bluuebunny/crossref_metadata_2025 huggingface dataset:
The Current Status of Medical Malpractice Countersuits
Authors: Sokol David J.
Published: February 2021

The dramatic growth of medical malpractice litigation in recent decades has contributed significantly to an overall increase in health care costs in this country. Although lawmakers, physicians, and other responsible citizens have proposed numerous solutions in an effort to curb die crisis, diese proposals have generally been ineffective.

In this Article the Audior endorses countersuits as die most appropriate response to frivolous medical malpractice actions. The Author also suggests that contingent fee systems, coupled with the economic motivation of private insurers to settle claims quickly, provide incentive for plaintiffs to initiate frivolous claims.

This Article analyzes the general legal approaches available for countersuits, emphasizing recent successful actions based on malicious prosecution and abuse of process, and proposes more widespread use of diese approaches.
Beshada v. Johns-Manville Products Corp.: The Function of State of the Art Evidence in Strict Products Liability
Authors: Berman Jack
Published: February 2021

In Beshada v. Johns-Manville Products Corp., the Supreme Court of New Jersey held that a state of the art defense is unavailable in cases brought under a theory of strict liability for failure to warn. The court indicated that asbestos producers may be held liable for their products' harms even if the health hazards of asbestos were unknown and not discoverable when the products were marketed. In a subsequent case, the New Jersey court held that state of the art evidence is relevant to whether a product is defective. This Case Comment examines these different uses of knowledge evidence in the disposition of products liability cases. It contends that manufacturers should not be held liable for unknowable risks. The Comment concludes that the state of the art defense establishes a logical limit on strict liability and promotes efficient resolution of products liability claims.
Access to Health Care and Equal Protection of the Law: The Need for a New Heightened Scrutiny
Authors: Mariner Wendy K.
Published: February 2021

Proposals to reduce national expenditures for health care under Medicare and other programs raise questions about the limits on legislative power to distribute health care benefits. The constitutional guarantee of equal protection has been a weak source of protection for the sick, largely because they fail to qualify for special scrutiny under traditional equal protection analysis. Recent decisions of the United States Supreme Court suggest that the Justices seek a newer, more flexible approach to reviewing claims of unequal protection. This Article examines the application of the equal protection guarantee to health-related claims. It argues that traditional equal protection analysis is too rigid and newer rationality review too imprecise to provide just eligibility determinations. The Article concludes that courts should subject claims of unequal protection in the health care context to heightened scrutiny, as health care plays a special role in assuring equality of opportunity.
Judicial Postponement of Death Recognition: The Tragic Case of Mary O'Connor
Authors: Gindes Daniel
Published: February 2021

A recent New York Court of Appeals decision seriously impedes the ability of incompetent patients to control their medical care. In the case of Mary O'Connor, the court virtually eliminated an incompetent's rights to bodily integrity and privacy. The court relied on formalistic evidentiary arguments to vitiate the patient's refusal of death-prolonging treatment. This Case Comment examines both the doctrine and policy underlying the O'Connor decision, suggesting that the court erred in its holding and reasoning.

An alternative framework is presented, arguing that courts should honor competently expressed patient decisions concerning medical treatment. New York's highest court, instead, posited an incompetent patient who becomes competent for a moment to render a decision. This legal fiction is nothing more than a thinly masked technique for imposition of the judges’ values on the patient. This Case Comment argues that in the absence of clear direction from the patient, family and loved ones generally should make care decisions for the patient.
In Camera Inspections of Privileged Records in Sexual Assault Trials: Balancing Defendants' Rights and State Interests Under Massachusetts's Bishop Test
Authors: Crowley Ellen M.
Published: February 2021

A sexual assault trial requires a court to balance evidentiary privileges enacted by a state legislature against a criminal defendant's constitutional trial rights. State legislatures enact various privileges which either limit or prohibit the discovery of confidential communications in criminal trials. Such statutes reflect a firmly based legislative effort to protect citizens’ private and personal confidences from unwarranted public scrutiny. When a defendant charged with sexual assault seeks to compel discovery of the victim's privileged medical, psychiatric, or counseling records, a conflict inevitably arises. States and victims assert that courts must respect statutory assurances of confidentiality; defendants assert that their constitutional right to a fair trial and their right to confront the witnesses and evidence against them mandates disclosure. Resolution of this pressing conflict requires a careful balancing of both the state's and defendant's interests on a case by case basis.
Research with Children
Authors: Glantz Leonard H.
Published: February 2021

In the United States we have very mixed feelings about research with human subjects. The Nuremberg Code (the Code), which provides a foundation for the protection of human subjects, was written by American judges in the context of trying Nazi doctors who committed atrocious acts of human experimentation on concentration camp inmates. The Code provides ten common-sense guidelines controlling research. For example, a researcher may not conduct research on human subjects without that subject's informed consent, or if there is ana priorireason to believe that the research will cause death or disabling injury to the subject. What is remarkable about the creation of the Code is that it was thought to be necessary to document and impose the most fundamental moral principles on researchers. The Code demonstrates a remarkable suspicion of research with human subjects and those who perform such research.
The Due Process Right to a Safe and Humane Environment for Patients in State Custody: The Voluntary/Involuntary Distinction
Authors: Kellogg Sarah C.
Published: February 2021

