Ongoing Escalation Research Articles

Dosage sensitivity shapes balanced expression and gene longevity of homoeologs after whole-genome duplications in angiosperms.

Following whole-genome duplication (WGD), duplicate gene pairs (homoeologs) can evolve varying degrees of expression divergence. However, the determinants influencing these relative expression level differences (RFPKM) between homoeologs remain elusive. In this study, we analyzed the RFPKM between homoeologs in 3 angiosperms, Nymphaea colorata, Nelumbo nucifera, and Acorus tatarinowii, all having undergone a single WGD since the origin of angiosperms. Our results show significant positive correlations in RFPKM of homoeologs among tissues within the same species, and among orthologs across these 3 species, indicating convergent expression balance/bias between homoeologous gene copies following independent WGDs. We linked RFPKM between homoeologs to gene attributes associated with dosage-balance constraints, such as protein-protein interactions, lethal-phenotype scores in Arabidopsis (Arabidopsis thaliana) orthologs, domain numbers, and expression breadth. Notably, homoeologs with lower RFPKM often had more interactions and higher lethal-phenotype scores, indicating selective pressures favoring balanced expression. Also, homoeologs with lower RFPKM were more likely to be retained after WGDs in angiosperms. Within Nelumbo, greater RFPKM between homoeologs correlated with increased cis- and trans-regulatory differentiation between species, highlighting the ongoing escalation of gene expression divergence. We further found that expression degeneration in 1 copy of homoeologs is inclined toward nonfunctionalization. Our research highlights the importance of balanced expression, shaped by dosage-balance constraints, in the evolutionary retention of homoeologs in plants.

Evaluation of Spontaneous Overtime Methemoglobin Formation in Post-Mortem Blood Samples from Real Cases in Critical Storage Conditions.

Nitrite/nitrate poisoning is an emerging problem, with an ongoing escalation of reported self-administration with suicidal intent in several countries. Nitrites toxicity mainly consists of their interaction with hemoglobin (Hb), causing its oxidization to methemoglobin (MetHb). In order to give support to the correct procedures for the analysis of these cases, this study aims to evaluate spontaneous sample degradation and consequent MetHb formation in the typical storage conditions of a forensic toxicology laboratory. Two different types of samples have been used in this study: the first stage of our study consisted of a retrospective analysis of blood samples obtained by judicial autopsies already stored in the toxicology laboratory, collected over four years (2018-2021), while the samples used for the second stage were appositely collected during judicial autopsies. The data obtained by the application of a derivative spectrophotometry method on these samples suggest that there seems not to be a maximum threshold for MetHb formation within which it is possible to state with a sufficient grade of certainty that the concentration of MetHb found is consistent with an ante-mortem formation and is not the result of an artifact due to sample degradation and storage conditions. On the other hand, the results suggest that MetHb formation depends on the time passed between sample collection and analysis, so that a tempestive sample processing, performed as soon as the samples are received in the laboratory, is crucial to obtain the maximum reliability and diagnostic values from the data when MetHb quantitation is necessary.

Язвенная болезнь – кто виноват и что делать?

The first successes in the treatment of peptic ulcer disease (PU) using antibiotics in combination with proton pump blockers contributed to the emergence of the hypothesis that H. pylori is the main cause of PU. Moreover, it was assumed that eradication of H. pylori could lead to elimination of ulcerative disease. However, 40 years after the discovery of H. pylori, it became clear that eradication therapy reduces the time to ulcer healing, improves the quality of life and prolongs remission, but does not eliminate PU. Nevertheless, the new Maastricht VI guidelines still proclaim H. pylori eradication as the main goal of therapy for H. pylori-associated diseases. The widespread use of antibiotics has saved millions of lives. At the same time, bacterial resistance to existing antibiotics due to the ongoing escalation of antibacterial therapy has been named by the World Health Organization as one of the main threats to humanity in this century. Therefore, the infectious concept of the pathogenesis of PU and the principles of its treatment require clarification.

