Miracle-dz/UniFAR-FTUs huggingface dataset:
Both protein dynamics and ligand concentration can shift the binding mechanism between conformational selection and induced fit

Significance Mechanisms of protein–ligand binding have long generated interest in wide circles, including enzyme catalysis, receptor function, and drug design. This study reconciles some of the conflicting views. Using simulations of a model protein–ligand system, we demonstrate that neither conformational selection (CS) nor induced fit (IF) is the sole mechanism governing protein–ligand binding. Instead, both intrinsic and extrinsic factors can shift the binding mechanism between CS and IF. CS dominates when both protein conformational transition rate and ligand concentration are low. With the increase of either factor, the binding mechanism shifts to IF. The rigorous theoretical framework established here can guide experiments and simulations in determining the fraction of binding events achieved via either CS or IF. This study aimed to shed light on the long debate over whether conformational selection (CS) or induced fit (IF) is the governing mechanism for protein–ligand binding. The main difference between the two scenarios is whether the conformational transition of the protein from the unbound form to the bound form occurs before or after encountering the ligand. Here we introduce the IF fraction (i.e., the fraction of binding events achieved via IF), to quantify the binding mechanism. Using simulations of a model protein–ligand system, we demonstrate that both the rate of the conformational transition and the concentration of ligand molecules can affect the IF fraction. CS dominates at slow conformational transition and low ligand concentration. An increase in either quantity results in a higher IF fraction. Despite the many-body nature of the system and the involvement of multiple, disparate types of dynamics (i.e., ligand diffusion, protein conformational transition, and binding reaction), the overall binding kinetics over wide ranges of parameters can be fit to a single exponential, with the apparent rate constant exhibiting a linear dependence on ligand concentration. The present study may guide future kinetics experiments and dynamics simulations in determining the IF fraction.
A Route to Permanent Valley Polarization in Monolayer MoS2

Realization of permanent valley polarization in Cr-doped monolayer MoS2 is found to be unfeasible because of extended moment formation. Introduction of an additional hole is suggested as a viable solution. V-doped monolayer MoS2 is demonstrated to sustain permanent valley polarization and therefore can serve as a prototype material for valleytronics.
RD‐CODOX‐M/IVAC with rituximab and intrathecal liposomal cytarabine in adult Burkitt lymphoma and ‘unclassifiable’ highly aggressive B‐cell lymphoma

Specific trials on adult Burkitt lymphoma (BL) and ‘unclassifiable’ lymphomas with features intermediate between BL and diffuse large B‐cell lymphoma (BL/DLBCL) are advocated which include substantial numbers of older patients, to improve treatment feasibility, while countering risks of systemic and central nervous system (CNS) recurrences. We prospectively evaluated a modified CODOX‐M/IVAC (CODOX‐M: cyclophosphamide, vincristine, doxorubicin, high‐dose methotrexate; IVAC: ifosfamide, etoposide and high‐dose cytarabine) regimen by the addition of rituximab (R) and liposome‐encapsulated cytarabine (D) to increase antitumour activity and halve the number of intrathecal treatments. Thirty adults (40% >60 years) with BL (n = 15) and BL/DLBCL (n = 15) were accrued. Primary endpoints were progression‐free survival (PFS), CNS recurrence, and liposomal cytarabine‐associated toxicity. Eighty percent of patients received the whole treatment programme, the remaining cases received at least three full courses. Application of the RD‐CODOX‐M/IVAC regimen resulted in remarkable 4‐year PFS (78%) and complete remission (CR) rates (93%). However, PFS was significantly lower in patients older than 60 years as compared to younger ones (49%vs 93%, P = 0·03; median, 36 months), despite high actual dose‐intensity, CR rate and tolerability. Reduced‐intensity intratechal prophylaxis through liposomal cytarabine was effective because the CNS failure rate was low (3·4%) and without severe neurological toxicities. The RD‐CODOX‐M/IVAC strategy is feasible and highly effective, but improving outcomes in elderly patients remains a priority.
Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

Significance Autism spectrum disorder (ASD) research is complicated by heterogeneity. There are several types of genetic risk factors for ASDs, and that diversity may be reflected in case presentation. This study presents evidence for systematic variation in the genetic architecture of ASDs in which higher functioning cases, defined through cognitive and behavioral assessments, are more likely to manifest familial influences. This finding suggests that genetic and neurobiological research into ASDs and other neuropsychiatric disorders may be pursued more efficiently through greater phenotypic characterization. Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions—phenotypically and genetically—although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.
Bortezomib combined with low‐dose cytarabine in Intermediate‐2 and high risk myelodysplastic syndromes. A phase I/II Study by the GFM

