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Karen's grandmothers
Karen adopts a grandmother from Stoneybrook Manor and learns funny dances and listens to old music.
Book
Structure of the human multidrug transporter ABCG2
ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional
in vitro
analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters.
The structure of human ABCG2 bound to an inhibitory antibody using cryo-electron microscopy, representing the first high-resolution structural data of a human multidrug transporter.
Structure of a human multi-drug transporter
ABCG2 is an ATP-binding cassette (ABC) transporter sometimes referred to as the breast cancer resistance protein. It is a multi-drug transporter that protects many tissues from foreign molecules and as such it has a key role in the effectiveness of commonly used oral drugs. It is also important in cancer treatments for the potential exploitation of the delivery of therapeutics to tumour cells. Here the authors present the structure of human ABCG2 bound to an inhibitory antibody, obtained using cryo-electron microscopy. This represents the first high-resolution structural data of a human multi-drug transporter. Two cholesterol molecules are bound to the multidrug binding pocket between the transmembrane domains, providing key information on substrate recognition by other ABC transporters.
Journal Article
Wandering souls : a novel
\"A boldly imagined debut novel about three Vietnamese siblings who seek refuge in the UK, expanding into a luminous meditation on ancestry and love. After the last American troops leave Vietnam, siblings Anh, Thanh, and Minh begin a perilous journey to Hong Kong with the promise that their parents and younger siblings will soon follow. But when tragedy strikes, the three children are left orphaned, and sixteen-year-old Anh becomes the caretaker for her two younger brothers overnight. In the years that follow, Anh and her brothers resettle in the UK and confront their new identities as refugees, first in overcrowded camps and resettlement centers and then, later, in a modernizing London plagued by social inequality and raging anti-immigrant sentiment. Anh works in a clothing factory to pay their bills. Minh loiters about with fellow unemployed high school dropouts. Thanh, the youngest, plays soccer with his British friends after class. As they mature, each sibling reckons with survivor's guilt, unmoored by their parents' absence. With every choice they make, their paths diverge further, until it's unclear if love alone can keep them together. Told through lyrical narrative threads, historical research, voices from lost family, and notes by an unnamed narrator determined to chart their fate, 'Wandering souls' captures the lives of a family marked by war and loss yet relentless in the pursuit of a better future. With urgency and precision, it affirms that the most important stories are those we claim for ourselves, establishing Cecile Pin as a masterful new literary voice.\"-- Provided by publisher.
Book
Structure and mechanism of the cation–chloride cotransporter NKCC1
Cation–chloride cotransporters (CCCs) mediate the electroneutral transport of chloride, potassium and/or sodium across the membrane. They have critical roles in regulating cell volume, controlling ion absorption and secretion across epithelia, and maintaining intracellular chloride homeostasis. These transporters are primary targets for some of the most commonly prescribed drugs. Here we determined the cryo-electron microscopy structure of the Na–K–Cl cotransporter NKCC1, an extensively studied member of the CCC family, from
Danio rerio
. The structure defines the architecture of this protein family and reveals how cytosolic and transmembrane domains are strategically positioned for communication. Structural analyses, functional characterizations and computational studies reveal the ion-translocation pathway, ion-binding sites and key residues for transport activity. These results provide insights into ion selectivity, coupling and translocation, and establish a framework for understanding the physiological functions of CCCs and interpreting disease-related mutations.
The cryo-EM structure of the zebrafish cation–chloride cotransporter NKCC1 reveals the domain organization, ion translocation pathway, ion-binding sites and key residues for binding activity, providing insights into the activity of this family of transporter proteins with key roles in physiology.
Journal Article
The deep end
On their a cross-country camping trip, Greg Heffley and his family find themselves stranded at an RV park that's not exactly a summertime paradise and when the skies open up and the water starts to rise, the Heffleys wonder if they can save their vacation--or if they're already in too deep.
Book
Prevalence and associated risk factors of post-traumatic stress disorder among survivors of the 2023 Turkey earthquake
Earthquakes can cause psychological trauma among survivors as well as physical trauma. This study aims to determine the prevalence of post-traumatic stress disorder (PTSD) and identify associated risk factors among earthquake survivors after the 2023 Turkey earthquake.
