bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic-Pharmacodynamic Analysis of Concentration-Response Relationship in Schizophrenia Patients Treated with Olanzapine or OLZ/SAM
Authors: Sun Lei , Mills Richard , Sadler Brian M. , Rege Bhaskar
Published: April 2022

Background

A combination of olanzapine and samidorphan (OLZ/SAM) that provides the efficacy of olanzapine while mitigating weight gain was recently approved by the Food and Drug Administration for the treatment of schizophrenia and bipolar I disorder. This exploratory population pharmacokinetic-pharmacodynamic analysis evaluated potential relationships between drug exposure and treatment effects.

Methods

Positive and Negative Syndrome Scale (PANSS) total score and/or bodyweight data from efficacy studies served as pharmacodynamic endpoints. Pharmacokinetic input came from predicted plasma drug concentrations using a population pharmacokinetic model for the corresponding studies. Regression and box plots were generated to investigate potential pharmacokinetic-pharmacodynamic relationships.

Results

PANSS total score and/or bodyweight records were paired with olanzapine and/or samidorphan concentrations from 1464 patients with schizophrenia. Within the clinical dose range for olanzapine (10-20 mg/day) and samidorphan (5-20 mg/day), no significant correlation was noted between (a) olanzapine concentrations and change in PANSS total score, or % change in body weight, in patients treated with OLZ/SAM or olanzapine, and (b) samidorphan concentration or samidorphan-to-olanzapine concentration ratio and % change in body weight. No meaningful difference in olanzapine and samidorphan concentrations or samidorphan-to-olanzapine concentration ratios was observed between patients with <10% and ≥10% weight gain.

Conclusions

The antipsychotic efficacy of olanzapine was not affected by samidorphan at any concentration of olanzapine. Furthermore, olanzapine-associated weight gain did not correlate with olanzapine dose or plasma concentration. Finally, the effect of OLZ/SAM on mitigation of olanzapine-associated weight gain was not affected by intersubject variability in olanzapine and/or samidorphan plasma concentrations.

Funding

Alkermes, Inc.
Psychosocial Stressors and Phase of Life Problems as a Cause of Somatic Symptom Disorder in Healthy Patients: Case Report
Authors: Bhimanadham Narmada Neerja , Ali Ornela , Hossain Asghar
Published: April 2022

Knowledge about the aging process and in particular changes affecting mental health in the elderly has been gradually acquired as more research studies focus on this topic. However, as the majority of studies are geared toward more commonly encountered mental health disorders such as depression and anxiety, there is less data for conditions that are encountered less frequently such as somatoform disorder. We present the case of a 62-year-old male who presents with idiopathic physical symptoms not explained by any medical conditions except somatic symptom disorder. A comprehensive review of the literature using databases, such as PubMed, NCBI, and Google Scholar was conducted to gain a better understanding of this specific disorder and to rule out similar conditions that present in a similar way. The purpose of this case report is to emphasize the fact that social stressors and phase of life problems could trigger somatic symptom disorder in otherwise healthy individuals.

Funding

No funding
Psychiatric Manifestations of Huntington’s Disease Case Report
Authors: Kukaj Pajtesa , Corzo Krysten
Published: April 2022

Huntington’s disease is a rare autosomal dominant disease with an estimated incidence of approximately 4-6.1/100,000 people within the United States. Often recognized for its progressive motor symptoms and cognitive decline, its psychiatric symptoms can be underrepresented. It is only within the past few years that we have come to appreciate the range and prevalence of neuropsychiatric symptoms that plague patients with chronic degenerative disease. Still, some patients’ neuropsychiatric symptoms may be misinterpreted as part of other psychiatric conditions. Specifically, prodromal phase symptoms such as agitation, impulsivity, depression, and more may present similarly to purely psychiatric disorders. This may complicate patient’s clinical picture consequently leading to delays in diagnosis and in treatment. Such delays can worsen prognosis and a patient’s quality of life. Here, we describe a multifaceted case of a patient who exhibited striking psychiatric symptoms as her primary presentation. This case helps highlight the importance of recognizing psychiatric symptoms including irritability, depression, as well as the less common psychotic features as early warning signs of impending progression of a neurodegenerative disorder such as Huntington’s disease.

Funding

No funding
Depression Screening of Patients with Neurological Disorders in an Outpatient Setting
Authors: Singer Roxanne , Gheorghiu Dorothy
Published: April 2022