Marrow cells from patients with higher‐risk myelodysplastic syndrome (MDS) exhibit constitutive nuclear factor (NF)‐κB activation. The proteasome inhibitor, bortezomib, has limited efficacy as a single agent in acute myeloid leukaemia. Its activity on leukaemic cell lines is potentiated by chemotherapy. We treated 43 higher‐risk MDS patients with bortezomib (1·5 mg/m2, days 1, 4, 8 and 11) and low dose cytarabine arabinoside (LDAC; 10 mg/m2, then 20 mg/m2 from days 1–14), every 28 d for four cycles. Median follow‐up was 29·7 months. Responses were seen in 12 of the 43 patients (28%), including complete response (CR, n = 1), marrow‐CR (n = 3), partial response (PR, n = 5) and haematological improvement (HI, n = 3). Responses were seen in 12 (36%) of the 33 previously untreated patients (11% CR, 13% PR, 2·5% HI), compared to none in the 12 previously treated patients (P < 0·01). Responders had better overall survival (median 18·2 vs. 10 months). One CR and 3 marrow‐CRs were seen in patients with complex karyotypes. Main toxicity was haematological, responsible for infection in six patients and bleeding in 3. Three patients with Grade 1–2 pre‐treatment haematotoxicity developed Grade 3–4 toxicity. Neuropathy was seen in 12% of patients. The addition of bortezomib to LDAC in higher‐risk MDS may improve results obtained with LDAC alone, especially in patients with unfavourable karyotypes.
Geologic carbon storage is unlikely to trigger large earthquakes and reactivate faults through which CO2 could leak

Significance Geologic carbon storage remains a safe option to mitigate anthropogenic climate change. Properly sited and managed storage sites are unlikely to induce felt seismicity because (i) sedimentary formations, which are softer than the crystalline basement, are rarely critically stressed; (ii) the least stable situation occurs at the beginning of injection, which makes it easy to control; (iii) CO2 will dissolve into brine at a significant rate, reducing overpressure; and (iv) CO2 will not flow across the caprock because of capillarity, but brine will, which will reduce overpressure further. Furthermore, CO2 leakage through fault reactivation is unlikely because the high clay content of caprocks ensures a reduced permeability and increased entry pressure along localized deformation zones. Zoback and Gorelick [(2012) Proc Natl Acad Sci USA 109(26):10164–10168] have claimed that geologic carbon storage in deep saline formations is very likely to trigger large induced seismicity, which may damage the caprock and ruin the objective of keeping CO2 stored deep underground. We argue that felt induced earthquakes due to geologic CO2 storage are unlikely because (i) sedimentary formations, which are softer than the crystalline basement, are rarely critically stressed; (ii) the least stable situation occurs at the beginning of injection, which makes it easy to control; (iii) CO2 dissolution into brine may help in reducing overpressure; and (iv) CO2 will not flow across the caprock because of capillarity, but brine will, which will reduce overpressure further. The latter two mechanisms ensure that overpressures caused by CO2 injection will dissipate in a moderate time after injection stops, hindering the occurrence of postinjection induced seismicity. Furthermore, even if microseismicity were induced, CO2 leakage through fault reactivation would be unlikely because the high clay content of caprocks ensures a reduced permeability and increased entry pressure along the localized deformation zone. For these reasons, we contend that properly sited and managed geologic carbon storage in deep saline formations remains a safe option to mitigate anthropogenic climate change.
Compartmentalization of the protein repair machinery in photosynthetic membranes