Why identification matters: an explorative study on six cases of family reunification

The escalating phenomenon of migration, accompanied by a disturbing surge in associated tragedies, has persistently violated internationally protected human rights. Absence of physical evidence, namely the presence of adequately identified corpses, may impede the full enjoyment of human rights and—in some cases—the course of justice as it obstructs the initiation of legal proceedings against individuals implicated in causing such catastrophes. It also presents administrative obstacles, as death certificates are indispensable in legitimizing statuses like orphanhood and widowhood. Family reunification, particularly for orphans, plays a significant role for those attempting to reconnect with their relatives all over the world. Likewise, for mothers, the acknowledgment of their marital status or widowhood can be a pathway to regain their marginalized right to social life. To elucidate this issue, we analyzed six representative cases from the tragic October 3, 2013, shipwreck near the Italian island of Lampedusa, where 366 individuals were retrieved dead from the sea. These cases underscore the practical challenges involved, highlighting the compelling need for continued efforts to ensure that this burdensome problem transcends from being a mere ethical, moral, and legal discourse. Although considerable progresses, these cases also reveal that substantial work still lies ahead. There is a pressing need for improved mechanisms to certify kinship ties, which are often the limiting factor in many reunifications, and can hinder the granting of custody to children. The severity and far-reaching implications of this problem necessitate thoughtful attention and action, especially considering the ongoing escalation in migration and related fatalities.

Phase 1/1b study of SY-5609, a selective and potent CDK7 inhibitor, in advanced solid tumors and in 2L/3L pancreatic ductal adenocarcinoma (PDAC) in combination with gemcitabine +/- nab-paclitaxel.

3080 Background: SY-5609 is an oral, highly selective and potent noncovalent inhibitor of CDK7, a key regulator of cell cycle progression and transcription. In this Phase 1 FIH study (NCT04247126), the single agent (SA) continuous daily dosing (CDD) regimen maximum tolerated dose (MTD) was 3 mg/day. Subsequently, enhanced tolerability was demonstrated using an intermittent 7 day on/7 day off (7/7) schedule at higher dose levels (Sharma 2021). SY-5609 preclinical data and early clinical activity provided the rationale for evaluating SY-5609 + gemcitabine (gem) +/- nab-paclitaxel (np) in PDAC. Herein, we present data from the ongoing SA dose escalation and SY-5609 + gem +/- nab-paclitaxel (np) safety lead-ins (SLIs). Methods: The 7/7 schedule was used to further evaluate SA escalation in pts with select solid tumors. In the PDAC combination SLIs, SY-5609, starting with a dose of 4 mg, is escalated using the 7/7 schedule in combination with biweekly gem (1000 mg/m2) +/- np (125 mg/m2). Evaluations included safety, clinical activity (RECIST v1.1), PK, and induction of peripheral blood PD marker POLR2A (Papadopoulos 2020). Results: As of 13 Jan 2023, 87 pts have been enrolled (70 SA, 14 SY-5609 + gem, 3 SY-5609 + gem/np), including 30 pts across the 4, 5, 6, 7, and 10 mg SA 7/7 cohorts included in the safety summary. MTD for the 7/7 schedule has not been reached. The 15 mg SA cohort is now enrolling. Most SA 7/7 AEs were low-grade; AEs included (>20%) nausea, diarrhea, fatigue, anorexia, and thrombocytopenia. No new safety signals were observed in the SY-5609 4 mg and 5 mg + gem and SY-5609 4 mg + gem/np cohorts; 1 pt (SY-5609 5 mg + gem) had a DLT of Gr3 diarrhea. The 10 mg + gem cohort is now enrolling. Most SY-5609 + gem +/- np AEs were low grade. AEs in the SLIs were consistent with the safety profile of either SY-5609 or gem +/- np and included (>20%) fatigue, anorexia, nausea, abdominal pain, and constipation. In the SA cohorts (response-evaluable, n=29), 100% (3/3) of pts in the 10 mg 7/7 cohort had stable disease (SD) as the best response, compared to 19% (5/26) SD rate in 4 to 7 mg SA 7/7 cohorts. Disease control rate in the combination SLIs (response-evaluable, n=11) was 45% (5/11), including 1 confirmed partial response (4 mg + gem) in a patient with liver metastases who had a reduction in CA 19-9 from 60,357 U/mL to 968 U/mL, and SD in 4 pts (3 in 5 mg + gem, 1 in 4 mg + gem/np). SA and SLI PK data support an emerging exposure-activity relationship. POLR2A PD marker data from SA and SLI cohorts correlate with exposure. Conclusions: To date, intermittent dosing of SY-5609 on the 7/7 schedule has acceptable tolerability alone and in combination with gem +/- np. Encouraging preliminary clinical activity and the emerging exposure-activity relationship supports the ongoing escalation of SY-5609 in SA and combination SLI cohorts; updated results will be presented. Clinical trial information: NCT04247126 .