In December 1995, the Eighth Circuit decided Kennedy v. Schafer, holding that a teenage patient who committed suicide while under treatment at a state psychiatric facility had a constitutionally protected liberty interest in a safe and humane environment under the Due Process Clause of the Fourteenth Amendment if her status changed from voluntary to involuntary during the course of her admission. The fifteen year old patient, Kathleen Kennedy, had been identified as a suicide risk, and had been placed on “Protective Suicide Precautions,” which required a designated staff member to keep her in constant eyesight and to interact with her at fifteen to twenty minute intervals. Despite these stringent requirements for supervision and contact, Kathleen was found dead in her room more than two hours after her last contact with a staff member. Her parents brought suit under 42 U.S.C. § 1983 against state and hospital officials, alleging that chronic understaffing and falsification of the records used to determine staffing levels amounted to a pattern of deliberate indifference to patient safety which violated their daughter’s protected liberty interest in a safe and humane environment.
Health and the Right to Privacy
Authors: Starr Paul
Published: February 2021

When Louis Brandeis and Samuel Warren introduced the phrase “the right to privacy” as the title of an article in the Harvard Law Review in December 1890, they were primarily concerned about a right of privacy from the news media. “The press,” they wrote, “is overstepping in every direction the obvious bounds of propriety and of decency. Gossip is no longer the resource of the idle and of the vicious, but has become a trade, which is pursued with industry as well as effrontery. To satisfy a prurient taste the details of sexual relations are spread broadcast in the columns of the daily papers.”
Telemedicine and Integrated Health Care Delivery: Compounding Malpractice Liability
Authors: Kuszler Patricia C.
Published: February 2021

Telemedicine became a significant part of the health care equation long before we realized what it was or how important it will be in the future. Telephone discussions and consultations between health care providers have been a part of medical practice since Alexander Graham Bell gifted society with telephones. Furthermore, who among us has not been transfixed watching and learning about open heart surgery on cable television? Propelled by the information superhighway and the breadth of emerging computer and communication technologies, telemedicine will change the face of medicine and methods of interaction between providers and patients. Access, quality and cost of health care may all improve, but not without the sacrifice of some time-honored norms in medical practice.
Tobacco Litigation: Smoke, Mirrors and Public Policy
Authors: LaFrance Arthur B.
Published: February 2021

My experience and reflections concerning tobacco litigation stem from representing the American Cancer Society in November of 1998,' when the State of Oregon asked Judge Anna Brown of the Circuit Court of Multnomah County in Portland to approve the settlement agreement reached between Oregon and the major tobacco manufacturers. The American Cancer Society inteivened in opposition. The agreement was a part of a multi-state settlement reached by forty-six state Attorneys Generals and the tobacco industry proposed to state courts during that same week and the ensuing weeks around the country. By October of 1999, the Master-Settlement Agreement (MSA) was approved by enough states that it was effectuated. Distributions pursuant to the agreement will begin in 2000 or 2001. Total disbursements over twenty years will exceed $240 billion, a huge amount of money by anyone's standards.
Health Care in Hawai'i: An Agenda for Research and Reform
Authors: Law Sylvia A.
Published: February 2021

In 1999, the United States Census Bureau reported that 16.3% of Americans did not have health insurance in 1998, up from 16.1% in 1997 and 13% in 1990. The increased lack of health insurance is particularly troubling because the unemployment rate is down and the economy is vibrant. The Census Bureau also reported that Hawafi led the Nation in providing health insurance, with only 8.8% of the population uninsured. This fact alone makes Hawai'i a model for the U.S. Hawaii's success goes beyond providing health insurance coverage. “Coverage is not care.” The state is also a model in terms of providing care through community health centers. Broad insurance coverage, and access to care through community based primary care centers, help to make the people of Hawai'i healthy. Further, Hawai'i's health care costs are lower than costs in the rest of the nation.
Tapping And Resolving Consumer Concerns About Health Care
Authors: Kinney Eleanor D.
Published: February 2021

Consumer concerns about their health care have attracted intense attention as more Americans get care through prepaid managed care plans. A recent poll sponsored by the Kaiser Family Foundation reported that over half of Americans believe that managed care has decreased the quality of their health care. Journalistic reports and widely publicized court decisions involving coverage denials for gravely ill people have fueled consumer concerns as well. Consumer protection and access to high quality health care is an issue that resonates deeply with the American public, and reforms are in order.
The Legal and Ethical Implications of Gag Clauses in Physician Contracts
Authors: Martin Julia A. , Bjerknes Lisa K.
Published: February 2021

Throughout history, those in power have feared the consequences of unfettered discourse within their society. The empowered have restricted and directly manipulated discourse in the context of doctor-patient discussions with surprising frequency, resulting in disturbing curtailments of individual autonomy. During the Cultural Revolution, the Chinese government dispatched physicians to peasants’ homes to convince them to use contraception. In the 1930s, the Soviet government expedited the completion of the Siberian railroad by ordering physicians to deny workers’ requests for medical leave and to conceal this order from those workers. Recently, Nicolae Ceausescu sought to increase the Romanian birth rate by prohibiting physicians from advising patients about birth control and barring the dissemination of information about condom use to prevent HIV transmission.