Significance The fitness and robustness of plants crucially depend on the molecular repair of the vulnerable photosystem II (PS II) supercomplex, embedded in photosynthetic thylakoid membranes. To maintain photosynthetic performance, plants evolved an efficient multistep PS II repair cycle. The PS II repair cycle relies on a well-defined order of reactions and partial separation of individual repair steps. By combining biochemical, spectroscopic, and ultrastructural techniques, we discover that plants establish reaction order and separation by confinement of the enzymes that catalyze the individual steps to spatially separated thylakoid subcompartments—grana, grana margins, and stroma lamellae—formed by the stacked membranes. Structural flexibility of the thylakoid architecture allows controlled access of the damaged PS II by the repair machinery. A crucial component of protein homeostasis in cells is the repair of damaged proteins. The repair of oxygen-evolving photosystem II (PS II) supercomplexes in plant chloroplasts is a prime example of a very efficient repair process that evolved in response to the high vulnerability of PS II to photooxidative damage, exacerbated by high-light (HL) stress. Significant progress in recent years has unraveled individual components and steps that constitute the PS II repair machinery, which is embedded in the thylakoid membrane system inside chloroplasts. However, an open question is how a certain order of these repair steps is established and how unwanted back-reactions that jeopardize the repair efficiency are avoided. Here, we report that spatial separation of key enzymes involved in PS II repair is realized by subcompartmentalization of the thylakoid membrane, accomplished by the formation of stacked grana membranes. The spatial segregation of kinases, phosphatases, proteases, and ribosomes ensures a certain order of events with minimal mutual interference. The margins of the grana turn out to be the site of protein degradation, well separated from active PS II in grana core and de novo protein synthesis in unstacked stroma lamellae. Furthermore, HL induces a partial conversion of stacked grana core to grana margin, which leads to a controlled access of proteases to PS II. Our study suggests that the origin of grana in evolution ensures high repair efficiency, which is essential for PS II homeostasis.
Electro-anatomical models of the cochlear implant

While cochlear implantation has become the standard of care in treating patients with severe to profound sensorineural hearing loss, the variation in benefit (communicative ability) individual patients derive from implantation remains both large and, for the most part, unexplained. One explanation for this variation is the status of the implanted ear which, when examined histopathologically. also displays substantial variation due to both the pathogenesis of hearing loss (etiology, etc.) and pathological changes initiated by implantation. For instance, across-patient variation in electrode position and insertion depth is clearly present. as are differential amounts of residual spiral ganglion survival. fibrous tissue formation and electrode encapsulation, cochlear ossification, and idiosyncratic damage to adjacent cochlear structures. Because of the complex geometric and electrical properties of the tissues found in the implanted ear. demonstrating the impact of pathological variability on neuronal excitation. and ultimately on behavioral performance. will likely require a detailed representation of the peripheral anatomy. Our approach has been to develop detailed, three-dimensional (3D) electro-anatomical models (EAMs) of the implanted ear capable of representing the aforementioned patient-specific types of pathological variation. In response to electric stimulation, these computational models predict an estimate of (1) the 3D electric field. (2) the cochleotopic pattern of neural activation, and (3) the electrically-evoked compound action potential (ECAP) recorded from intracochlear electrodes. This thesis focuses on three aims. First. two patient-specific EAMs are formulated from hundreds of digital images of the histologically-sectioned temporal bones of two patients, attempting to incorporate the detailed pathology of each. Second. model predictions are compared to relevant reports from the literature, data collected from a cohort of implanted research subjects, and. most importantly, to archival data collected during life from the same two patients used to derive our models. The latter comparisons to archival data (in the form of intracochlear potential recordings, psychophysical threshold measures, and ECAP recordings) collectively show a promising correspondence between model-predicted and empirically-measured data,. Third, by making incremental adjustments to the anatomical representation in the model, the impact of individual attributes are investigated, mechanisms that may degrade benefit suggested, and potential interventions explored.
Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process

Significance How malignant gliomas arise in a mature brain remains a mystery, which hinders the development of effective treatments. Which cell types can escape their quiescent, adult state and how they do so is unknown. Additionally, because gliomas are only detected at advanced stages, the full course of transformation remains uncharacterized. Here we report that adult oligodendrocyte precursor cells, despite their relatively quiescent properties, can be reactivated to a highly proliferative state by p53 and NF1 mutations and give rise to malignant gliomas. Furthermore, we describe the early phase of gliomagenesis for the first time, revealing a multistep process of reactivation, dormancy, and final transformation in which mammalian target of rapamycin signaling plays a critical role at both early and late steps. How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas.
Multistep hierarchical self-assembly of chiral nanopore arrays

Significance Bent-core mesogenic molecules form smectic liquid crystal phases in which the molecular layers are locally polar and chiral, and have a built-in tendency for saddle splay curvature, a combination that fills bulk neat bent-core smectics with self-assembled helical nanofilament bundles of twisted layers. This observation led us to explore the growth mode of such smectics under conditions of nanoconfinement and the remarkable observation reported here that single nanofilaments readily grow in linear nanoscale pores, generating a new motif of hierarchically self-assembled hybrid organic/inorganic structures for applications in chiral synthesis and separation. A series of simple hierarchical self-assembly steps achieve self-organization from the centimeter to the subnanometer-length scales in the form of square-centimeter arrays of linear nanopores, each one having a single chiral helical nanofilament of large internal surface area and interfacial interactions based on chiral crystalline molecular arrangements.
Sheep and Rabbit Cell Agglutinins in Horse Serum Sickness and Infectious Mononucleosis