Depression is a widespread comorbidity associated with a number of neurological disorders. Untreated depression has negative impacts on patients with neurological disorders, including intensification of pain, increase in symptomatology, impaired quality of life, and nonadherence to treatment. Nonadherence can lead to disease progression, resulting in poor outcomes. Early detection of depression and prompt intervention can substantially impact the mortality, morbidity, and disease burden of this at-risk population. The American Academy of Neurology recommends screening for neurological disease-specific depression comorbidities, while the United States Preventive Services Task Force recommends routine depression screening for the general adult population. However, fewer than 5% of adults are screened in primary care, and as many as 50% of patients remain undiagnosed without a standardized program. Specialty neurology clinic visits could be a point of screening for high-risk neurology patients to positively affect outcomes. A review of the literature supports using a validated tool such as the Patient Health Questionnaire (PHQ-9) to screen for depression in outpatient settings. This quality improvement project was implemented at a private neurology practice that currently has no formalized protocol to identify depressive symptomatology. The PHQ-9 was integrated into the review of systems for patients meeting inclusion criteria with the aim of screening 90% of patients and referring 90% of those who screen positive to mental health services. Descriptive data were used to evaluate current practice status and indications for change. A total of 476 patients were seen during the time frame for this quality improvement inquiry. There were 100 patients excluded related to cognitive impairment for a sample total of n = 376. Over a period of 30 days, the goal was to screen 90% of patients. Despite challenges related to the impact of COVID-19 on the practice’s delivery of care, 83.2% of patients received screening, which was 92% of our goal. Of those screened and diagnosed with depression, 100% were referred to a mental health provider, thereby exceeding the goal. An unanticipated outcome was that 46.3% of patients diagnosed with depression declined a referral to mental health.

Funding

No funding
Psychosis Associated with Chronic Subdural Hematoma
Authors: Syed Shahan , Ingram Kristofer
Published: April 2022

Introduction

Subdural hematoma (SDH) is a diagnosis characterized by a wide array of symptoms. In the absence of apparent neurological deficits, behavioral abnormalities alone make SDH a difficult diagnosis. Chronic subdural hematoma presents with alteration in sensorium, raised intracranial pressure, and motor weakness. Depending on the degree of cerebral compression and location, convulsions or personality changes can also be seen. Common psychiatric manifestation with CSDH is a cognitive impairment which may mimic delirium or dementia. We report a case of an elderly male with no prior psychiatric history who developed insidious psychotic symptoms.

Case Presentation

Patient is an 83-year-old male with no prior psychiatric history brought in by police for making suicidal and homicidal threats to family members with increasingly aggressive behavior. He later endorsed a 3-week history of depression symptomatology related to a recent motor vehicle accident. Prior history of chronic myeloid leukemia, hypertension, and hypercholesterolemia with an unremarkable family and social history. On evaluation, the patient was uncooperative, irritable, and verbally aggressive. Laboratory testing, EKG, and MMSE were performed and grossly normal. Noncontrast head CT demonstrated bilateral chronic subdural hematomas. The patient refused neurology consult and proposed interventions but was compliant with risperidone 0.5 mg twice daily. His delusions and aggressive behavior improved drastically and was discharged.

Discussion

Chronic Subdural Hematoma (CSDH) is amongst the most common neurosurgical conditions in the United States with an incidence of 10 per 100,000 annually. Risk factors for CSDH include age, male gender, trauma, coagulopathy, chronic alcoholism, vascular malformations, and metastatic tumors. Noncontrast head CT is diagnostic for CSDH, but MRI should be considered in acute ischemia, infection, or dural-based neoplasms. The DSM-5 criteria for Psychotic Disorder Due to Another Medical Condition include prominent delusions that are the direct pathophysiological consequence of another medical condition and cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The diversity in symptoms is correlated with increased ICP caused primarily by the ruptured bridging veins. Traditional management of CSDH has been trephination, however, nonsurgical options are available including high-dose corticosteroids to inhibit the formation of new blood vessels thereby reducing mortality. Recurrence is possible and may constitute surgical obliteration of the subdural space.

Conclusion

Chronic subdural hematoma should be considered in the differential diagnosis of new-onset psychosis, particularly in patients with other risk factors. A thorough history and physical are vital to ascertain this diagnosis and noncontrast head imaging is confirmatory. Management varies based on the etiology of the CSDH.

Funding

No funding
Profound Anemia Induced by Lamotrigine in a 16-Year-Old Female with Sickle Cell Trait and Mood Disorder: A Case Report and One-Year Follow-Up
Authors: Jahan Sultana , O’Neill Ellen
Published: April 2022

Introduction

Lamotrigine is an antiepileptic drug of the phenyltriazine class with inhibitory effects on voltage-sensitive sodium channels, leading to an inhibition in the release of glutamate and resulting in a general inhibitory effect on cortical neuronal function. Lamotrigine is also a weak dihydrofolate reductase inhibitor. The drug is approved by the U.S. Food and Drug Administration for maintenance treatment of bipolar type I disorder in adults. There have been reports of hematologic adverse effects with lamotrigine therapy. This case report describes a 16-year-old female who developed profound anemia while on lamotrigine therapy.

Method

Ms. X was a 16-year-old African-American female with sickle cell trait and mood disorder referred by the Division of Youth Services (DYS). Her medication regimen included lamotrigine 200 mg in the morning, aripiprazole 5 mg in the morning, and mixed amphetamine salts extended-release 30 mg in the morning. While at DYS, she developed fatigue and headaches with exertion. Her blood work detected a very low hemoglobin level of 3.1 g/dL and a very low hematocrit of 10.9%. Her MCV, MCH, and MCHC were within the normal range. The remainder of her blood count and other labs were within normal limits. The patient’s blood pressure was 105/70 mm Hg and her pulse was 109. The patient was sent to the local emergency room immediately; upon hospital admission, she received 4 units of packed red blood cells via transfusion.

