Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Evaluating Tissue Mechanical Properties Using Quantitative Mueller Matrix Polarimetry and Neural Network

Evaluation of the mechanical properties of biological tissues has always been an important issue in the field of biomedicine. The traditional method for mechanical properties measurement is to perform in vitro tissue deformation experiments. With the fast development of optical and image processing techniques, more and more non-invasive and non-contact optical methods have been applied to the analysis of tissue mechanical features. In this study, we use Mueller matrix polarimetry to quantitatively obtain the mechanical properties of bovine tendon tissues. Firstly, to study the structural information and the changes in the optical characteristics of the tendon tissue under different stretching states, 3 × 3 Mueller matrix images of bovine tendon tissue samples are acquired by backscattering measurement setups based on a polarized camera. Then, we extract the frequency distribution histograms (FDHs) of the Mueller matrix elements to reveal the structural changes of the tendon tissue more clearly during the stretching process. Last, we calculate the Mueller matrix transformation (MMT) parameters, the total anisotropy t1 and the anisotropy direction α1 of the tendon tissue samples under different stretching processes to quantitatively characterize their structural changes under different mechanical states. The central moments of the MMT parameters can be used to distinguish the different stretching states of the tendon tissue. For better discrimination based on the MMT parameters, we design a multilayer neural network that takes the first-order moments of the MMT parameters as the input features. After training, a high-precision classification model of the stretching states of tendon tissue samples is finally obtained, and the total classification accuracy achieves 98%. The experimental results show that the Mueller matrix polarimetry can be a potential non-contact tool for tissue mechanical properties evaluation

KIF20A Predicts Poor Survival of Patients and Promotes Colorectal Cancer Tumor Progression through the JAK/STAT3 Signaling Pathway

Kinesin family member 20A (KIF20A) has been recently reported to be upregulated and associated with increased invasiveness and metastasis in several malignancies. However, the role of KIF20A in colorectal cancer (CRC) is still unclear. This study is aimed at investigating the potential roles of KIF20A in the development of CRC. The results of bioinformatics analysis, immunohistochemical staining, and Western blot analysis showed that KIF20A was overexpressed in CRC tissues compared with adjacent normal tissues. High expression of KIF20A in CRC tissues was associated with depth of invasion, lymphatic node metastasis, distant metastasis, and TNM stage. Moreover, the Kaplan-Meier survival analysis showed that CRC patients with high KIF20A expression had poor prognoses. Cox regression analysis revealed that KIF20A was an independent prognostic factor in patients with CRC. Further studies suggested that knockdown of KIF20A was able to reduce cell proliferation and migration by inhibiting the JAK/STAT3 pathway. Taken together, we propose that KIF20A plays a critical role in the tumorigenesis and tumor progression of colorectal cancer and could represent a potential therapeutic target for CRC

Expert consensus statement on therapeutic drug monitoring and individualization of linezolid

Linezolid is an oxazolidinone antibacterial drug, and its therapeutic drug monitoring and individualized treatment have been challenged since its approval. With the in-depth clinical research of linezolid, we have changed our attitude toward its therapeutic drug monitoring and our view of individualized treatment. On the basis of summarizing the existing clinical studies, and based on the practical experience of each expert in their respective professional fields, we have formed this expert consensus. Our team of specialists is a multidisciplinary team that includes pharmacotherapists, clinical pharmacology specialists, critical care medicine specialists, respiratory specialists, infectious disease specialists, emergency medicine specialists and more. We are committed to the safe and effective use of linezolid in patients in need, and the promotion of its therapeutic drug monitoring

Flat band-engineered spin-density wave and the emergent multi-kk magnetic state in the topological kagome metal Mn3_{3}Sn

Magnetic kagome metals, in which topologically non-trivial band structures and electronic correlation are intertwined, have recently emerged as an exciting platform to explore exotic correlated topological phases, that are usually not found in weakly interacting materials described within the semi-classical picture of electrons. Here, via a comprehensive single-crystal neutron diffraction and first-principles density functional theory study of the archetypical topological kagome metal Mn$_3$Sn, which is also a magnetic Weyl fermion material and a promising chiral magnet for antiferromagnetic spintronics, we report the realisation of an emergent spin-density wave (SDW) order, a hallmark correlated many-body phenomenon, that is engineered by the Fermi surface nesting of topological flat bands. We further reveal that the phase transition, from the well-known high-temperature coplanar and non-collinear k = 0 inverse triangular antiferromagnetic order to a double-$k$ non-coplanar modulated incommensurate magnetic structure below $T_1$ = 280 K, is primarily driven by the SDW instability. The double-$k$ nature of this complex low-temperature magnetic order, which can be regarded as an intriguing superposition of a longitudinal SDW with a modulation wavevector k$_L$ and a transverse incommensurate helical magnetic order with a modulation wavevector k$_T$, is unambiguously confirmed by our observation of the inter-modulation high-order harmonics of the type of 2k$_L$+k$_T$. This discovery not only solves a long-standing puzzle concerning the nature of the phase transition at $T_1$, but also provides an extraordinary example on the intrinsic engineering of correlated many-body phenomena in topological matter. The identified multi-$k$ magnetic state can be further exploited for the engineering of the new modes of magnetization and chirality switching in antiferromagnetic spintronics