It is generally conceded that immediate, accelerated and delayed anaphylactic reactions are fundamentally identical processes differing only in the speed and severity of response. The delayed serum reactions, which so frequently follow an initial injection of horse serum have never been satisfactorily explained. Individual predisposition is not commonly accepted since Park (1), Lamson (2) and many others have demonstrated that skin sensitivity tests are not always reliable guides in serum sickness. According to Von Pirquet and Schick (3) the formation of antibodies after an injection of horse serum precedes the complete disappearance of antigen from the blood and a reaction between these antibodies and residual antigen could account for the delayed response. Wells (4), Longcope and Rackeman (5) and others are inclined to favor this explanation. Weil (6), Opie (7) and Oguchi and Hamano (8), however, have shown that when antigen and antibody coexist in the same serum the residual antigen is not specific for the new formed antibodies.
Study of the Implementation of a New Community Health Nurse Role in Scotland

In 2006 the Scottish Executive began a radical and far reaching Review of Nursing in the Community (RONIC). This review proposed the absorption of district nursing, health visiting, school nursing and family health nursing into a single community health nurse role (CHN) role. The new role was piloted in three Health Boards across Scotland. This publication reports on the findings of a study which explored the implementation of the new role in these areas. The report provides insight into some of the structural and other challenges which affected the uptake and implementation of the Community Health Nurse. The research concluded that while there was broad support for the core elements of the role such as self-care, public health approaches and prevention, the study participants thought that rather than focussing on changing nurse roles, more should be done to improve interagency working and foster better collaboration among the existing nursing disciplines. The study highlighted a number of issues of relevance to ongoing work of the Modernising Nursing in the Community Programme.
SUMOylation of phytochrome-B negatively regulates light-induced signaling in Arabidopsis thaliana

Significance The photoreceptor phytochrome-B (phyB) cycles between its active Pfr [far red light (FRL)-absorbing state λmax, 730 nm] and inactive Pr [red light (RL)-absorbing state λmax, 660 nm] forms and regulates as red/far red light-activated/inactivated molecular switch plant growth and development. Here we show that conjugation of small ubiquitin-like modifier to the photoreceptor inhibits interaction of phyB Pfr with its immediate signaling partner PHYTOCHROME INTERACTING FACTOR 5 (PIF5). The impaired interaction of these proteins negatively affects photomorphogenic responses; thus, SUMOylation similar to phosphorylation plays a role in desensitizing phyB-mediated signaling. OVERLY TOLERANT TO SALT 1 and 2 (OTS1 and OTS2) are involved in regulating phyB action as these SUMO proteases mediate deconjugation of SUMO from phyB. The red/far red light absorbing photoreceptor phytochrome-B (phyB) cycles between the biologically inactive (Pr, λmax, 660 nm) and active (Pfr; λmax, 730 nm) forms and functions as a light quality and quantity controlled switch to regulate photomorphogenesis in Arabidopsis. At the molecular level, phyB interacts in a conformation-dependent fashion with a battery of downstream regulatory proteins, including PHYTOCHROME INTERACTING FACTOR transcription factors, and by modulating their activity/abundance, it alters expression patterns of genes underlying photomorphogenesis. Here we report that the small ubiquitin-like modifier (SUMO) is conjugated (SUMOylation) to the C terminus of phyB; the accumulation of SUMOylated phyB is enhanced by red light and displays a diurnal pattern in plants grown under light/dark cycles. Our data demonstrate that (i) transgenic plants expressing the mutant phyBLys996Arg-YFP photoreceptor are hypersensitive to red light, (ii) light-induced SUMOylation of the mutant phyB is drastically decreased compared with phyB-YFP, and (iii) SUMOylation of phyB inhibits binding of PHYTOCHROME INTERACTING FACTOR 5 to phyB Pfr. In addition, we show that OVERLY TOLERANT TO SALT 1 (OTS1) de-SUMOylates phyB in vitro, it interacts with phyB in vivo, and the ots1/ots2 mutant is hyposensitive to red light. Taken together, we conclude that SUMOylation of phyB negatively regulates light signaling and it is mediated, at least partly, by the action of OTS SUMO proteases.