Results

After a blood transfusion, the patient’s hemoglobin level improved to 9.7 g/dL. The patient’s symptoms had improved significantly; her headaches and fatigue with exertion were gone. It was suspected that her profound anemia was induced by lamotrigine. She was discharged from the hospital with instructions to stop lamotrigine and visit a hematology specialist. Several weeks later, she underwent a hematologic evaluation, including a bone marrow biopsy and genetic testing, which were unremarkable. Her hemoglobin level remained stable.

Conclusion

The patient’s anemia resolved after the discontinuation of lamotrigine. The patient was followed for 1 year with blood work performed every few months. Her hemoglobin level did not drop further and in fact slowly increased to 13.9 g/dL spontaneously over the next year. In the literature, there have been reports of blood dyscrasias that may or may not be associated with hypersensitivity syndrome in patients who take lamotrigine. Considering hematologic adverse effects, it may be prudent to consider a baseline blood count before starting lamotrigine and repeat this test 3 to 6 months after initiation. It remains unclear whether lamotrigine use with a background of sickle cell trait in this patient put her at an increased risk of profound anemia. Further studies are required to explore the effects of this commonly used medicine.

Funding

No funding
Distorted Born iterative method with back-propagation improves permittivity reconstruction
Authors: Magdum Amit , Erramshetty Mallikarjun
Published: April 2022

The distorted Born iterative method (DBIM) is a widely used quantitative reconstruction algorithm to solve the inverse scattering problems of microwave imaging. The major mathematical challenges in solving such problems are non-uniqueness, non-linearity, and ill-posedness. Due to these issues, the optimization algorithm converges to a local minimum. This drawback can be overcome by selecting the correct initial guess solution, which helps to escape local minima and thus guides the inversion algorithm to a satisfactory result. This study uses a back-propagation algorithm to calculate the initial estimate, which significantly accelerates the rate of convergence and improves the accuracy of the standard DBIM approach. The results of this method are compared with zero initialization and Born-approximated initialization. For comparison, weak as well as strong scattering profiles of synthetic and experimental dataset are considered. The results suggest that the proposed method provides a significant improvement in terms of computing cost and efficiency. Furthermore, the proposed technique has the potential to successfully push the limits of reconstructible contrast.
Sub‐Seasonal Predictability of North American Monsoon Precipitation
Authors: Prein Andreas F. , Towler Erin , Ge Ming , Llewellyn Dagmar , Baker Sarah , Tighi Shana , Barrett Lucas
Published: April 2022

North American Monsoon (NAM) rainfall is a vital water resource in the United States Southwest, providing 60–80% of the region's annual precipitation. However, NAM rainfall is highly variable and water managers lack skillful guidance on summer rainfall that could help inform their management decisions and operations. Here we show that NAM season (June–October) precipitation can be forecasted by the European Centre for Medium‐Range Weather Forecast's model months ahead at catchment scales. This is possible by identifying the frequency of days with synoptic‐scale moisture advection into the NAM region, which greatly improves predictability over directly utilizing modeled precipitation. Other forecasting systems fail to provide useful guidance due to deficiencies in their data assimilation systems and biases in representing key synoptic features of the NAM including its teleconnections.
Modelling the Transmission Component in TIR Reflectance Spectra of Sandstones to Understand the Effect of Surface Roughness and Clinging Fines
Authors: Rost E. , Green A. A. , van der Werff H. M. A. , Schodlok M. C. , van der Meer F. D. , Hecker C. A.
Published: April 2022

Surface roughness of rocks influences the spectral shape and amplitude of thermal infrared spectra, but the relationship is poorly understood. This research aims to understand the physical processes that cause the observed spectral variation by modeling the reflectance spectra with a nonlinear transmission model. We designed a model that combines rock surface reflection with transmission through clinging fines that coat the surface. The novelty of this approach is that it does not model individual particles, but compiles different combinations of thin particle transmission and reflectance of the solid surface until it has an optimal fit with actual measured rock spectra. We use directional‐hemispherical reflectance spectra of two quartz sandstones with a varying surface roughness, a transmission spectrum of a powder from one of these sandstones, and a pure mineral (kaolinite) transmission spectrum as input for the model. The model reproduces spectral amplitude and shape of the principal quartz reststrahlen doublet of three out of four measured sandstone spectra. It also correctly displays the strong bands of the quartz reststrahlen doublet. With the model we demonstrate that reflectance and transmission based modeling is a promising technique for identification and correction of spectral characteristics that result from a different surface roughness.
Surface Gravity Wave Interferometry and Ocean Current Monitoring With Ocean‐Bottom DAS
Authors: Williams Ethan F. , Zhan Zhongwen , Martins Hugo F. , Fernández‐Ruiz María R. , Martín‐López Sonia , González‐Herráez Miguel , Callies Jörn
Published: April 2022