Restraints on doctor-patient discussions have not been limited to socialist regimes. In 1988, the Bush Administration implemented a federal regulation prohibiting physicians from discussing abortion with patients in federally funded clinics.
Drug Testing of Health Care Workers: Toward a Coherent Hospital Policy
Authors: Devon Dana
Published: February 2021

Spurred by President Ronald Reagan's 1986 Executive Order seeking to establish a drug-free workplace and by the growing empirical data purporting to show a loss of time, money and productivity due to the adverse effects of substance abuse, employers in both the public and private sector have implemented drug testing programs on an unprecedented scale. Today, employers subject an estimated thirty million workers to some type of employer-sponsored drug and alcohol testing in the workplace. A 1996 survey by the American Management Association reports that eighty-one percent of all major corporations now employ some type of drug testing program, a fourfold increase in nine years.

While drag testing in the health care sector is rising, it still lags behind other industries. When a hospital does test, it often exempts a crucial job classification—physicians. This Article's thesis centers on the potential liability hospitals face by failing to include drug testing in its hiring and credentialing process.
Brief For Bioethicists For Privacy as Amicus Curiae Supporting Appellees
Authors: Annas George J. , Glantz Leonard H. , Mariner Wendy K.
Published: February 2021

Amicus is an ad hoc group of 57 philosophers, theologians, attorneys and physicians … who teach medical ethics to medical students and physicians. The members believe that permitting competent adults to make important, personal medical decisions in consultation with their physician is a fundamental principle of medical ethics, and that the doctor-patient relationship deserves the constitutional protection the Court has afforded it under the right of privacy.
Grammatical gender in L2 Swedish in Finnish-speaking immersion students: A comparison with non-immersion students
Authors: Nyqvist Eeva-Liisa , Lahtinen Sinikka
Published: February 2021

Swedish grammatical gender is challenging for Finnish-speaking learners of Swedish due to its abstract meaning, the complex nature of Swedish NPs and the low salience of the morphology used to mark gender. Our study compares the expression of gender in texts written in Swedish by Finnish-speaking 12- and 15-year-old immersion students with that of 16-year-old non-immersion students. The results show that NPs with gender agreement, i.e. those with several morphemes marking gender, are more difficult than NPs with only one marker. In all informant groups, uter is significantly easier than neuter, but uter is also overused, as approximately 75% of all Swedish nouns are uter in modern Swedish. Comparisons between different informant groups show that non-immersion students often reach a significantly higher level of accuracy than immersion students, which indicates that formal teaching has a positive effect.
Parental perspectives on negotiations over diet and physical activity: how do we involve parents in adolescent health interventions?
Authors: Shaw Sarah , Correia Simao Sara , Jenner Sarah , Lawrence Wendy T , Woods-Townsend Kathryn , Vogel Christina A , Farrell David , Inskip Hazel , Baird Janis , Morrison Leanne , Barker Mary , Strömmer Sofia T ,   the EACH-B study group
Published: February 2021

Objective:

To identify the ways in which parental involvement can be incorporated into interventions to support adolescent health behaviour change.

Design:

Data from semi-structured interviews were analysed using inductive thematic analysis.

Setting:

Southampton, Hampshire, UK.

Participants:

A convenience sample of twenty-four parents of adolescents.

Results:

Parents consider themselves to play an important role in supporting their adolescents to make healthy choices. Parents saw themselves as gatekeepers of the household and as role models to their adolescents but recognised this could be both positive and negative in terms of health behaviours. Parents described the changing dynamics of the relationships they have with their adolescents because of increased adolescent autonomy. Parents stated that these changes altered their level of influence over adolescents’ health behaviours. Parents considered it important to promote independence in their adolescents; however, many described this as challenging because they believed their adolescents were likely to make unhealthy decisions if not given guidance. Parents reported difficulty in supporting adolescents in a way that was not viewed as forceful or pressuring.

Conclusions:

When designing adolescent health interventions that include parental components, researchers need to be aware of the disconnect between public health recommendations and the everyday reality for adolescents and their parents. Parental involvement in adolescent interventions could be helpful but needs to be done in a manner that is acceptable to both adolescents and parents. The findings of this study may be useful to inform interventions which need to consider the transitions and negotiations which are common in homes containing adolescents.
Teargas and Selfie Cams: Foreign Protests and Media in the Digital Age
Authors: Green-Riley Naima , Kruszewska-Eduardo Dominika , Fu Ze
Published: February 2021

This study explores the impact of repression of foreign protests and the media source reporting the news upon American foreign policy preferences for democracy promotion abroad. We use two survey experiments featuring carefully edited video treatments to show that even short media clips presenting foreign protests as violently repressed increase American support for targeted sanctions against the hostile regime; however, these treatments alone do not inspire respondents to political action. Furthermore, we do not find evidence that mobile treatment magnifies the effects of violence.
Future Changes in the Frequency and Destructiveness of Landfalling Tropical Cyclones Over East Asia Projected by High‐Resolution AGCMs
Authors: Hsu Pang‐Chi , Chen Kuan‐Chieh , Tsou Chih‐Hua , Hsu Huang‐Hsiung , Hong Chi‐Cherng , Liang Hsin‐Chien , Tu Chia‐Ying , Kitoh Akio
Published: February 2021

