the SWIR hyperspectral images in order to classify the main elements of the brickwork.

Discovery of inhibitors against SARS-CoV-2 main protease using fragment-based drug design

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19), in which the main protease (Mpro) plays an important role in the virus's life cycle. In this work, two representative peptide inhibitors (11a and PF-07321332) were selected, and their interaction mechanisms of non-covalently bound with Mpro were firstly investigated by means of molecular dynamical simulation. Then, using the fragment-based drug design method, some fragments from the existing SARS-CoV and SARS-CoV-2 inhibitors were selected to replace the original P2 and P3 fragments, resulting in some new molecules. Among them, two molecules (O-74 and N-98) were confirmed by molecular docking and molecular dynamics simulation, and ADMET properties prediction was employed for further verification. The results shown that they presented excellent activity and physicochemical properties, and had the potential to be new inhibitors for SARS-CoV-2 main protease.

Fragment expansion with NUDELs - poised DNA-encoded libraries.

Optimisation of the affinity of lead compounds is a critical challenge in the identification of drug candidates and chemical probes and is a process that takes many years. Fragment-based drug discovery has become established as one of the methods of choice for drug discovery starting with small, low affinity compounds. Due to their low affinity, the evolution of fragments to desirable levels of affinity is often a key challenge. The accepted best method for increasing the potency of fragments is by iterative fragment growing, which can be very time consuming and complex. Here, we introduce a paradigm for fragment hit optimisation using poised DNA-encoded chemical libraries (DELs). The synthesis of a poised DEL, a partially constructed library that retains a reactive handle, allows the coupling of any active fragment for a specific target protein, allowing rapid discovery of potent ligands. This is illustrated for bromodomain-containing protein 4 (BRD4), in which a weakly binding fragment was coupled to a 42-member poised DEL via Suzuki-Miyaura cross coupling resulting in the identification of an inhibitor with 51 nM affinity in a single step, representing an increase in potency of several orders of magnitude from an original fragment. The potency of the compound was shown to arise from the synergistic combination of substructures, which would have been very difficult to discover by any other method and was rationalised by X-ray crystallography. The compound showed attractive lead-like properties suitable for further optimisation and demonstrated BRD4-dependent cellular pharmacology. This work demonstrates the power of poised DELs to rapidly optimise fragments, representing an attractive generic approach to drug discovery.

Fragmenty Krocínovy kašny z Lapidária Národního muzea. Pohled restaurátora

Fragments of Krocín’s fountain from the Lapidarium of the National Museum – a restorer’s perspective Krocín’s fountain in Prague’s Old Town Square is an impressive and beautiful stone sculpture work from the second half of the 16th century. Its partial historical reconstruction is now part of the permanent exhibition “Stone Sculpture Monu­ments in Bohemia from the 11th to the 19th century“ in the Lapidarium of the National Museum. However, only part of the fragments taken over by the National Museum were used for the historical reconstruction in 1991, with another large part remaining stored in the Lapidarium’s depository. Given the planned reconstruction of the Lapidarium building, and the necessary intervention in the permanent exhibition, the question arises of whether it would be possible to display Krocín’s fountain on a larger scale in the future. The aim of this article is to evaluate the physical condition of the original stone fragments that were not used for the exhibition reconstruction. Twenty stone fragments from Krocín’s fountain underwent restoration and laboratory research. Finally, documentation is presented of the conservation of the two most damaged fragments, which were treated in collaboration with students of the Sculpture Workshop of the Academy of Fine Arts in Prague.

Clinical Outcomes of Surgical Crown Reattachment as Treatment for Complicated Crown-Root Fractures: A Retrospective Study.