This prospective cross-sectional study was conducted in the emergency department of a tertiary university hospital between May 6, 2023, and May 16, 2023. An online questionnaire was sent to the participants. The questionnaire form consisted of three parts. In the first part, the sociodemographic characteristics of the participants were included. In the second part, the participants were asked about their experiences with the earthquake. In the third part, the post-traumatic stress disorder checklist for the Diagnostic and Statistical Manual of Mental Disorders, which screens PTSD among the participants, was included. Participants who did not complete all the questions and had severe communication disorders were excluded.
The prevalence of probable PTSD among the participants was 51.4% (n = 197). Age (OR: 0.96 95% CI: 0.93–99), female gender (OR: 4.54 95% CI: 2.39–8.61), being the head of the family (OR: 2.00 95% CI: 1.04–3.82), bereavement (OR: 1.71 95% CI: 1.03–2.82), lost loved ones (OR: 3.15 95% CI: 1.67–5.92), low social support (OR: 1.80 95% CI: 1.12–2.90) and receiving emergency care at the field (OR: 6.67 95% CI: 1.03–43.2) were the associated risk factors of PTSD among earthquake survivors.
The prevalence of PTSD among survivors three months after the 2023 Turkey earthquake is over half of the survivors. Younger age, female gender, being the head of the family, bereavement, lost loved ones, low social support, and receiving emergency care in the field were the associated risk factors of PTSD among earthquake survivors. Considering survivors may visit EDs until other outpatient clinics are re-established and the high rate of PTSD, rapid psychological evaluations can be performed in emergency departments. Emergency physicians should be aware of possible risk factors and high rate of PTSD.
Journal Article
Banyan Moon : a novel
\"Three Vietnamese American women mourning the death of the family matriarch recount their lives and childhoods at a crumbling, gothic manor called Banyan House, where the secrets of her grandmother's past come to light\"-- Provided by publisher.
Book
Prediction of post-traumatic stress disorder in family members of ICU patients: a machine learning approach
PurposePost-traumatic stress disorder (PTSD) can affect family members of patients admitted to the intensive care unit (ICU). Easily accessible patient’s and relative’s information may help develop accurate risk stratification tools to direct relatives at higher risk of PTSD toward appropriate management.MethodsPTSD was measured 90 days after ICU discharge using validated instruments (Impact of Event Scale and Impact of Event Scale-Revised) in 2374 family members. Various supervised machine learning approaches were used to predict PTSD in family members and evaluated on an independent held-out test dataset. To better understand variables’ contributions to PTSD predicted probability, we used machine learning interpretability methods on the best predictive algorithm.ResultsNon-linear ensemble learning tree-based methods showed better predictive performances (Random Forest—area under curve, AUC = 0.73 [0.68–0.77] and XGBoost—AUC = 0.73 [0.69–0.78]) than regularized linear models, kernel-based models, or deep learning models. In the best performing algorithm, most important features that positively contributed to PTSD’s predicted probability were all non-modifiable factors, namely, lower patient’s age, longer duration of ICU stay, relative’s female sex, lower relative’s age, relative being a spouse/child, and patient’s death in ICU. A sensitivity analysis in bereaved relatives did not alter the algorithm’s predictive performance.ConclusionWe propose a machine learning-based approach to predict PTSD in relatives of ICU patients at an individual level. In this model, PTSD is mostly influenced by non-modifiable factors.
Journal Article
My Baba's garden
A story about the special relationship between a child and his grandmother and the time they spend looking for worms for the garden.
Book
Cellular Models and In Vitro Assays for the Screening of modulators of P-gp, MRP1 and BCRP
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are highly expressed in tumor cells, as well as in organs involved in absorption and secretion processes, mediating the ATP-dependent efflux of compounds, both endogenous substances and xenobiotics, including drugs. Their expression and activity levels are modulated by the presence of inhibitors, inducers and/or activators. In vitro, ex vivo and in vivo studies with both known and newly synthesized P-glycoprotein (P-gp) inducers and/or activators have shown the usefulness of these transport mechanisms in reducing the systemic exposure and specific tissue access of potentially harmful compounds. This article focuses on the main ABC transporters involved in multidrug resistance [P-gp, multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP)] expressed in tissues of toxicological relevance, such as the blood-brain barrier, cardiovascular system, liver, kidney and intestine. Moreover, it provides a review of the available cellular models, in vitro and ex vivo assays for the screening and selection of safe and specific inducers and activators of these membrane transporters. The available cellular models and in vitro assays have been proposed as high throughput and low-cost alternatives to excessive animal testing, allowing the evaluation of a large number of compounds.
Journal Article