Future changes in the frequency and destructiveness of landfalling tropical cyclones (TCs) over East Asia were investigated by analyzing the simulations of two high‐resolution (20–25‐km) atmospheric general circulation models forced by sea surface temperature (SST) in the present period (1979–2003) and under future warming conditions (2075–2099) of the RCP8.5 scenario. The present‐day simulations capture well the genesis count, tracks, and intensity associated with TCs striking the coastal areas of Taiwan‐East China (TWCN), the South China Sea‐Indochina (SCS) and the vicinity of Japan (JP). The frequency of landfalling TCs over TWCN, SCS, and JP is projected to nearly half by the end of the 21st century. However, these landfalling TCs induce enhanced destructive threats of stronger winds and heavier precipitation under the future warmer climate. Through attribution analysis we found the reduced frequency of landfalling TCs to be mainly caused by a decline in TC genesis count (rather than TC track changes), while the increased intensity of landfalling TCs is linked with changes in the TC intensification rate (as opposed to duration changes). Diagnoses of the genesis potential index and eddy energetics further suggest that the mid‐tropospheric drying and weakened synoptic‐scale eddy activity resulting from anticyclonic and downward circulations over the main TC genesis region create an unfavorable environment for TC genesis. In contrast, warmer SST, reduced vertical wind shear and enhanced efficiency of eddy kinetic energy generations appear over the regions before TC landfall, resulting in a more rapid intensification of TCs that later approach the coastal areas.
Dangerous Heat, Unequal Consequences
Authors: Moutinho Sofia , Gawthrop Elisabeth
Published: February 2021

How two neighborhoods in Arizona and Florida became hot spots for sickening heat.
Where Do People Fit into a Global Hazard Model?
Authors: Sima Richard
Published: February 2021

By incorporating human systems, scientists are modeling geohazards with equity in mind.
Natural Hazards Have Unnatural Impacts—What More Can Science Do?
Authors: Howley Korena
Published: February 2021

As disadvantaged communities suffer disproportionately from natural hazards, scientists, policymakers, and emergency managers explore why policies are failing—and what can be done about it.
Transcriptional regulatory network for the establishment of CD8+ T cell exhaustion
Authors: Seo Wooseok , Jerin Chandsultana , Nishikawa Hiroyoshi
Published: February 2021

Chronic infection with persistent antigenic stimulation results in the generation of exhausted CD8+ T cells, which are considered defective effector CD8+ T cells, and thus compromises effective immune responses. However, recent studies have illustrated that exhausted CD8+ T cells may be purposely generated and maintained to provide mild immune responses against chronic infection or cancer, which can be safer over a long period of time than strong immune responses. Indeed, a specific population of exhausted CD8+ T cells that behaves similarly to self-renewing stem cells and provides a continuous supply of exhausted CD8+ T cells has been identified, indicating that this population can be considered progenitors of exhausted CD8+ T cells. Furthermore, several ground-breaking studies in the last few years have shed new light on the transcriptional regulatory network governing the generation and propagation of exhausted CD8+ T cells, which involves T cell receptor (TCR) signaling that leads to NFAT-TCF1 (nuclear factor of activated T cells-T cell factor 1) activity followed by activation of the TOX/NR4A axis. Elucidation of the intracellular signaling pathways will help to define the definitive developmental stages leading to exhausted CD8+ T cells, which can be exploited to advance our never-ending battle against cancer. This review will summarize the recent discoveries that have deepened our understanding of the exhaustion program of cytotoxic CD8+ T cells.
H2A.Z overexpression suppresses senescence and chemosensitivity in pancreatic ductal adenocarcinoma
Authors: Ávila-López P. A. , Guerrero G. , Nuñez-Martínez H. N. , Peralta-Alvarez C. A. , Hernández-Montes G. , Álvarez-Hilario L. G. , Herrera-Goepfert R. , Albores-Saavedra J. , Villegas-Sepúlveda N. , Cedillo-Barrón L. , Montes-Gómez A. E. , Vargas M. , Schnoor M. , Recillas-Targa F. , Hernández-Rivas R.
Published: February 2021

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable and devastating malignant tumors. Epigenetic modifications such as DNA methylation and histone modification regulate tumor initiation and progression. However, the contribution of histone variants in PDAC is unknown. Here, we demonstrated that the histone variant H2A.Z is highly expressed in PDAC cell lines and PDAC patients and that its overexpression correlates with poor prognosis. Moreover, all three H2A.Z isoforms (H2A.Z.1, H2A.Z.2.1, and H2A.Z.2.2) are highly expressed in PDAC cell lines and PDAC patients. Knockdown of these H2A.Z isoforms in PDAC cell lines induces a senescent phenotype, cell cycle arrest in phase G2/M, increased expression of cyclin-dependent kinase inhibitor CDKN2A/p16, SA-β-galactosidase activity and interleukin 8 production. Transcriptome analysis of H2A.Z-depleted PDAC cells showed altered gene expression in fatty acid biosynthesis pathways and those that regulate cell cycle and DNA damage repair. Importantly, depletion of H2A.Z isoforms reduces the tumor size in a mouse xenograft model in vivo and sensitizes PDAC cells to gemcitabine. Overexpression of H2A.Z.1 and H2A.Z.2.1 more than H2A.Z.2.2 partially restores the oncogenic phenotype. Therefore, our data suggest that overexpression of H2A.Z isoforms enables cells to overcome the oncoprotective barrier associated with senescence, favoring PDAC tumor grow and chemoresistance. These results make H2A.Z a potential candidate as a diagnostic biomarker and therapeutic target for PDAC.
In-vivo imaging of targeting and modulation of depression-relevant circuitry by transcranial direct current stimulation: a randomized clinical trial
Authors: Jog Mayank. S. , Kim Elizabeth , Anderson Cole , Kubicki Antoni , Kayathi Rishikesh , Jann Kay , Yan Lirong , Leaver Amber , Hellemann Gerhard , Iacoboni Marco , Woods Roger P. , Wang Danny J. J. , Narr Katherine L.
Published: February 2021