This retrospective study evaluated the clinical outcomes of surgical crown reattachment in the treatment of complicated crown-root fractures in permanent teeth in 35 patients. Treatments were defined as follows: surgical crown reattachment combined with internal fixation with a fiberreinforced core post, ostectomy, and reattachment of the original crown fragment. Patients were examined to record the periodontal pocket depth (PD), marginal bone loss, tooth migration, and coronal fragment looseness or loss. In most cases, the fracture lines on the palatal aspect were located below the alveolar crest. About 20% to 30% of teeth had periodontal pockets ≥ 3 mm present at least 1 year after surgery. Significant PD differences were observed between the traumatized teeth and adjacent untraumatized teeth at 6 months. The available evidence suggests that surgical crown reattachment is a feasible and effective technique for managing complicated crown-root fractures in permanent teeth.

Prehistoric nests of Mud Dauber Wasps (Hymenoptera: Sphecidae) discovered in Transylvania, Romania

Fragments of mud dauber wasp’s nests dating from the Bronze Age (Noua culture, about 1500–1200 BC) from a Romanian archaeological site are described. The present discovery represents, to our knowledge, the first reported fragments of mud dauber nests recuperated from an archaeological site in Romania and probably among the rare ones from Europe. The archaeological site called Zoltan-“Nisipărie” is placed in the Covasna County, south-eastern Transylvania. The five fragments belong to two nests made by Sceliphron sp. wasps genus and they were described in terms of general and detailed morphology and morphometry. Two nest fragments preserve in situ secondary cells, showing evidence of nest reoccupation by other insects. Another important aspect of this discovery is the opportunity to extract and analyse a whole secondary cell from the original nest fragment. Various impressions of vegetal material (grass, straws etc.) and a seed on the nest fragments’ surface were observed using microscopic techniques. The preserved pieces recovered from archaeological investigations provide important data regarding the local environmental conditions during the recent period of Bronze Age in an anthropized environment of the Noua culture.

Development of a CSRML version of the Analog identification Methodology (AIM) fragments and their evaluation within the Generalised Read-Across (GenRA) approach

The Analog Identification Methodology (AIM) was developed over 20 years ago to identify analogues to support read-across at the US Environmental Protection Agency. However, the current public version of the standalone tool, released in 2012, is no longer usable on Windows operating systems supported by Microsoft. Additionally, the structural logic for analogue selection is based on older, customised Simplified molecular-input-line-entry system (SMILES)-type features that are incompatible with modern cheminformatics tools. Given these limitations, a case study was undertaken to explore a more transparent, extensible method of implementing the AIM fragments using Chemical Subgraphs and Reactions Mark-up Language (CSRML). A CSRML file was developed to codify the original AIM fragments, and the extent to which AIM fragments were faithfully replicated was assessed using the AIM Database. The overall mean performance of the CSRML-AIM across all fragments in terms of sensitivity, specificity, and Jaccard similarity was 89.5%, 99.9%, and 82.2%, respectively. Comparing the AIM fragments with public ToxPrints using a large set of ∼25,000 substances of regulatory interest to EPA found them to be dissimilar, with an average maximum Jaccard score of 0.24 for AIM and 0.29 for ToxPrint fingerprints. Both fragment sets were then used as inputs in the automated read-across approach, Generalised Read-Across (GenRA), to evaluate the quality of fit in predicting rat acute oral toxicity LD50 values with the coefficient of determination (R2) and root mean squared error (RMSE). The performance of AIM fragments was R2=0.434 and RMSE=0.663 whereas that of ToxPrints was R2=0.477 and RMSE=0.638. A bootstrap resampling using 100 iterations found the mean and the 95th confidence interval of R2 to be 0.349 [0.319, 0.379] for AIM fragments and 0.377 [0.338, 0.412] for ToxPrints. Although AIM and ToxPrints performed similarly in predicting LD50, they differed in their performance at a local level, revealing that their features can offer complementary insights.

