Craniomandibular trauma and tooth loss in northern dogs and wolves : implications for the archaeological study of dog husbandry and domestication

Funding: Funding for this project was provided by an ERC Advanced Grant (#295458) to Dr. David Anderson, University of Aberdeen (http://erc.europa.eu). Financial support to Mikhail V. Sablin was provided by the Russian Foundation for Basic Research (Grant 13-04-00203; http://www.rfbr.ru/rffi/ru). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscripPeer reviewedPublisher PD

CBCT and MRT – diagnostical duet in stomatological arthrology

Однією із найпоширеніших причин звернення пацієнтів до лікаря-стоматолога є патологія скронево- нижньощелепного суглобу (СНЩС). Окремий інтерес викликають дисфункції СНЩС, які мають поліетіологічний характер та найрізноманітніші клінічні прояви. Запорукою успіху у лікуванні цього контингенту пацієнтів є комплексна діагностична тактика лікаря. У роботі пропонується удосконалений та систематизований алгоритм обстеження пацієнта, що дозволить комплексно оцінити стан СНЩС та оточуючих тканин

Mirror symmetry breaking through an internal degree of freedom leading to directional motion

We analyze here the minimal conditions for directional motion (net flow in phase space) of a molecular motor placed on a mirror-symmetric environment and driven by a center-symmetric and time-periodic force field. The complete characterization of the deterministic limit of the dissipative dynamics of several realizations of this minimal model, reveals a complex structure in the phase diagram in parameter space, with intertwined regions of pinning (closed orbits) and directional motion. This demonstrates that the mirror-symmetry breaking which is needed for directional motion to occur, can operate through an internal degree of freedom coupled to the translational one.Comment: Accepted for publication in Phys. Rev.

Dogs accompanied humans during the Neolithic expansion into Europe

International audienceNear Eastern Neolithic farmers introduced several species of domestic plants and animals as they dispersed into Europe. Dogs were the only domestic species present in both Europe and the Near East prior to the Neolithic. Here, we assessed whether early Near Eastern dogs possessed a unique mitochondrial lineage that differentiated them from Mesolithic European populations. We then analysed mitochondrial DNA sequences from 99 ancient European and Near Eastern dogs spanning the Upper Palaeolithic to the Bronze Age to assess if incoming farmers brought Near Eastern dogs with them, or instead primarily adopted indigenous European dogs after they arrived. Our results show that European pre-Neolithic dogs all possessed the mitochondrial haplogroup C, and that the Neolithic and Post-Neolithic dogs associated with farmers from Southeastern Europe mainly possessed haplogroup D. Thus, the appearance of haplogroup D most probably resulted from the dissemination of dogs from the Near East into Europe. In Western and Northern Europe, the turnover is incomplete and haplogroup C persists well into the Chalcolithic at least. These results suggest that dogs were an integral component of the Neolithic farming package and a mitochondrial lineage associated with the Near East was introduced into Europe alongside pigs, cows, sheep and goats. It got diluted into the native dog population when reaching the Western and Northern margins of Europe

Diagnostics of testicular torsion using the TWIST scale (Testicular Workup for Ischemia and Suspected Torsion)

Introduction. Testicular torsion (TT) is the most common pediatric emergency urological pathology. To reduce the duration of the diagnostic stage, systems for assessing the risks of testicular torsion based on anamnesis and clinical symptoms were proposed. In 2013, Barbosa et al. proposed the TWIST system (testicular examination for ischemia and suspected torsion), which became the most well-known and widespread. This system makes it possible to identify groups of patients who do not require scrotal ultrasound, which reduces the number of stages in the diagnosis of TT.Objective. To evaluate the experience of using and diagnostic significance of the TWIST scale based on available data in scientific publications.Materials & methods. Review and analysis of literature data on the use of the TWIST scale.Results. We conducted an analysis of 13 publications, in which the results of using TWIST with statistical analysis were published. In all articles, the final diagnosis was established according to Doppler scrotal ultrasound or intraoperatively. Analysis of publications shows that even in large foreign medical centers there is a problem of emergency scrotal ultrasound, which increases the time of testicular ischemia with ТТ. To use the TWIST scale, only history and physical examination data are needed. Any specialist can use the scale in his practise. The low probability of TT in the low-risk group makes it possible not to perform routine scrotal revision, and, consequently, material and human resources are saved.Conclusion. Literature analysis has shown that the use of the original TWIST scale proposed by J.A. Barbosa, in case of suspected testicular torsion, has sufficient diagnostic accuracy, high sensitivity and specificity of TT detection, which significantly reduces the need for ultrasound, reduces the diagnostic time before surgery, that increases testicular survival