Recent clinical trials of transcranial direct current stimulation (tDCS) in depression have shown contrasting results. Consequently, we used in-vivo neuroimaging to confirm targeting and modulation of depression-relevant neural circuitry by tDCS. Depressed participants (N = 66, Baseline Hamilton Depression Rating Scale (HDRS) 17-item scores ≥14 and <24) were randomized into Active/Sham and High-definition (HD)/Conventional (Conv) tDCS groups using a double-blind, parallel design, and received tDCS individually targeted at the left dorsolateral prefrontal cortex (DLPFC). In accordance with Ampere’s Law, tDCS currents were hypothesized to induce magnetic fields at the stimulation-target, measured in real-time using dual-echo echo-planar-imaging (DE-EPI) MRI. Additionally, the tDCS treatment trial (consisting of 12 daily 20-min sessions) was hypothesized to induce cerebral blood flow (CBF) changes post-treatment at the DLPFC target and in the reciprocally connected anterior cingulate cortex (ACC), measured using pseudo-continuous arterial spin labeling (pCASL) MRI. Significant tDCS current-induced magnetic fields were observed at the left DLPFC target for both active stimulation montages (Brodmann’s area (BA) 46: pHD = 0.048, Cohen’s dHD = 0.73; pConv = 0.018, dConv = 0.86; BA 9: pHD = 0.011, dHD = 0.92; pConv = 0.022, dConv = 0.83). Significant longitudinal CBF increases were observed (a) at the left DLPFC stimulation-target for both active montages (pHD = 3.5E−3, dHD = 0.98; pConv = 2.8E−3, dConv = 1.08), and (b) at ACC for the HD-montage only (pHD = 2.4E−3, dHD = 1.06; pConv = 0.075, dConv = 0.64). These results confirm that tDCS-treatment (a) engages the stimulation-target, and (b) modulates depression-relevant neural circuitry in depressed participants, with stronger network-modulations induced by the HD-montage. Although not primary outcomes, active HD-tDCS showed significant improvements of anhedonia relative to sham, though HDRS scores did not differ significantly between montages post-treatment.
Understanding the impact of immune-mediated selection on lung cancer evolution
Authors: Rosenthal Rachel , Swanton Charles , McGranahan Nicholas
Published: February 2021

Understanding how a tumour evolves and avoids immune recognition is paramount to improving cancer immunotherapy and patient outcome. Here we examine our recent integration of multi-region genomic, transcriptomic, epigenomic, pathology, and clinical data, highlight the need for a systematic examination of immune escape mechanisms, and discuss implications for immunotherapy approaches.
p53 induces ARTS to promote mitochondrial apoptosis
Authors: Hao Qian , Chen Jiaxiang , Liao Junming , Huang Yingdan , Gan Yu , Larisch Sarit , Zeng Shelya X. , Lu Hua , Zhou Xiang
Published: February 2021

Apoptosis related protein in TGF-β signaling pathway (ARTS) was originally discovered in cells undergoing apoptosis in response to TGF-β, but ARTS also acts downstream of many other apoptotic stimuli. ARTS induces apoptosis by antagonizing the anti-apoptotic proteins XIAP and Bcl-2. Here we identified the pro-apoptotic Sept4/ARTS gene as a p53-responsive target gene. Ectopic p53 and a variety of p53-inducing agents increased both mRNA and protein levels of ARTS, whereas ablation of p53 reduced ARTS expression in response to multiple stress conditions. Also, γ-irradiation induced p53-dependent ARTS expression in mice. Consistently, p53 binds to the responsive DNA element on the ARTS promoter and transcriptionally activated the promoter-driven expression of a luciferase reporter gene. Interestingly, ARTS binds to and sequesters p53 at mitochondria, enhancing the interaction of the latter with Bcl-XL. Ectopic ARTS markedly augments DNA damage stress- or Nutlin-3-triggered apoptosis, while ablation of ARTS preferentially impairs p53-induced apoptosis. Altogether, these findings demonstrate that ARTS collaborates with p53 in mitochondria-engaged apoptosis.
Exosomes in ovarian cancer ascites promote epithelial–mesenchymal transition of ovarian cancer cells by delivery of miR-6780b-5p
Authors: Cai Jing , Gong Lanqing , Li Guodong , Guo Jing , Yi Xiaoqing , Wang Zehua
Published: February 2021