Тематичне новаторство публікацій Софії Яблонської у галицькій пресі міжвоєнної доби

The paper focuses on the creative heritage of Sofia Yablinska, a Ukrainian journalist who made a round-the-world trip and was a popular author of Western Ukrainian publications in the 1930s. There is no profound research on this young intellectual from the perspective of the special interests of Ukrainian scientists. Her literary achievements have only sporadically attracted some attention since 1990 in the context of asserting the independence of the Ukrainian state in the world. Her contribution to the formation of such a genre of journalistic creativity as the travel essay (report) dedicated to her travels to distant worlds (Southeast Asia, the Far East, etc.) has been clarified. The thematic spectrum of publications by Sofia Yablonska in Galician periodicals of the interwar period has been highlighted. The paper is focused on the main thematic areas of her creative output. The author highlighted the significance of Sofia Yablonska’s travel journalism and her role in familiarizing the readership with the history and culture, religion, customs and traditions, management of the economy, and way of life of people and tribes in exotic lands. The readers’ feedback demonstrated her great talent for attracting their attention to original plots and descriptions of distant countries and the mental characteristics and existence of people in the realities of other worlds. Sofia Yablonska was convinced of the equality of the peoples of both colonized countries and colonizing states, which has been especially emphasized in the paper. The gender problems of the contemporary world and their coverage by Sofia Yablonska have also been analyzed. The author stated the need for further study of this interesting and original intellectual fragment of the Ukrainian press of the interwar period in order to learn more about the unity of the world of people and the world of nature, understanding and perceiving the universality of life on the planet, and emotional involvement in the problems of humanity at all latitudes and longitudes. Keywords: Sofia Yablonska, interwar period, Western Ukraine, travel essay (report), round-the-world trip, colonization, exotic places, gender equality

Fossil eggshells from the Early Cretaceous Okurodani Formation, northern central Japan

ABSTRACT Seven isolated eggshell fragments and six eggshell impressions were collected from the Okurodani Formation (Hauterivian to Barremian) in Shokawa, Takayama City, Gifu Prefecture, Japan. To date, these specimens represent the oldest fossil eggshells in the country. Microscopic observations classified the eggshells into Testudoolithidae indet., Ramoprismatoolithus okurai oogen. et oosp. nov. and indeterminate type. For Testudoolithidae indet., the eggshell microstructure and estimated egg size suggest that they could be laid by any of the cryptodiran turtles reported by skeletal remains from the formation: Trionychoidea, Xinjiangchelyidae and Sinemydidae. Ramoprismatoolithus okurai bears prismatic microstructure and ramifying ridges on the outer surface, the combination of which is unusual for prismatoolithid eggshells. Based on morphological observations and phylogenetic analyses, Ramoprismatoolithus was ascribed to troodontid or closely related non-avian maniraptorans. The remaining specimens consist of eggshell surface impressions without original fragments, for which oospecies and taxonomic affinity are indeterminate. These findings demonstrate that eggshell fragments shed light on small-bodied taxa that are poorly represented by skeletal remains in the region. While the fossil record of small maniraptoran species from the early Early Cretaceous is relatively scarce worldwide, Ramoprismatoolithus adds to this record and extends the confirmed geographic range of this clade.http://www.zoobank.org/urn:lsid:zoobank.org:act:E023F0B5-59F3-47DD-B804-345A92750BEF

Assay Performance of a Label-Free, Solution-Phase CYFRA 21-1 Determination.

CYFRA 21.1, a cytokeratin fragment of epithelial origin, has long been a valuable blood-based biomarker. As with most biomarkers, the clinical diagnostic value of CYFRA 21.1 is dependent on the quantitative performance of the assay. Looking toward translation, it is shown here that a free-solution assay (FSA) coupled with a compensated interferometric reader (CIR) can be used to provide excellent analytical performance in quantifying CYFRA 21.1 in patient serum samples. This report focuses on the analytical performance of the high-sensitivity (hs)-CYFRA 21.1 assay in the context of quantifying the biomarker in two indeterminate pulmonary nodule (IPN) patient cohorts totaling 179 patients. Each of the ten assay calibrations consisted of 6 concentrations, each run as 7 replicates (e.g., 10 × 6 × 7 data points) and were performed on two different instruments by two different operators. Coefficients of variation (CVs) for the hs-CYFRA 21.1 analytical figures of merit, limit of quantification (LOQ) of ca. 60 pg/mL, Bmax, initial slope, probe–target binding affinity, and reproducibility of quantifying an unknown were found to range from 2.5 to 8.3%. Our results demonstrate the excellent performance of our FSA-CIR hs-CYFRA 21-1 assay and a proof of concept for potentially redefining the performance characteristics of this existing important candidate biomarker.