Delivery after a previous cesarean section reviewed.

At the start of the 20th century, cesarean section (CS) was uncommon in obstetrics. By the end of the century, CS rates had increased dramatically worldwide. Although the explanation for the increase is multifactorial, a major driver in the ongoing escalation is the increase in women who are delivered by repeat CS. This is due, in part, to the fact that there has been a sharp fall in vaginal birth after CS (VBAC) rates as fewer women are offered a trial of labor after CS (TOLAC), due principally to fears of a catastrophic intrapartum uterine rupture. This paper reviewed international VBAC policies and trends. A number of themes emerged. The risk of intrapartum rupture and its associated complications is low and may sometimes be overestimated. Individual maternity hospitals in both developed and developing countries are inadequately resourced to safely supervise a TOLAC. Efforts to mitigate the risks of TOLAC by careful patient selection and good clinical practices may be underutilized. Given the serious short-term and long-term consequences of rising CS rates for women and for maternity services generally, a review of TOLAC policies worldwide should be prioritized and consideration given to convening a Global Consensus Development Conference on Delivery after CS.

The New Cold War: Cyber Frontline

Abstract The ongoing escalation of animosities between the United States, the Russian Federation and the People’s Republic of China is beginning to resemble the Cold War, which as a historical period might have ended in the twentieth century, but still endures as a state of hostilities between the countries, expressed in the form of an indirect conflict. These countries are actively growing their cyber capabilities that enable indirect and covert operations aimed at their opponents. In cyberspace, the states involved express the hostilities and the aims they try to achieve in the least detectable way. As a result, cyberspace has been securitized. It has been recognized by NATO as a domain of activities. In the United States, the National Cybersecurity Strategy has been published, recognizing cyberspace as an integral part of the economy and defence. A similar document called the Information Security Doctrine was issued in the Russian Federation, which manifests Russia’s aspirations in the field of information technology. The militarization of this area shows that cyberspace is becoming a battlefield in the new cold war. The Russian military invasion of Ukraine is complemented by the activities in the cyberspace. I analyse the new confrontation between the above-mentioned powers, looking for features of the Cold War in it. In particular, I examine the cyber capabilities of the United States, Russia and China. The article claims that the concept of cold war may be applicable to numerous historical eras, including the one that is still in effect now.

Safety and Efficacy from a Phase 1b/2 Study of IMGN632 in Combination with Azacitidine and Venetoclax for Patients with CD123-Positive Acute Myeloid Leukemia

Safety and Efficacy from a Phase 1b/2 Study of IMGN632 in Combination with Azacitidine and Venetoclax for Patients with CD123-Positive Acute Myeloid Leukemia