The cross‐correlation of a diffuse or random wavefield at two points has been demonstrated to recover an empirical estimate of the Green's function under a wide variety of source conditions. Over the past two decades, the practical development of this principle, termed ambient noise interferometry, has revolutionized the fields of seismology and acoustics. Yet, because of the spatial sparsity of conventional water column and seafloor instrumentation, such array‐based processing approaches have not been widely utilized in oceanography. Ocean‐bottom distributed acoustic sensing (OBDAS) repurposes pre‐existing optical fibers laid in seafloor cables as dense arrays of broadband strain sensors, which observe both seismic waves and ocean waves. The thousands of sensors in an OBDAS array make ambient noise interferometry of ocean waves straightforward for the first time. Here, we demonstrate the application of ambient noise interferometry to surface gravity waves observed on an OBDAS array near the Strait of Gibraltar. We focus particularly on a 3‐km segment of the array on the continental shelf, containing 300 channels at 10‐m spacing. By cross‐correlating the raw strain records, we compute empirical ocean surface gravity wave Green's functions for each pair of stations. We first apply beamforming to measure the time‐averaged dispersion relation along the cable. Then, we exploit the non‐reciprocity of waves propagating in a flow to recover the depth‐averaged current velocity as a function of time using a waveform stretching method. The result is a spatially continuous matrix of current velocity measurements with resolution <100 m and <1 hr.
Lateral Growth Mechanism of Proto‐Tibetan Plateau in the Late Paleogene: Implications From Detailed Crustal Structures of the Hoh Xil Basin
Authors: Wei Yunhao , He Rizheng , Yuan Xiaohui , Li Wei , Ji Zhanbo , Niu Xiao , Li Zongxu
Published: April 2022

The Hoh Xil Basin (HXB) was located in the foreland of the proto‐Tibetan Plateau and has obtained a high elevation and thick crust since the Late Oligocene. However, crust thickening cannot be explained by the limited amount of upper crustal shortening and requires a further mechanism. Based on a linear dense nodal array, we use the receiver function method to study the detailed crustal structure beneath the HXB. Our images reveal that the HXB crust has been thickened to >70 km and is thicker than the protoplateau's crust. A series of north‐dipping interfaces imaged in the lower crust implies widespread imbrication structures. Considering the uplift history of the plateau, we propose that isostatic‐driven adjustments could equalize crustal thickness variations across the protoplateau margin in the Paleogene, and the HXB was elevated by extensive imbrications accommodated to a northward injection of the protoplateau lower crust in the Late Paleogene.
Role of main RNA modifications in cancer: N6-methyladenosine, 5-methylcytosine, and pseudouridine
Authors: Xue Chen , Chu Qingfei , Zheng Qiuxian , Jiang Shiman , Bao Zhengyi , Su Yuanshuai , Lu Juan , Li Lanjuan
Published: April 2022

Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes. Epigenetic modifications regulate many biological processes, such as growth, aging, and various diseases, including cancer. With the advancement of next-generation sequencing technology, the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research. This review studied several common RNA modifications, such as N6-methyladenosine, 5-methylcytosine, and pseudouridine. The deposition and roles of these modifications in coding and noncoding RNAs are summarized in detail. Based on the RNA modification background, this review summarized the expression, function, and underlying molecular mechanism of these modifications and their regulators in cancer and further discussed the role of some existing small-molecule inhibitors. More in-depth studies on RNA modification and cancer are needed to broaden the understanding of epigenetics and cancer diagnosis, treatment, and prognosis.
Hypoxia-induced NFATc3 deSUMOylation enhances pancreatic carcinoma progression
Authors: Tong Yingying , Zhang Zheng , Cheng Yurong , Yang Jing , Fan Cong , Zhang Xuyang , Yang Jiandong , Wang Li , Guo Dong , Yan Dong
Published: April 2022

The transcriptional regulator nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3) is constitutively activated in several cancer types and plays important roles in cancer development and progression. Heavily phosphorylated NFATc3 resides in the cytoplasm of resting cells, and dephosphorylated NFATc3 translocates to the nucleus to activate expression of target genes in cells exposed to stimuli, for instance, hypoxia. Apart from phosphorylation, various post-translational modifications have been reported to regulate NFAT transcriptional activity. However, the mechanisms remain elusive. Here, we have demonstrated that NFATc3 is activated in human pancreatic ductal adenocarcinoma (PDAC) cells and that excessive activation of NFATc3 is correlated to advanced stages of PDAC and short survival time of PDAC patients. NFATc3 is deSUMOylated at K384 by SENP3 under hypoxia, which impairs the interaction between NFATc3 and phosphokinase GSK-3β, subsequently decreases NFATc3 phosphorylation and increases its nuclear occupancy. Knockdown of SENP3 greatly decreased hypoxia-induced NFATc3 nuclear occupancy. Our results highlight that SENP3-mediated deSUMOylation acts as an essential modulator of NFATc3, which is instrumental in PDAC tumor progression under hypoxia.
Dual mTORC1/2 inhibition compromises cell defenses against exogenous stress potentiating Obatoclax-induced cytotoxicity in atypical teratoid/rhabdoid tumors
Authors: Parkhurst Ashlyn , Wang Sabrina Z. , Findlay Tyler R. , Malebranche Kristen J. , Odabas Arman , Alt Jesse , Maxwell Micah J. , Kaur Harpreet , Peer Cody J. , Figg William D. , Warren Katherine E. , Slusher Barbara S. , Eberhart Charles G. , Raabe Eric H. , Rubens Jeffrey A.
Published: April 2022

Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy and have a dismal 4-year event-free survival (EFS) of 37%. We have previously shown that mTOR activation contributes to AT/RT’s aggressive growth and poor survival. Targeting the mTOR pathway with the dual mTORC1/2 inhibitor TAK-228 slows tumor growth and extends survival in mice bearing orthotopic xenografts. However, responses are primarily cytostatic with limited durability. The aim of this study is to understand the impact of mTOR inhibitors on AT/RT signaling pathways and design a rational combination therapy to drive a more durable response to this promising therapy. We performed RNASeq, gene expression studies, and protein analyses to identify pathways disrupted by TAK-228. We find that TAK-228 decreases the expression of the transcription factor NRF2 and compromises AT/RT cellular defenses against oxidative stress and apoptosis. The BH3 mimetic, Obatoclax, is a potent inducer of oxidative stress and apoptosis in AT/RT. These complementary mechanisms of action drive extensive synergies between TAK-228 and Obatoclax slowing AT/RT cell growth and inducing apoptosis and cell death. Combination therapy activates the integrative stress response as determined by increased expression of phosphorylated EIF2α, ATF4, and CHOP, and disrupts the protective NOXA.MCL-1.BIM axis, forcing stressed cells to undergo apoptosis. Combination therapy is well tolerated in mice bearing orthotopic xenografts of AT/RT, slows tumor growth, and extends median overall survival. This novel combination therapy could be added to standard upfront therapies or used as a salvage therapy for relapsed disease to improve outcomes in AT/RT.
Teneurins assemble into presynaptic nanoclusters that promote synapse formation via postsynaptic non-teneurin ligands
Authors: Zhang Xuchen , Lin Pei-Yi , Liakath-Ali Kif , Südhof Thomas C.
Published: April 2022

Extensive studies concluded that homophilic interactions between pre- and postsynaptic teneurins, evolutionarily conserved cell-adhesion molecules, encode the specificity of synaptic connections. However, no direct evidence is available to demonstrate that teneurins are actually required on both pre- and postsynaptic neurons for establishing synaptic connections, nor is it known whether teneurins are localized to synapses. Using super-resolution microscopy, we demonstrate that Teneurin-3 assembles into presynaptic nanoclusters of approximately 80 nm in most excitatory synapses of the hippocampus. Presynaptic deletions of Teneurin-3 and Teneurin-4 in the medial entorhinal cortex revealed that they are required for assembly of entorhinal cortex-CA1, entorhinal cortex-subiculum, and entorhinal cortex-dentate gyrus synapses. Postsynaptic deletions of teneurins in the CA1 region, however, had no effect on synaptic connections from any presynaptic input. Our data suggest that different from the current prevailing view, teneurins promote the establishment of synaptic connections exclusively as presynaptic cell-adhesion molecules, most likely via their nanomolar-affinity binding to postsynaptic latrophilins.
Synthetic cells with self-activating optogenetic proteins communicate with natural cells
Authors: Adir Omer , Albalak Mia R. , Abel Ravit , Weiss Lucien E. , Chen Gal , Gruber Amit , Staufer Oskar , Kurman Yaniv , Kaminer Ido , Shklover Jeny , Shainsky-Roitman Janna , Platzman Ilia , Gepstein Lior , Shechtman Yoav , Horwitz Benjamin A. , Schroeder Avi
Published: April 2022

Development of regulated cellular processes and signaling methods in synthetic cells is essential for their integration with living materials. Light is an attractive tool to achieve this, but the limited penetration depth into tissue of visible light restricts its usability for in-vivo applications. Here, we describe the design and implementation of bioluminescent intercellular and intracellular signaling mechanisms in synthetic cells, dismissing the need for an external light source. First, we engineer light generating SCs with an optimized lipid membrane and internal composition, to maximize luciferase expression levels and enable high-intensity emission. Next, we show these cells’ capacity to trigger bioprocesses in natural cells by initiating asexual sporulation of dark-grown mycelial cells of the fungus Trichoderma atroviride. Finally, we demonstrate regulated transcription and membrane recruitment in synthetic cells using bioluminescent intracellular signaling with self-activating fusion proteins. These functionalities pave the way for deploying synthetic cells as embeddable microscale light sources that are capable of controlling engineered processes inside tissues.
Experimental demonstration of continuous quantum error correction
Authors: Livingston William P. , Blok Machiel S. , Flurin Emmanuel , Dressel Justin , Jordan Andrew N. , Siddiqi Irfan
Published: April 2022

The storage and processing of quantum information are susceptible to external noise, resulting in computational errors. A powerful method to suppress these effects is quantum error correction. Typically, quantum error correction is executed in discrete rounds, using entangling gates and projective measurement on ancillary qubits to complete each round of error correction. Here we use direct parity measurements to implement a continuous quantum bit-flip correction code in a resource-efficient manner, eliminating entangling gates, ancillary qubits, and their associated errors. An FPGA controller actively corrects errors as they are detected, achieving an average bit-flip detection efficiency of up to 91%. Furthermore, the protocol increases the relaxation time of the protected logical qubit by a factor of 2.7 over the relaxation times of the bare comprising qubits. Our results showcase resource-efficient stabilizer measurements in a multi-qubit architecture and demonstrate how continuous error correction codes can address challenges in realizing a fault-tolerant system.
TGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance
Authors: Buemi Valentina , Schillaci Odessa , Santorsola Mariangela , Bonazza Deborah , Broccia Pamela Veneziano , Zappone Annie , Bottin Cristina , Dell’Omo Giulia , Kengne Sylvie , Cacchione Stefano , Raffa Grazia Daniela , Piazza Silvano , di Fagagna Fabrizio d’Adda , Benetti Roberta , Cortale Maurizio , Zanconati Fabrizio , Del Sal Giannino , Schoeftner Stefan
Published: April 2022