Intra-Domain Cysteines (IDC), a New Strategy for the Development of Original Antibody Fragment-Drug Conjugates (FDCs).

Antibody–drug conjugates (ADCs) derived from a full immunoglobulin-G (IgG) are associated with suboptimal solid-tumor penetration and Fc-mediated toxicities. Antibody fragment–drug conjugates (FDCs) could be an alternative. Nevertheless, innovative solutions are needed to implant cysteines as conjugation sites in the single-chain fragment variable (scFv) format, which is the backbone from which many other antibody formats are built. In addition, the bioconjugation site has the utmost importance to optimize the safety and efficacy of bioconjugates. Our previous intra-tag cysteine (ITC) strategy consisted of introducing a bioconjugation motif at the C-terminal position of the 4D5.2 scFv, but this motif was subjected to proteolysis when the scFv was produced in CHO cells. Considering these data, using three intra-domain cysteine (IDC) strategies, several parameters were studied to assess the impact of different locations of a site-specific bioconjugation motif in the variable domains of an anti-HER2 scFv. In comparison to the ITC strategy, our new IDC strategy allowed us to identify new fragment–drug conjugates (FDCs) devoid of proteolysis and exhibiting enhanced stability profiles, better affinity, and better ability to kill selectively HER2-positive SK-BR-3 cells in vitro at picomolar concentrations. Thus, this work represents an important optimization step in the design of more complex and effective conjugates.

Internal Similarity Network for Rejoining Oracle Bone Fragment Images

Rejoining oracle bone fragments plays an import role in studying the history and culture of the Shang dynasty by its characters. However, current computer vision technology has a low accuracy in judging whether the texture of oracle bone fragment image pairs can be put back together. When rejoining fragment images, the coordinate sequence and texture features of edge pixels from original and target fragment images form a continuous symmetrical structure, so we put forward an internal similarity network (ISN) to rejoin the fragment image automatically. Firstly, an edge equidistant matching (EEM) algorithm was given to search similar coordinate sequences of edge segment pairs on the fragment image contours and to locally match the edge coordinate sequence of an oracle bone fragment image. Then, a target mask-based method was designed in order to put two images into a whole and to cut a local region image by the local matching edge. Next, we calculated a convolution feature gradient map (CFGM) of the local region image texture, and an internal similarity pooling (ISP) layer was proposed to compute the internal similarity of the convolution feature gradient map. Finally, ISN was contributed in order to evaluate a similarity score of a local region image texture and to determine whether two fragment images are a coherent whole. The experiments show that the correct judgement probability of ISN is higher than 90% in actual rejoining work and that our method searched 37 pairs of correctly rejoined oracle bone fragment images that have not been discovered by archaeologists.

Non-invasive techniques for characterization of original Roman mosaic fragments

Abstract In this study, it was reported the preliminary results on the chemical and structural composition of decorative elements remains from original Roman mosaic fragments collected from the Roman Mosaic Museum, Constanta (Romania). These investigations were carried out by using non-destructive and micro-invasive techniques such as optical microscopy, X-ray diffraction, field emission - scanning electron microscopy - energy dispersive X-ray spectroscopy, vibrational spectroscopy (i.e., FTIR and Raman). The studied fragments, apart from being beneficial to different restoration opportunities of this Roman mosaic, could be also included in its modification through air pollution. The major and minor phase components of the studied mosaic fragments were determined, the crystal structure of the main phases was analyzed, and their three-dimension spatial arrangement was reconstructed. The similar composition of the major phases of all mosaic fragments can indicate a generic recipe for making mosaic elements, but minor phases were presumably added for coloring of mosaic pieces. Some degradation areas inside the volume of the mosaic fragments were found by means of the X-ray diffraction method. The areas are probably related to the formation of iron hydroxides during chemical interactions of mosaic fragments with the sea and urban polluted atmosphere. The results can also offer important information about the original materials that were used in the Roman period.