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination With Fulvestrant in Patients With AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.

PURPOSE:The activating mutation AKT1 E17K occurs in ~7% of ER+ metastatic breast cancer (MBC). We report, from a multipart, first-in-human, Phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of AKT1 E17K-mutant ER+ MBC patients. PATIENTS AND METHODS:Patients with an AKT1 E17K mutation, detected by local (NGS) or central (plasma-based BEAMing) testing, received capivasertib 480 mg bid, 4 days on, 3 days off, weekly or 400 mg bid combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS) and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort. RESULTS:From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although this latter group may have had more aggressive disease at baseline. AKT1 E17K mutations were detectable in plasma by BEAMing (95%, 41/43), ddPCR (80%, 33/41) and NGS (76%, 31/41). A 50% decrease in AKT1 E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy (most frequent grade ≥3 adverse events: rash [9% vs 20%], hyperglycemia [5% vs 30%], diarrhea [5% vs 10%]). CONCLUSIONS:Capivasertib demonstrated clinically meaningful activity in heavily pretreated AKT1 E17K-mutant ER+ MBC patients, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination

A seesaw model for intermolecular gating in the kinesin motor protein

Recent structural observations of kinesin-1, the founding member of the kinesin group of motor proteins, have led to substantial gains in our understanding of this molecular machine. Kinesin-1, similar to many kinesin family members, assembles to form homodimers that use alternating ATPase cycles of the catalytic motor domains, or “heads”, to proceed unidirectionally along its partner filament (the microtubule) via a hand-over-hand mechanism. Cryo-electron microscopy has now revealed 8-Å resolution, 3D reconstructions of kinesin-1•microtubule complexes for all three of this motor’s principal nucleotide-state intermediates (ADP-bound, no-nucleotide, and ATP analog), the first time filament co-complexes of any cytoskeletal motor have been visualized at this level of detail. These reconstructions comprehensively describe nucleotide-dependent changes in a monomeric head domain at the secondary structure level, and this information has been combined with atomic-resolution crystallography data to synthesize an atomic-level "seesaw" mechanism describing how microtubules activate kinesin’s ATP-sensing machinery. The new structural information revises or replaces key details of earlier models of kinesin’s ATPase cycle that were based principally on crystal structures of free kinesin, and demonstrates that high-resolution characterization of the kinesin–microtubule complex is essential for understanding the structural basis of the cycle. I discuss the broader implications of the seesaw mechanism within the cycle of a fully functional kinesin dimer and show how the seesaw can account for two types of "gating" that keep the ATPase cycles of the two heads out of sync during processive movement

First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results.

PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts

Neck-motor interactions trigger rotation of the kinesin stalk

Rotation of the coiled-coil stalk of the kinesin-14 motors is thought to drive displacements or steps by the motor along microtubules, but the structural changes that trigger stalk rotation and the nucleotide state in which it occurs are not certain. Here we report a kinesin-14 neck mutant that releases ADP more slowly than wild type and shows weaker microtubule affinity, consistent with defective stalk rotation. Unexpectedly, crystal structures show the stalk fully rotated – neck-motor interactions destabilize the stalk, causing it to rotate and ADP to be released, and alter motor affinity for microtubules. A new structural pathway accounts for the coupling of stalk rotation – the force-producing stroke – to changes in motor affinity for nucleotide and microtubules. Sequential disruption of salt bridges that stabilize the unrotated stalk could cause the stalk to initiate and complete rotation in different nucleotide states