Carborane‐Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron‐Capture Therapy (BNCT)

Based on the previously reported potent and selective sulfone hydroxamate inhibitors SC‐76276, SC‐78080 (SD‐2590), and SC‐77964, potent MMP inhibitors have been designed and synthesized to append a boron‐rich carborane cluster by employing click chemistry to target tumor cells that are known to upregulate gelatinases. Docking against MMP‐2 suggests binding involving the hydroxamate zinc‐binding group, key H‐bonds by the sulfone moiety with the peptide backbone residues Leu82 and Leu83, and a hydrophobic interaction with the deep P1’ pocket. The more potent of the two triazole regioisomers exhibits an IC50 of 3.7 nM versus MMP‐2 and IC50 of 46 nM versus MMP‐9

Phenomenology of Lepton Masses and Mixing with Discrete Flavor Symmetries

The observed pattern of fermion masses and mixing is an outstanding puzzle in particle physics, generally known as the flavor problem. Over the years, guided by precision neutrino oscillation data, discrete flavor symmetries have often been used to explain the neutrino mixing parameters, which look very different from the quark sector. In this review, we discuss the application of non-Abelian finite groups to the theory of neutrino masses and mixing in the light of current and future neutrino oscillation data. We start with an overview of the neutrino mixing parameters, comparing different global fit results and limits on normal and inverted neutrino mass ordering schemes. Then, we discuss a general framework for implementing discrete family symmetries to explain neutrino masses and mixing. We discuss CP violation effects, giving an update of CP predictions for trimaximal models with nonzero reactor mixing angle and models with partial $\mu-\tau$ reflection symmetry, and constraining models with neutrino mass sum rules. The connection between texture zeroes and discrete symmetries is also discussed. We summarize viable higher-order groups, which can explain the observed pattern of lepton mixing where the non-zero $\theta_{13}$ plays an important role. We also review the prospects of embedding finite discrete symmetries in the Grand Unified Theories and with extended Higgs fields. Models based on modular symmetry are also briefly discussed. A major part of the review is dedicated to the phenomenology of flavor symmetries and possible signatures in the current and future experiments at the intensity, energy, and cosmic frontiers. In this context, we discuss flavor symmetry implications for neutrinoless double beta decay, collider signals, leptogenesis, dark matter, as well as gravitational waves.Comment: 55 pages + references, invited review submitted to Progress in Particle and Nuclear Physic

Reply to Guy et al.: Support for a bottleneck in the 2011 Escherichia coli O104:H4 outbreak in Germany

In our paper (1), we analyzed isolates from the Escherichia coli O104:H4 outbreaks in Germany and France in May to July 2011. We concluded that, although the German outbreak was larger, the German isolates represent a clade within the greater diversity of the French outbreak. We proposed several hypotheses to explain these findings, including that the lineage leading to the German outbreak went through a narrow bottleneck that purged diversity. Guy et al. (2) report the genomes of eight additional E. coli O104:H4 isolates sampled from the German outbreak. By focusing on the numbers of SNPs in their samples, they suggest that the German outbreak is more diverse than we reported and is similar to the French outbreak. In fact, Guy et al.’s data (2) strongly support our conclusion that the German outbreak represents a clade within the diversity

The influence of long-term treadmill exercise on bone mass and articular cartilage in ovariectomized rats

<p>Abstract</p> <p>Background</p> <p>Loss of bone quality and deterioration of articular cartilage are commonly seen after menopause. While exercise may protect against tissue degeneration, a clear link has yet to be established. The aim of the present study is to investigate the influence of long-term treadmill exercise on changes in bone mass and articular cartilage in ovariectomized rats.</p> <p>Methods</p> <p>Sixty female Sprague-Dawley rats were randomly assigned to 4 groups: ovariectomized (OVX), ovariectomized plus treadmill exercise (OVX-RUN), treadmill exercise alone (RUN), and control (CON) groups. After 36 weeks, the following variables were compared among the 4 groups. Bone mass was evaluated by trabecular bone volume and bone mineral density (BMD). Articular cartilage in the knee joints was evaluated by histology analysis and a modified Mankin score.</p> <p>Results</p> <p>Rats in the ovariectomized groups (OVX and OVX-RUN) had significantly lower BMD and bone mass than the non-ovariectomized rats (CON and RUN), indicating that exercise did little to preserve bone mass. However, the sedentary OVX group had a significantly worse modified Mankin score (7.7 ± 1.4) than the OVX-RUN group (4.8 ± 1.0), whose scores did not differ significantly from the other 2 non-operated groups. The articular cartilage in the sedentary OVX rats was relatively thinner, hypocellular, and had more clefts than in the other 3 groups.</p> <p>Conclusion</p> <p>This study suggests that long-term exercise protects articular cartilage in OVX rats but does not retard the loss of bone mass seen in after menopause.</p