The poor prognosis of ovarian cancer is mainly due to metastasis, and the specific mechanism underlying ovarian cancer metastasis is not clear. Ascites-derived exosomes (ADEs) play an important role in the progression of ovarian cancer, but the mechanism is unknown. Here, we found that ADEs promoted ovarian cancer metastasis not only in vitro but also in vivo. This promotive function was based on epithelial–mesenchymal transition (EMT) of ovarian cancer cells. Bioinformatics analysis of RNA sequencing microarray data indicated that miR-6780b-5p may be the key microRNA (miRNA) in ADEs that facilitates cancer metastasis. Moreover, the expression of exosomal miR-6780b-5p correlated with tumor metastasis in ovarian cancer patients. miR-6780b-5p overexpression promoted and miR-6780b-5p downregulation suppressed EMT of ovarian cancer cells. These results suggest that ADEs transfer miR-6780b-5p to ovarian cancer cells, promoting EMT and finally facilitating ovarian cancer metastasis.
CircRNAs: a new target for the diagnosis and treatment of digestive system neoplasms
Authors: Li Jie , Xu Qiang , Huang Zi-jian , Mao Ning , Lin Zhi-tao , Cheng Long , Sun Bei , Wang Gang
Published: February 2021

A circRNA is a type of endogenous noncoding RNA that consists of a closed circular RNA molecule formed by reverse splicing; these RNAs are widely distributed in a variety of biological cells. In contrast to linear RNAs, circRNAs have no 5′ cap or 3′ poly(A) tail. They have a stable structure, a high degree of conservation, and high stability, and they are richly and specifically expressed in certain tissues and developmental stages. CircRNAs play a very important role in the occurrence and progression of malignant tumors. According to their origins, circRNAs can be divided into four types: exon-derived circRNAs (ecRNAs), intron-derived circRNAs (ciRNAs), circRNAs containing both exons and introns (EIciRNAs) and intergenic circRNAs. A large number of studies have shown that circRNAs have a variety of biological functions, participate in the regulation of gene expression and play an important role in the occurrence and progression of tumors. In this paper, the structure and function of circRNAs are reviewed, along with their biological role in malignant tumors of the digestive tract, in order to provide a reference for the diagnosis and treatment of digestive system neoplasms.
Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma
Authors: Dou Renjie , Qian Jinjun , Wu Wei , Zhang Yanxin , Yuan Yuxia , Guo Mengjie , Wei Rongfang , Yang Shu , Jurczyszyn Artur , Janz Siegfried , Beksac Meral , Gu Chunyan , Yang Ye
Published: February 2021

Steroid 5α-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling (GEP) of sequential MM samples during the disease course, we found that the aberrant expression of SRD5A1 was correlated with progression and poor prognosis in MM patients. In this study, the oncogenic roles of SRD5A1 were validated in human MM cell lines (ARP1 and H929) and the xenograft MM model as well as the 5TMM mouse model. MTT and flow cytometry were used to assess MM cell proliferation, cell cycle, and apoptosis post inducible knockdown SRD5A1 by lentivirus-mediated short-hairpin RNA (shRNA). Transcriptomic sequencing, immunofluorescence, and western blot were used to investigate the effects of SRD5A1 suppression on cell apoptosis and autophagy. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family protein-mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. Meanwhile, the autophagy inhibitor (3-methyladenine) and SRD5A1 inhibitor (Dutasteride) were utilized to evaluate their anti-myeloma effect. Thus, our results demonstrated that SRD5A1 downregulation simultaneously regulated both the apoptosis and the autophagic process in MM cells. The dual autophagy–apoptosis regulatory SRD5A1 may serve as a biomarker and potential target for MM progression and prognosis.
A superconducting switch actuated by injection of high-energy electrons
Authors: Ritter M. F. , Fuhrer A. , Haxell D. Z. , Hart S. , Gumann P. , Riel H. , Nichele F.
Published: February 2021

Recent experiments with metallic nanowires devices seem to indicate that superconductivity can be controlled by the application of electric fields. In such experiments, critical currents are tuned and eventually suppressed by relatively small voltages applied to nearby gate electrodes, at odds with current understanding of electrostatic screening in metals. We investigate the impact of gate voltages on superconductivity in similar metal nanowires. Varying materials and device geometries, we study the physical mechanism behind the quench of superconductivity. We demonstrate that the transition from superconducting to resistive state can be understood in detail by tunneling of high-energy electrons from the gate contact to the nanowire, resulting in quasiparticle generation and, at sufficiently large currents, heating. Onset of critical current suppression occurs below gate currents of 100fA, which are challenging to detect in typical experiments.
Flexible categorization in perceptual decision making
Authors: Prat-Ortega Genís , Wimmer Klaus , Roxin Alex , de la Rocha Jaime
Published: February 2021

Perceptual decisions rely on accumulating sensory evidence. This computation has been studied using either drift diffusion models or neurobiological network models exhibiting winner-take-all attractor dynamics. Although both models can account for a large amount of data, it remains unclear whether their dynamics are qualitatively equivalent. Here we show that in the attractor model, but not in the drift diffusion model, an increase in the stimulus fluctuations or the stimulus duration promotes transitions between decision states. The increase in the number of transitions leads to a crossover between weighting mostly early evidence (primacy) to weighting late evidence (recency), a prediction we validate with psychophysical data. Between these two limiting cases, we found a novel flexible categorization regime, in which fluctuations can reverse initially-incorrect categorizations. This reversal asymmetry results in a non-monotonic psychometric curve, a distinctive feature of the attractor model. Our findings point to correcting decision reversals as an important feature of perceptual decision making.
Spatially mapped single-cell chromatin accessibility
Authors: Thornton Casey A. , Mulqueen Ryan M. , Torkenczy Kristof A. , Nishida Andrew , Lowenstein Eve G. , Fields Andrew J. , Steemers Frank J. , Zhang Wenri , McConnell Heather L. , Woltjer Randy L. , Mishra Anusha , Wright Kevin M. , Adey Andrew C.
Published: February 2021