Pathways that direct the selection of the telomerase-dependent or recombination-based, alternative lengthening of telomere (ALT) maintenance pathway in cancer cells are poorly understood. Using human lung cancer cells and tumor organoids we show that formation of the 2,2,7-trimethylguanosine (TMG) cap structure at the human telomerase RNA 5′ end by the Trimethylguanosine Synthase 1 (TGS1) is central for recruiting telomerase to telomeres and engaging Cajal bodies in telomere maintenance. TGS1 depletion or inhibition by the natural nucleoside sinefungin impairs telomerase recruitment to telomeres leading to Exonuclease 1 mediated generation of telomere 3′ end protrusions that engage in RAD51-dependent, homology directed recombination and the activation of key features of the ALT pathway. This indicates a critical role for 2,2,7-TMG capping of the RNA component of human telomerase (hTR) in enforcing telomerase-dependent telomere maintenance to restrict the formation of telomeric substrates conductive to ALT. Our work introduces a targetable pathway of telomere maintenance that holds relevance for telomere-related diseases such as cancer and aging.
Evolution of the murine gut resistome following broad-spectrum antibiotic treatment
Authors: de Nies Laura , Busi Susheel Bhanu , Tsenkova Mina , Halder Rashi , Letellier Elisabeth , Wilmes Paul
Published: April 2022

The emergence and spread of antimicrobial resistance (AMR) represent an ever-growing healthcare challenge worldwide. Nevertheless, the mechanisms and timescales shaping this resistome remain elusive. Using an antibiotic cocktail administered to a murine model along with a longitudinal sampling strategy, we identify the mechanisms by which gut commensals acquire antimicrobial resistance genes (ARGs) after a single antibiotic course. While most of the resident bacterial populations are depleted due to the treatment,Akkermansia muciniphilaand members of the Enterobacteriaceae, Enterococcaceae, and Lactobacillaceae families acquire resistance and remain recalcitrant. We identify specific genes conferring resistance against the antibiotics in the corresponding metagenome-assembled genomes (MAGs) and trace their origins within each genome. Here we show that, while mobile genetic elements (MGEs), including bacteriophages and plasmids, contribute to the spread of ARGs, integrons represent key factors mediating AMR in the antibiotic-treated mice. Our findings suggest that a single course of antibiotics alone may act as the selective sweep driving ARG acquisition and incidence in gut commensals over a single mammalian lifespan.
Two-photon-absorbing ruthenium complexes enable near infrared light-driven photocatalysis
Authors: Han Guanqun , Li Guodong , Huang Jie , Han Chuang , Turro Claudia , Sun Yujie
Published: April 2022

One-photon-absorbing photosensitizers are commonly used in homogeneous photocatalysis which require the absorption of ultraviolet (UV) /visible light to populate the desired excited states with adequate energy and lifetime. Nevertheless, the limited penetration depth and competing absorption by organic substrates of UV/visible light calls upon exploring the utilization of longer-wavelength irradiation, such as near-infrared light (λirr > 700 nm). Despite being found applications in photodynamic therapy and bioimaging, two-photon absorption (TPA), the simultaneous absorption of two photons by one molecule, has been rarely explored in homogeneous photocatalysis. Herein, we report a group of ruthenium polypyridyl complexes possessing TPA capability that can drive a variety of organic transformations upon irradiation with 740 nm light. We demonstrate that these TPA ruthenium complexes can operate in an analogous manner as one-photon-absorbing photosensitizers for both energy-transfer and photoredox reactions, as well as function in concert with a transition metal co-catalyst for metallaphotoredox C–C coupling reactions.
Ultrasensitive barocaloric material for room-temperature solid-state refrigeration
Authors: Ren Qingyong , Qi Ji , Yu Dehong , Zhang Zhe , Song Ruiqi , Song Wenli , Yuan Bao , Wang Tianhao , Ren Weijun , Zhang Zhidong , Tong Xin , Li Bing
Published: April 2022

One of the greatest obstacles to the real application of solid-state refrigeration is the huge driving fields. Here, we report a giant barocaloric effect in inorganic NH4I with reversible entropy changes of $$\Delta {S}_{{P}_{0}\to P}^{{{\max }}}$$
Δ

S

P

0

→
P

max

∼71 J K−1 kg−1 around room temperature, associated with a structural phase transition. The phase transition temperature, Tt, varies dramatically with pressure at a rate of dTt/dP ∼0.79 K MPa−1, which leads to a very small saturation driving pressure of ΔP ∼40 MPa, an extremely large barocaloric strength of $$\left|\Delta {S}_{{P}_{0}\to P}^{{{\max }}}/\Delta P\right|$$