New Boron Delivery Agents

This proceeding article compiles current research on the development of boron delivery drugs for boron neutron capture therapy that was presented and discussed at the National Cancer Institute (NCI) Workshop on Neutron Capture Therapy that took place on April 20-22, 2022. The most used boron sources are icosahedral boron clusters attached to peptides, proteins (such as albumin), porphyrin derivatives, dendrimers, polymers, and nanoparticles, or encapsulated into liposomes. These boron clusters and/or carriers can be labeled with contrast agents allowing for the use of imaging techniques, such as PET, SPECT, and fluorescence, that enable quantification of tumor-localized boron and their use as theranostic agents.C.V. thanks the Spanish Ministerio de Economiay Competitividad (PID2019-106832RB-100) and the Generalitat de Catalunya (2017SGR1720). H.N. received a Grant-in-Aid for Scientific Research (B) (No. 21H02066) from MEXT, Japan. M.G.H.V. thanks the National Institutes of Health grant number T34 GM136452. R.P. thanks the National Institutes of Health, grant number R21 CA259911 and the Department of Neurosurgery, Cedars Sinai MedicalCenter, Los Angeles.With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe

Standard Model Theory for the FCC-ee Tera-Z stage

The future 100-km circular collider FCC at CERN is planned to operate in one of its modes as an electron-positron FCC-ee machine. We give an overview comparing the theoretical status to the experimental demands of one of four foreseen FCC-ee operating stages, Z-boson resonance energy physics, called the FCC-ee Tera-Z stage for short. The FCC-ee Tera-Z will deliver the highest integrated luminosities as well as very small systematic errors for a study of the Standard Model (SM) with unprecedented precision. In fact, the FCC-ee Tera-Z will allow the study of at least one more perturbative order in quantum field theory compared to the LEP/SLC precision. The real problem is that the present precision of theoretical calculations of the various SM observables does not match that of the anticipated experimental measurements. The bottle-necks to overcoming this situation are identified. In particular, the issues of precise QED unfolding and the correct calculation of SM pseudo-observables are critically reviewed. In an Executive Summary, we specify which basic theoretical calculations are needed to meet the strong experimental expectations at the FCC-ee Tera-Z. Several methods, techniques and tools needed for higher-order multi-loop calculations are presented. By inspection of the Z-boson partial and total decay width analyses, it is argued that at the beginning of operation of the FCC-ee Tera-Z, the theory predictions may be tuned to be precise enough not to limit the physics interpretation of the measurements. This statement is based on anticipated progress in analytical and numerical calculations of multi-loop and multi-scale Feynman integrals and on the completion of two-loop electroweak radiative corrections to the SM pseudo-observables this year. However, the above statement is conditional as the theoretical issues demand a very dedicated and focused investment by the community.Comment: Published versio

Low-frequency vibratory exercise reduces the risk of bone fracture more than walking: a randomized controlled trial

BACKGROUND: Whole-body vibration (WBV) is a new type of exercise that has been increasingly tested for the ability to prevent bone fractures and osteoporosis in frail people. There are two currently marketed vibrating plates: a) the whole plate oscillates up and down; b) reciprocating vertical displacements on the left and right side of a fulcrum, increasing the lateral accelerations. A few studies have shown recently the effectiveness of the up-and-down plate for increasing Bone Mineral Density (BMD) and balance; but the effectiveness of the reciprocating plate technique remains mainly unknown. The aim was to compare the effects of WBV using a reciprocating platform at frequencies lower than 20 Hz and a walking-based exercise programme on BMD and balance in post-menopausal women. METHODS: Twenty-eight physically untrained post-menopausal women were assigned at random to a WBV group or a Walking group. Both experimental programmes consisted of 3 sessions per week for 8 months. Each vibratory session included 6 bouts of 1 min (12.6 Hz in frequency and 3 cm in amplitude with 60° of knee flexion) with 1 min rest between bouts. Each walking session was 55 minutes of walking and 5 minutes of stretching. Hip and lumbar BMD (g·cm(-2)) were measured using dual-energy X-ray absorptiometry and balance was assessed by the blind flamingo test. ANOVA for repeated measurements was adjusted by baseline data, weight and age. RESULTS: After 8 months, BMD at the femoral neck in the WBV group was increased by 4.3% (P = 0.011) compared to the Walking group. In contrast, the BMD at the lumbar spine was unaltered in both groups. Balance was improved in the WBV group (29%) but not in the Walking group. CONCLUSION: The 8-month course of vibratory exercise using a reciprocating plate is feasible and is more effective than walking to improve two major determinants of bone fractures: hip BMD and balance