Egy ismeretlen váci reneszánsz balusztrádról

In 1913 László Éber wrote a paper about the rood screen of the baroque cathedral of Vác. He was the first who revealed that sixteen pieces from the renaissance-style carved stone elements of the rood screen were made in the late medieval period. the stone material of the pieces is marl of the Buda region. there were other stone carvings masoned in the cathedral: four dividing pillars of this balustrade, other two with Jagellonian signs from red marble and two tables with the coat of arms of Miklós Báthori (bishop of Vác, 1474–1506). The balustrade elements can be seen in the baroque cathedral thought to be in strong connections with some dividing pillars from Buda castle. there were two ideas about the dating of the Vác balustrade: either they were made during the reign of King Matthias corvinus or after his death during the Jagellonian era. In 1992 árpád Mikó discovered a barrel on the backside of one pillar, which is one of the emblems of King Matthias. there is another important question: what was the original finding place of the pillars? Éber wrote, that it is plausible that Miklós Báthori was the order of the balustrade and it was stood in the medieval cathedral of Vác, which was destroyed during the Ottoman era. is it possible that they came from the site, which now laid under and around the baroque Franciscan church and monastery in Vác? I examined the written sources from the 18–19th centuries and it turned out, that there is no information about it.On the other hand, there are several other renaissance fragments from Vác, most of them were also made of marl of the Buda region. the fragments kept by the local museum came into light by archaeological excavations between 1912 and 2019, on the site where the medieval episcopate laid. From the first time, researchers (based on Éber) wrote that the findings stand close to the ones in the cathedral’s rood screen. Most of them are well known – we could say – because tibor Koppány published every known piece in 1994. He wrote about a few other balustrade fragments too, but his descriptions are very short, and we can see drawings of only ca. one-third of all pieces. so i decided to see the original fragments and found that those small pieces kept by the museum don’t come from that balustrade can be seen today in the cathedral.The most important difference is the shaping of the baluster’s foot rings. they are divided: there is a vertical section and after that, the ring widens into a curved form. Furthermore, the image field of the dividing pillars framed in a more complex mode. On the image fields probably tapes, garlands, trophies were carved, but there is not any intact one, only very small pieces, which came to light in every corner of the site. so the balustrade’s original place couldn’t be determined certainly. nevertheless, because of the fine surfaces of the carvings, i think the balustrade stood inside, maybe in the medieval cathedral, perhaps in the chapel of saint nicolaus where Miklós Báthori was buried.Among the early renaissance-style pieces known from the medieval Hungarian Kingdom, there are a few analogies. First of all, we can see the very same solution on the foot rings of the Jagellonian era dividing pillars from Hungarian red marble in Vác. they belong to a group of red marble carvings: the other elements of this group can be found in Buda and esztergom. Furthermore, from the marl of the Buda region stone material i know only one other example where the baluster foot rings are similar: the gallery of the castle chapel in siklós. so i think we can say certainly that the „new” balustrade fragments from Vác were made during the Jagellonian era.

GLTM: A Global-Local Attention LSTM Model to Locate Dimer Motif of Single-Pass Membrane Proteins.