Δ

S

P

0

→
P

max

/
Δ
P

∼1.78 J K−1 kg−1 MPa−1, as well as a broad temperature span of ∼41 K under 80 MPa. Comprehensive characterizations of the crystal structures and atomic dynamics by neutron scattering reveal that a strong reorientation-vibration coupling is responsible for the large pressure sensitivity of Tt. This work is expected to advance the practical application of barocaloric refrigeration.
Experimental evidence of tetrahedral symmetry breaking in SiO2 glass under pressure
Authors: Kono Yoshio , Ohara Koji , Kondo Nozomi M. , Yamada Hiroki , Hiroi Satoshi , Noritake Fumiya , Nitta Kiyofumi , Sekizawa Oki , Higo Yuji , Tange Yoshinori , Yumoto Hirokatsu , Koyama Takahisa , Yamazaki Hiroshi , Senba Yasunori , Ohashi Haruhiko , Goto Shunji , Inoue Ichiro , Hayashi Yujiro , Tamasaku Kenji , Osaka Taito , Yamada Jumpei , Yabashi Makina
Published: April 2022

Bimodal behavior in the translational order of silicon’s second shell in SiO2 liquid at high temperatures and high pressures has been recognized in theoretical studies, and the fraction of the S state with high tetrahedrality is considered as structural origin of the anomalous properties. However, it has not been well identified in experiment. Here we show experimental evidence of a bimodal behavior in the translational order of silicon’s second shell in SiO2 glass under pressure. SiO2 glass shows tetrahedral symmetry structure with separation between the first and second shells of silicon at low pressures, which corresponds to the S state structure reported in SiO2 liquid. On the other hand, at high pressures, the silicon’s second shell collapses onto the first shell, and more silicon atoms locate in the first shell. These observations indicate breaking of local tetrahedral symmetry in SiO2 glass under pressure, as well as SiO2 liquid.
Evanescent scattering imaging of single protein binding kinetics and DNA conformation changes
Authors: Zhang Pengfei , Zhou Lei , Wang Rui , Zhou Xinyu , Jiang Jiapei , Wan Zijian , Wang Shaopeng
Published: April 2022

Evanescent illumination has been widely used to detect single biological macromolecules because it can notably enhance light-analyte interaction. However, the current evanescent single-molecule detection system usually requires specially designed microspheres or nanomaterials. Here we show that single protein detection and imaging can be realized on a plain glass surface by imaging the interference between the evanescent lights scattered by the single proteins and by the natural roughness of the cover glass. This allows us to quantify the sizes of single proteins, characterize the protein–antibody interactions at the single-molecule level, and analyze the heterogeneity of single protein binding behaviors. In addition, owing to the exponential distribution of evanescent field intensity, the evanescent imaging system can track the analyte axial movement with high resolution, which can be used to analyze the DNA conformation changes, providing one solution for detecting small molecules, such as microRNA. This work demonstrates a label-free single protein imaging method with ordinary consumables and may pave a road for detecting small biological molecules.
Structural insights into TRPV2 activation by small molecules
Authors: Pumroy Ruth A. , Protopopova Anna D. , Fricke Tabea C. , Lange Iris U. , Haug Ferdinand M. , Nguyen Phuong T. , Gallo Pamela N. , Sousa Bárbara B. , Bernardes Gonçalo J. L. , Yarov-Yarovoy Vladimir , Leffler Andreas , Moiseenkova-Bell Vera Y.
Published: April 2022

Transient receptor potential vanilloid 2 (TRPV2) is involved in many critical physiological and pathophysiological processes, making it a promising drug target. Here we present cryo-electron microscopy (cryo-EM) structures of rat TRPV2 in lipid nanodiscs activated by 2-aminoethoxydiphenyl borate (2-APB) and propose a TRPV2-specific 2-ABP binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer. In silico docking and electrophysiological studies confirm the key role of His521 and Arg539 in 2-APB activation of TRPV2. Additionally, electrophysiological experiments show that the combination of 2-APB and cannabidiol has a synergetic effect on TRPV2 activation, and cryo-EM structures demonstrate that both drugs were able to bind simultaneously. Together, our cryo-EM structures represent multiple functional states of the channel, providing a native picture of TRPV2 activation by small molecules and a structural framework for the development of TRPV2-specific activators.
Microscopic theory of exciton and trion polaritons in doped monolayers of transition metal dichalcogenides
Authors: Zhumagulov Yaroslav Vladimirovich , Chiavazzo Salvatore , Gulevich Dmitry Romanovich , Perebeinos Vasili , Shelykh Ivan Andreevich , Kyriienko Oleksandr
Published: April 2022