RELATIONSHIP BETWEEN COGNITIVE RESERVE, MOTOR RESERVE AND THALAMUS VOLUMETRY IN OLDER ADULTS

With the increasing worldwide population, an ongoing escalation in mild cognitive impairment and dementia is predicted. Motor reserve – the cumulative physical activity experience gained throughout life, as well as cognitive reserve – the brain’s ability to overcome a pathology, such as neurodegenerative disorders, - has been identified as protective factors in cognitive decline. Thus, this study aimed to investigate the relationship between cognitive reserve, motor reserve, and brain volumetry in older adults. 44 older adults (M = 70, SD = 5.18, 77.3% female) with no self-reported significant neurological, ongoing oncological etc. disorders that might limit their participation in the study were involved in the study. All participants underwent a thorough life-style and psychological assessment, as well as structural brain MRI analysis. Overall, our study indicated the significance of a combination of lifestyle factors in predicting thalamic volume. The results of this study indicate that life-long participation in physical, intellectual, and social activities could be beneficial for preserving the volume of thalamus, which is among the first to decline due to aging.

Wound Healing Effect of Acokanthera schimperi Schweinf (Apocynaceae) Methanol Leaf Extract Ointment in Mice and Its in-vitro Antioxidant Activity.

BackgroundAcokanthera schimperi is traditionally used for the treatment of wounds and various bacterial infections. Due to the ongoing escalation of antimicrobial resistance, there is an increasing demand for the appropriate wound care and hence, the present study was initiated to investigate the wound healing effects of the leaf extract ointments of A. schimperi in mice and its in-vitro antioxidant activity.MethodsThe crude extract was prepared as 5% and 10% w/w ointments for topical use in mice. Wound contraction and epithelialization period were determined in excision and infected models, whereas tensile strength was determined in an incision model. Besides, its antioxidant activity was evaluated using the DPPH method.ResultsIn this study, the 10% w/w extract ointment did not cause toxicity at the 2000 mg/kg limit dose. In the excision model, the 10% w/w ointment exhibited a significant wound contraction effect starting from day 6 to 14 with a complete epithelization shown on day 13. Besides, the 5%w/w ointment showed a significant wound contraction effect starting from day 6 onwards, and a significant decrease in the epithelization period observed on day 16. Conversely, both the 10% w/w and 5% w/w ointments showed significant wound contraction effects starting from day 4 and onwards in the infected model. However, a complete epithelization period was observed on days 14 and 18 in the 10%w/w and 5% w/w/extract ointment treated groups, respectively. In the incision model, the 10% (w/w) and 5% (w/w) extract ointments showed a significant increase in tensile strength by 36.80 and 32.23%, respectively. Moreover, the antioxidant activity of the extract was concentration-dependent with an IC50 value of 5.49± 0.38 µg/µL.ConclusionThe potential wound healing effects of this plant may provide a candidate source in the discovery of new drugs for the treatment of wounds.

Recent Advances in Nanotechnology-Aided Materials in Combating Microbial Resistance and Functioning as Antibiotics Substitutes.

The ongoing escalation of drug-resistant bacteria creates the leading challenges for human health. Current predictions show that deaths due to bacterial illness will be more in comparison to cancer in 2050. Irrational use of antibiotics, prolonged regimen and using as a prophylactic treatment for various infections are leading cause of microbial resistance. It is an emerging approach to introduce evolving nanomaterials (NMs) as a base of antibacterial therapy to overcome the bacterial resistance pattern. NMs can implement several bactericidal ways and turn into a challenge for bacteria to survive and develop resistance against NMs. All the pathways depend on the surface chemistry, shape, core material and size of NMs. Because of these reasons, NMs based stuff shows a critical role in advancing the treatment efficiency by interacting with the cellular system of bacteria and functioned as an antibiotic substitute. We divided this review into two sections. The first part highlights the development of microbial resistance to antibiotics and their mechanisms. The second section details the NMs mechanisms to combat antibiotic resistance. In short, we try to summarize the advances in NMs role to deal with microbial resistance and giving solution as antibiotics substitute.