High-throughput single-cell epigenomic assays can resolve cell type heterogeneity in complex tissues, however, spatial orientation is lost. Here, we present single-cell combinatorial indexing on Microbiopsies Assigned to Positions for the Assay for Transposase Accessible Chromatin, or sciMAP-ATAC, as a method for highly scalable, spatially resolved, single-cell profiling of chromatin states. sciMAP-ATAC produces data of equivalent quality to non-spatial sci-ATAC and retains the positional information of each cell within a 214 micron cubic region, with up to hundreds of tracked positions in a single experiment. We apply sciMAP-ATAC to assess cortical lamination in the adult mouse primary somatosensory cortex and in the human primary visual cortex, where we produce spatial trajectories and integrate our data with non-spatial single-nucleus RNA and other chromatin accessibility single-cell datasets. Finally, we characterize the spatially progressive nature of cerebral ischemic infarction in the mouse brain using a model of transient middle cerebral artery occlusion.
The secreted endoribonuclease ENDU-2 from the soma protects germline immortality in C. elegans
Authors: Qi Wenjing , Gromoff Erika D. V. , Xu Fan , Zhao Qian , Yang Wei , Pfeifer Dietmar , Maier Wolfgang , Long Lijiang , Baumeister Ralf
Published: February 2021

Multicellular organisms coordinate tissue specific responses to environmental information via both cell-autonomous and non-autonomous mechanisms. In addition to secreted ligands, recent reports implicated release of small RNAs in regulating gene expression across tissue boundaries. Here, we show that the conserved poly-U specific endoribonuclease ENDU-2 in C. elegans is secreted from the soma and taken-up by the germline to ensure germline immortality at elevated temperature. ENDU-2 binds to mature mRNAs and negatively regulates mRNA abundance both in the soma and the germline. While ENDU-2 promotes RNA decay in the soma directly via its endoribonuclease activity, ENDU-2 prevents misexpression of soma-specific genes in the germline and preserves germline immortality independent of its RNA-cleavage activity. In summary, our results suggest that the secreted RNase ENDU-2 regulates gene expression across tissue boundaries in response to temperature alterations and contributes to maintenance of stem cell immortality, probably via retaining a stem cell specific program of gene expression.
Accelerating target deconvolution for therapeutic antibody candidates using highly parallelized genome editing
Authors: Mattsson Jenny , Ekdahl Ludvig , Junghus Fredrik , Ajore Ram , Erlandsson Eva , Niroula Abhishek , Pertesi Maroulio , Frendéus Björn , Teige Ingrid , Nilsson Björn
Published: February 2021

Therapeutic antibodies are transforming the treatment of cancer and autoimmune diseases. Today, a key challenge is finding antibodies against new targets. Phenotypic discovery promises to achieve this by enabling discovery of antibodies with therapeutic potential without specifying the molecular target a priori. Yet, deconvoluting the targets of phenotypically discovered antibodies remains a bottleneck; efficient deconvolution methods are needed for phenotypic discovery to reach its full potential. Here, we report a comprehensive investigation of a target deconvolution approach based on pooled CRISPR/Cas9. Applying this approach within three real-world phenotypic discovery programs, we rapidly deconvolute the targets of 38 of 39 test antibodies (97%), a success rate far higher than with existing approaches. Moreover, the approach scales well, requires much less work, and robustly identifies antibodies against the major histocompatibility complex. Our data establish CRISPR/Cas9 as a highly efficient target deconvolution approach, with immediate implications for the development of antibody-based drugs.
Interaction of 7SK with the Smn complex modulates snRNP production
Authors: Ji Changhe , Bader Jakob , Ramanathan Pradhipa , Hennlein Luisa , Meissner Felix , Jablonka Sibylle , Mann Matthias , Fischer Utz , Sendtner Michael , Briese Michael
Published: February 2021

Gene expression requires tight coordination of the molecular machineries that mediate transcription and splicing. While the interplay between transcription kinetics and spliceosome fidelity has been investigated before, less is known about mechanisms regulating the assembly of the spliceosomal machinery in response to transcription changes. Here, we report an association of the Smn complex, which mediates spliceosomal snRNP biogenesis, with the 7SK complex involved in transcriptional regulation. We found that Smn interacts with the 7SK core components Larp7 and Mepce and specifically associates with 7SK subcomplexes containing hnRNP R. The association between Smn and 7SK complexes is enhanced upon transcriptional inhibition leading to reduced production of snRNPs. Taken together, our findings reveal a functional association of Smn and 7SK complexes that is governed by global changes in transcription. Thus, in addition to its canonical nuclear role in transcriptional regulation, 7SK has cytosolic functions in fine-tuning spliceosome production according to transcriptional demand.
Strand-specific single-cell methylomics reveals distinct modes of DNA demethylation dynamics during early mammalian development
Authors: Sen Maya , Mooijman Dylan , Chialastri Alex , Boisset Jean-Charles , Popovic Mina , Heindryckx Björn , Chuva de Sousa Lopes Susana M. , Dey Siddharth S. , van Oudenaarden Alexander
Published: February 2021