We study a doped transition metal dichalcogenide (TMDC) monolayer in an optical microcavity. Using the microscopic theory, we simulate spectra of quasiparticles emerging due to the interaction of material excitations and a high-finesse optical mode, providing a comprehensive analysis of optical spectra as a function of Fermi energy and predicting several modes in the strong light-matter coupling regime. In addition to exciton-polaritons and trion-polaritons, we report polaritonic modes that become bright due to the interaction of excitons with free carriers. At large doping, we reveal strongly coupled modes corresponding to excited trions that hybridize with a cavity mode. We also demonstrate that the increase of carrier concentration can change the nature of the system’s ground state from the dark to the bright one. Our results offer a unified description of polaritonic modes in a wide range of free electron densities.
Degenerate plaquette physics as key ingredient of high-temperature superconductivity in cuprates
Authors: Danilov Michael , van Loon Erik G. C. P. , Brener Sergey , Iskakov Sergei , Katsnelson Mikhail I. , Lichtenstein Alexander I.
Published: April 2022

We study the physics of high-temperature cuprate superconductors starting from the highly degenerate four-site plaquette of the $$t-t^{\prime} -U$$

t
−

t

′

−
U

Hubbard model as a reference system. The degeneracy causes strong fluctuations when a lattice of plaquettes is constructed. We show that there is a large binding energy between holes when a set of four plaquettes is considered. The next-nearest-neighbour hopping $$t^{\prime}$$

t

′

plays a crucial role in the formation of these strongly bound electronic bipolarons whose coherence at lower temperature could be the explanation for superconductivity. A complementary approach is cluster dual fermion starting from a single degenerate plaquette, which contains the relevant short-ranged fluctuations from the beginning. It gives d-wave superconductivity as the leading instability under a reasonably broad range of parameters. The origin of the pseudogap is also discussed in terms of the coupling of degenerate plaquettes. Thus, some of the essential elements of cuprate superconductivity appear from the local plaquette physics.
SARS-CoV-2-specific T-cell epitope repertoire in convalescent and mRNA-vaccinated individuals
Authors: Lang-Meli Julia , Luxenburger Hendrik , Wild Katharina , Karl Vivien , Oberhardt Valerie , Salimi Alizei Elahe , Graeser Anne , Reinscheid Matthias , Roehlen Natascha , Reeg David B. , Giese Sebastian , Ciminski Kevin , Götz Veronika , August Dietrich , Rieg Siegbert , Waller Cornelius F. , Wengenmayer Tobias , Staudacher Dawid , Huzly Daniela , Bengsch Bertram , Kochs Georg , Schwemmle Martin , Emmerich Florian , Boettler Tobias , Thimme Robert , Hofmann Maike , Neumann-Haefelin Christoph
Published: April 2022

Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8+ T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines.
Exocomets size distribution in the $$\beta$$ Pictoris planetary system
Authors: Lecavelier des Etangs Alain , Cros Lucie , Hébrard Guillaume , Martioli Eder , Duquesnoy Marc , Kenworthy Matthew A. , Kiefer Flavien , Lacour Sylvestre , Lagrange Anne-Marie , Meunier Nadège , Vidal-Madjar Alfred
Published: April 2022

The star $$\beta$$
β
 Pictoris harbors a young planetary system of about 20 million years old, which is characterized by the presence of a gaseous and dusty debris disk, at least two massive planets and many minor bodies. For more than thirty years, exocomets transiting the star have been detected using spectroscopy, probing the gaseous part of the cometary comas and tails. The detection of the dusty component of the tails can be performed through photometric observations of the transits. Since 2018, the Transiting Exoplanet Survey Satellite has observed $$\beta$$
β
 Pic for a total of 156 days. Here we report an analysis of the TESS photometric data set with the identification of a total of 30 transits of exocomets. Our statistical analysis shows that the number of transiting exocomet events (N) as a function of the absorption depth (AD) in the light curve follows a power law in the form $$dN(AD) \propto AD^{-\alpha }$$

d
N

(
A
D
)

∝
A

D

-
α

, where $$\alpha =2.3\pm 0.4$$

α
=
2.3
±
0.4

. This distribution of absorption depth leads to a differential comet size distribution proportional to $$R^{-\gamma }$$

R

-
γ

, where $$\gamma =3.6 \pm 0.8$$

γ
=
3.6
±
0.8

, showing a striking similarity to the size distribution of comets in the Solar system and the distribution of a collisionally relaxed population ($$\gamma _{{\text{D}}}= 3.5$$

γ
D

=
3.5

).
Efficient dendritic learning as an alternative to synaptic plasticity hypothesis
Authors: Hodassman Shiri , Vardi Roni , Tugendhaft Yael , Goldental Amir , Kanter Ido
Published: April 2022

Synaptic plasticity is a long-lasting core hypothesis of brain learning that suggests local adaptation between two connecting neurons and forms the foundation of machine learning. The main complexity of synaptic plasticity is that synapses and dendrites connect neurons in series and existing experiments cannot pinpoint the significant imprinted adaptation location. We showed efficient backpropagation and Hebbian learning on dendritic trees, inspired by experimental-based evidence, for sub-dendritic adaptation and its nonlinear amplification. It has proven to achieve success rates approaching unity for handwritten digits recognition, indicating realization of deep learning even by a single dendrite or neuron. Additionally, dendritic amplification practically generates an exponential number of input crosses, higher-order interactions, with the number of inputs, which enhance success rates. However, direct implementation of a large number of the cross weights and their exhaustive manipulation independently is beyond existing and anticipated computational power. Hence, a new type of nonlinear adaptive dendritic hardware for imitating dendritic learning and estimating the computational capability of the brain must be built.