Meeting the challenges posed by an escalating diabetes healthcare burden: A mixed methods study

Background: The ongoing escalation in the incidence of diabetes is contributing to a growing burden on health services because patients with diabetes as a co-morbidity are now spread throughout the hospital (rather than being located in specific areas). Thus, there is a need for expertise in diabetes care throughout services to ensure optimal care and reduce threats to patient safety.Aims and objectives: To identify new strategies to maintain optimal care for patients with diabetes while in hospital.Design: Mixed methods underpinned by Appreciative Inquiry.Methods: The Diabetes Knowledge Questionnaire Survey (DKQS) (n = 173); focus group interviews with nurses and midwives (n = 40), and individual interviews with recently discharged hospital patients (n = 6). Quantitative data were analysed using descriptive statistics and qualitative data by thematic analysis.Results: Highlight a need to enhance knowledge and confidence of diabetes management among nursing, midwifery, medical and ancillary staff through the introduction of focused education strategies. This, together with improved communication and team work, is required to relieve the burdens on frontline nursing staff and patients caused by delays in prescribing and reviewing insulin requirements and in accessing needed food for people with diabetes.Conclusions: In seeking solutions to the challenges in caring for hospitalised patients with diabetes there is a need to work across the entire hospital workforce and to develop effective and efficient methods for ensuring appropriate skills and knowledge of diabetes management for staff across complex and rapidly changing hospital systems.Relevance to clinical practice: The introduction and implementation of innovative educational and organisational strategies are needed to assist in meeting the challenges posed by an escalating diabetes healthcare burden. The safety of patients with diabetes can be optimised with the timely availability of appropriate meals and snacks, and enhanced coordination and communication between and within multidisciplinary teams.

Portraying Protracted Conflict in the Entertainment Industry

Protracted conflicts are common and complex, and differ from other types of disputes because of their ongoing escalation, non-negotiable issues, unsuccessful interventions, and passage of time. Prior research on this topic lacks good operationalizations of these features. This not only makes it difficult to compare research on how journalists and media portray such conflict but also challenging to analyze such phenomena. Hence, this study develops codes for features of protracted conflict and then applies those to the case of the news coverage (n = 148) of the 2008–2009 negotiations between the Screen Actors Guild of America and the Alliance of Motion Picture and Television Producers. Results demonstrate the applicability of these features to describe news coverage of a labor management conflict setting, illustrate how these features vary over time and show how features are interrelated, to reveal two underlying dimensions of the particular conflict (temporal context and resolution flexibility) and possibly protracted conflicts in general.

Graduate Medical Education in Tactical Medicine and the Impact of ACGME Accreditation of EMS Fellowships.

Physician interest in tactical medicine as an area of professional practice has grown significantly over the past decade. The prevalence of physician involvement in terms of medical oversight and operational support of civilian tactical medicine has experienced tremendous growth during this timeframe. Factors contributing to this trend are multifactorial and include enhanced law enforcement agency understanding of the role of the tactical physician, support for the engagement of qualified medical oversight, increasing numbers of physicians formally trained in tactical medicine, and the ongoing escalation of intentional mass-casualty incidents worldwide. Continued vigilance for the sustenance of adequate and appropriate graduate medical education resources for physicians seeking training in the comprehensive aspects of tactical medicine is essential to ensure continued advancement of the quality of casualty care in the civilian high-threat environment.

Chronic pramipexole treatment increases tolerance for sucrose in normal and ventral tegmental lesioned rats.