DNA methylation (5mC) is central to cellular identity. The global erasure of 5mC from the parental genomes during preimplantation mammalian development is critical to reset the methylome of gametes to the cells in the blastocyst. While active and passive modes of demethylation have both been suggested to play a role in this process, the relative contribution of these two mechanisms to 5mC erasure remains unclear. Here, we report a single-cell method (scMspJI-seq) that enables strand-specific quantification of 5mC, allowing us to systematically probe the dynamics of global demethylation. When applied to mouse embryonic stem cells, we identified substantial cell-to-cell strand-specific 5mC heterogeneity, with a small group of cells displaying asymmetric levels of 5mCpG between the two DNA strands of a chromosome suggesting loss of maintenance methylation. Next, in preimplantation mouse embryos, we discovered that methylation maintenance is active till the 16-cell stage followed by passive demethylation in a fraction of cells within the early blastocyst at the 32-cell stage of development. Finally, human preimplantation embryos qualitatively show temporally delayed yet similar demethylation dynamics as mouse embryos. Collectively, these results demonstrate that scMspJI-seq is a sensitive and cost-effective method to map the strand-specific genome-wide patterns of 5mC in single cells.
Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9
Authors: Rodriguez Ernesto , Boelaars Kelly , Brown Kari , Eveline Li R. J. , Kruijssen Laura , Bruijns Sven C. M. , van Ee Thomas , Schetters Sjoerd T. T. , Crommentuijn Matheus H. W. , van der Horst Joost C. , van Grieken Nicole C. T. , van Vliet Sandra J. , Kazemier Geert , Giovannetti Elisa , Garcia-Vallejo Juan J. , van Kooyk Yvette
Published: February 2021

Changes in glycosylation during tumour progression are a key hallmark of cancer. One of the glycan moieties generally overexpressed in cancer are sialic acids, which can induce immunomodulatory properties via binding to Siglec receptors. We here show that Pancreatic Ductal Adenocarcinoma (PDAC) tumour cells present an increased sialylation that can be recognized by Siglec-7 and Siglec-9 on myeloid cells. We identified the expression of the α2,3 sialyltransferases ST3GAL1 and ST3GAL4 as main contributor to the synthesis of ligands for Siglec-7 and Siglec-9 in tumour cells. Analysing the myeloid composition in PDAC, using single cell and bulk transcriptomics data, we identified monocyte-derived macrophages as contributors to the poor clinical outcome. Tumour-derived sialic acids dictate monocyte to macrophage differentiation via signalling through Siglec-7 and Siglec-9. Moreover, triggering of Siglec-9 in macrophages reduce inflammatory programmes, while increasing PD-L1 and IL-10 expression, illustrating that sialic acids modulate different myeloid cells. This work highlights a critical role for sialylated glycans in controlling immune suppression and provides new potential targets for cancer immunotherapy in PDAC.
Quantifying information accumulation encoded in the dynamics of biochemical signaling
Authors: Tang Ying , Adelaja Adewunmi , Ye Felix X.-F. , Deeds Eric , Wollman Roy , Hoffmann Alexander
Published: February 2021

Cellular responses to environmental changes are encoded in the complex temporal patterns of signaling proteins. However, quantifying the accumulation of information over time to direct cellular decision-making remains an unsolved challenge. This is, in part, due to the combinatorial explosion of possible configurations that need to be evaluated for information in time-course measurements. Here, we develop a quantitative framework, based on inferred trajectory probabilities, to calculate the mutual information encoded in signaling dynamics while accounting for cell-cell variability. We use it to understand NFκB transcriptional dynamics in response to different immune threats, and reveal that some threats are distinguished faster than others. Our analyses also suggest specific temporal phases during which information distinguishing threats becomes available to immune response genes; one specific phase could be mapped to the functionality of the IκBα negative feedback circuit. The framework is generally applicable to single-cell time series measurements, and enables understanding how temporal regulatory codes transmit information over time.
Probing intramolecular vibronic coupling through vibronic-state imaging
Authors: Kong Fan-Fang , Tian Xiao-Jun , Zhang Yang , Yu Yun-Jie , Jing Shi-Hao , Zhang Yao , Tian Guang-Jun , Luo Yi , Yang Jin-Long , Dong Zhen-Chao , Hou J. G.
Published: February 2021

Vibronic coupling is a central issue in molecular spectroscopy. Here we investigate vibronic coupling within a single pentacene molecule in real space by imaging the spatial distribution of single-molecule electroluminescence via highly localized excitation of tunneling electrons in a controlled plasmonic junction. The observed two-spot orientation for certain vibronic-state imaging is found to be evidently different from the purely electronic 0–0 transition, rotated by 90°, which reflects the change in the transition dipole orientation from along the molecular short axis to the long axis. Such a change reveals the occurrence of strong vibronic coupling associated with a large Herzberg–Teller contribution, going beyond the conventional Franck–Condon picture. The emergence of large vibration-induced transition charges oscillating along the long axis is found to originate from the strong dynamic perturbation of the anti-symmetric vibration on those carbon atoms with large transition density populations during electronic transitions.