Single-pass membrane proteins, which constitute up to 50% of all transmembrane proteins, are typically active in significant conformational changes, such as a dimer or other oligomers, which is essential for understanding the function of transmembrane proteins. Finding the key motifs of oligomers through experimental observation is a routine method used in the field to infer the potential conformations of other members of the transmembrane protein family. However, approaches based on experimental observation need to consume a lot of time and manpower costs; moreover, they are hard to reveal the potential motifs. A proposed approach is to build an accurate and efficient transmembrane protein oligomer prediction model to screen the key motifs. In this paper, an attention-based Global-Local structure LSTM model named GLTM is proposed to predict dimers and screen potential dimer motifs. Different from traditional motifs screening based on highly conserved sequence search frame, a self-attention mechanism has been employed in GLTM to locate the highest dimerization score of subsequence fragments and has been proven to locate most known dimer motifs well. The proposed GLTM can reach 97.5% accuracy on the benchmark dataset collected from Membranome2.0. The three characteristics of GLTM can be summarized as follows: First, the original sequence fragment was converted to a set of subsequences which having the similar length of known motifs, and this additional step can greatly enhance the capability of capturing motif pattern; Second, to solve the problem of sample imbalance, a novel data enhancement approach combining improved one-hot encoding with random subsequence windows has been proposed to improve the generalization capability of GLTM; Third, position penalization has been taken into account, which makes a self-attention mechanism focused on special TM fragments. The experimental results in this paper fully demonstrated that the proposed GLTM has a broad application perspective on the location of potential oligomer motifs, and is helpful for preliminary and rapid research on the conformational change of mutants.

Evolution of cranial capacity revisited: A view from the late Middle Pleistocene cranium from Xujiayao, China

The Late Middle Pleistocene hominin fossils from the Xujiayao site in northern China have been closely studied in light of their morphological variability. However, all previous studies have focused on separated cranial fragments. Here, we report the first reconstruction of a fairly complete posterior cranium, Xujiayao 6 (XJY 6), confidently dated to ∼200–160 ka, which facilitated an assessment of its overall cranial size. XJY 6 was reconstructed from three of the original fragments—the PA1486 (No.7/XJY 6a) occipital bone, PA1490 (No.10/XJY 6b) right parietal bone, and PA1498 (No.17/XJY 15) left temporal bone—which originated from the same young adult individual. The XJY 6 endocranial capacity, estimated by measuring endocranial volume, was estimated using multiple regression formulae derived from ectocranial and endocranial measurements on select samples of Pleistocene hominins and recent modern humans. The results indicate that the larger pooled sample of both Pleistocene and recent modern humans was more robust for the endocranial capacity estimate. Based on the pooled sample using the ectocranial and endocranial measurements, we conservatively estimate the XJY 6 endocranial volume to be ∼1700 cm3 with a 95% confidence interval of 1555–1781 cm3. This is close to Xuchang 1, which dates to 125–105 ka and whose endocranial volume is ∼1800 cm3. Thus, XJY 6 provides the earliest evidence of a brain size that falls in the upper range of Neanderthals and modern Homo sapiens. XJY 6, together with Xuchang 1, Homo floresiensis, Homo luzonensis, and Homo naledi, challenge the general pattern that brain size gradually increases over geological time. This study also finds that hominin brain size expansion occurred at different rates across time and space.

Finite element analysis for fracture resistance of reattached human tooth fragment with different types of retentive preparation techniques.

Restoration of traumatized incisors by reattachment of the original tooth fragment appears to be the most conservative treatment approach. But the measurement of forces acting on natural tooth in-vivo poses many challenges. The advent of finite element analysis (FEA) has made it possible to demonstrate the propagation of stress through each part of a tooth and its restoration. The objective of this study was to evaluate and compare the fracture resistance of reattached human tooth fragment with different types of retentive preparation techniques using finite element analysis. An intact maxillary central incisor was obtained, scanned by laser and its Computer Assisted Device (CAD) model was generated and then converted to Finite Element Model(FEM). Mechanical properties of tooth specimen and materials were added on the generated mesh. These reattached fragments were then fractured with a force applied at 30°, 45°, 70° and 90° to the long axis of tooth. FEA Calculation was run with the setup. The highest fracture strength recovery was found with internal dentinal groove (64.97%) followed by labial double chamfer with lingual over-contour (54.49%), subsequently by labial and lingual double chamfer (51.31%) and least was with simple reattachment (28.27%). Fracture resistance varied with different retentive techniques and greatest strength was offered by internal dentinal groove preparation.

Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors.

Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram‐negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub‐micromolar, non‐peptidic, fragment‐like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.