The loss of dopamine neurons observed in Parkinson's disease (PD) elicits severe motor control deficits which are reduced by the use of dopamine agonists. However, recent works have indicated that D3-preferential agonists such as pramipexole can induce impulse control disorders (ICDs) such as food craving or compulsive eating. In the present study, we performed an intermittent daily feeding experiment to assess the effect of chronic treatment by pramipexole and VTA bilateral lesion on tolerance for sucrose solution. The impact of such chronic treatment on spontaneous locomotion and spatial memory was also examined. Changes in sucrose tolerance could indicate the potential development of a change in food compulsion or addiction related to the action of pramipexole. Neither the bilateral lesion of the VTA nor chronic treatment with pramipexole altered the spontaneous locomotion or spatial memory in rats. Rats without pramipexole treatment quickly developed a stable intake of sucrose solution in the 12 h access phase. On the contrary, when under daily pramipexole treatment, rats developed a stronger and ongoing escalation of their sucrose solution intakes. In addition, we noted that the change in sucrose consumption was sustained by an increase of the expression of the Dopamine D3 receptor in the core and the shell regions of the nucleus accumbens. The present results may suggest that long-term stimulation of the Dopamine D3 receptor in animals induces a strong increase in sucrose consumption, indicating an effect of this receptor on certain pathological aspects of food eating.

China’s Regional Strategy and Challenges in East Asia

China has rapidly developed a sophisticated regionalism strategy in East Asia. Minimising the region’s “China threat” perception has been a significant consideration in this strategy. Unfortunately, the ongoing escalation of tension concerning territorial disputes over the Diaoyutai / Senkaku Islands and the South China Sea, initiated by a series of high-profile naval exercises in the latter half of 2010, has reinforced the “China threat” perception and bolstered the hedging strategies of countries in the region. China is aware of its relative disadvantage, and it has been keeping its options open while allowing ASEAN to maintain the initiative.

‘Foreigners’, Nationalism and the ‘Colonial Fracture’

The riots that shook the French banlieues in 2005, while unique in their geographic extension and political resonance, are but the most recent manifestation of an ongoing escalation of violence and repression that has periodically rocked the economically devastated, socially fractured and highly cosmopolitan cityscape of post-industrial France. The stigmatization of unemployed youths and outcast working-class families as ‘foreign’ is a complex and multi-layered phenomenon. This article traces the history of the so-called ‘immigrant problem’, and of policy responses to it, from the time of the Algerian war to the republican nationalist backlash against multiculturalism over the past two decades. The trauma of decolonization, increased visibility of Maghrebi, West African, Antillian and other communities with origins outside of Europe, fears of ‘islamicization’, and political/ideological controversies over how the nation's history should be remembered and taught to future generations, have weighed heavily on the representation of immigrants and their descendants as unassimilated threats to national cohesion. Far from limiting their agency to criminality and random social violence, the youths of the banlieues have played an active role in redefining the terms in which citizenship and national identity, as well as the colonial heritage of France, are cast in the arena of public debate, challenging state policies and well-entrenched historical myths in the process.

Disrupting Escalation of Terror in Russia to Prevent Catastrophic Attacks

The recent spate of deadly terrorist attacks in Russia has plunged the country into what President Vladimir Putin has rightfully described as a “total war” against the networks of terror. This article will analyze the trends in this war, and will conclude that the logical outcome of the ongoing escalation in number, scope, and cruelty of terrorist attacks in Russia will be an act of catastrophic terrorism. The horrendous hostage-taking drama in the North Ossetian town of Beslan—in which more than 330, including 160 children, were killed—clearly demonstrates that ideologically-driven extremists have already passed the moral threshold between conventional terror acts and catastrophic terrorism. We will demonstrate that networks of these extremists are constantly expanding their capabilities, both organizational and operational, in this total war to inflict damage of catastrophic proportions on Russia either by conventional means or through the use of nuclear, biological and chemical (NBC) materials. We will also demonstrate that the most violent and organized of these networks—the anti-Russian insurgents in the Northern Caucasus—are becoming increasingly motivated to resort to acts of catastrophic terrorism, as their current tactics of conventional attacks have failed to have any impact on the Kremlin’s staunch refusal to negotiate either with the Islamist or secular wings of separatists in the region. The hostage-taking drama in Beslan in September 2004 is the latest evidence of the Islamist wing’s preparedness to kill hundreds of noncombatants, including children, as well as sacrifice their own lives as they strive to win