bluuebunny/crossref_metadata_2025 huggingface dataset:
Journey to the centre of the universe
Authors: Close Frank
Published: November 2023

This chapter provides an overview of the fundamental particles of matter and their role in building the universe at large. It tackles the discovery of a particle called the Higgs boson, which was discovered by CERN, a particle physics laboratory in Geneva. The discovery of the Higgs boson confirms that the world is immersed in an all-pervading field, which moulds the interactions of fundamental particles and gives rise to structures. The chapter details the characteristics and inner structure of atoms, which are known to be the smallest piece of an element that can exist. It also elaborates on several forces of Nature, such as gravity and electric and magnetic forces.
How we learn what things are made of, and what we found
Authors: Close Frank
Published: November 2023

This chapter details the inner structure of atoms that concerns electrons, nuclear particles, and quarks. It explains how viewing, heating, and breaking an object to find out what something is made of requires energy. One of the great discoveries in quantum theory was that particles can have wavelike character, and waves can act like staccato bundles of particles, known as quanta. The chapter also considers the correlation between temperature and wavelength, which explains how bodies at different temperatures will tend to radiate at different wavelengths. It also looks into the result of heavy and light objects hitting light and heavy targets respectively.
The heart of the matter
Authors: Close Frank
Published: November 2023

This chapter focuses on the roles, masses, and properties of quarks, electrons, and radioactivity in making life. It notes the discovery of atomic structure, protons, and quarks as a result of scattering beams of high-energy particles. Three quarks, which have different electrical charges, clustered together are sufficient to make a proton or a neutron. The neutron has no electrical charge overall, but its quarks give it a magnetic moment. Electric charge is preserved in the beta decay of a neutron as the proton has one unit positive, counterbalancing the negative electron. The chapter also looks into the occurrence of quarks and electrons in mirror form through antiparticles, which are also the seeds of antimatter.
Accelerators: cosmic and man-made
Authors: Close Frank
Published: November 2023

This chapter covers the development of cosmic and man-made accelerators. It explains that electrically charged particles are accelerated by electric forces, and how applying enough electric force to an electron will allow that electron to go faster and faster in a straight line. The idea of creating a ring-shaped accelerator originated with Ernest Lawrence, who used a magnetic field to bend the particles into a circular orbit. The chapter then details the function of the Large Hadron Collider, Stanford Linear Accelerator, Cosmotron, and cyclotron. It notes how the difference between matter and antimatter resulted in the interest in the properties of strange particles and antiparticles called kaons.
Detectors: cameras and time machines
Authors: Close Frank
Published: November 2023

This chapter explores the evolution of detectors that ranged between cameras and time machines. The cloud chamber was the first detector capable of revealing trails of charged particles. In the late 1940s, high-quality photographic emulsions became available which became the very earliest work on radioactivity and the discovery of X-rays. The chapter looks into the limitations of the bubble chamber and how the spark chamber improved ability to record the trails of particles. It then explains how the origins and nature of matter have depended upon advances in the construction of ever more powerful accelerators and the development of sophisticated means of recording the collisions.
Where has matter come from?
Authors: Close Frank
Published: November 2023

This chapter considers the origin of matter. It explains how atoms formed inside long-dead stars where they were all cooked from protons, the nuclei of the simplest atomic element, also known as hydrogen. Hydrogen is relatively uncommon on Earth, but is the most common atomic element in the universe at large. The chapter notes how the first part of the solar fusion cycle produces antimatter. It also looks into the process of converting hydrogen to helium in the Sun. The basic pieces of nuclear matter, quarks, emerged from the Big Bang along with electrons, and then the universe rapidly cooled so that the quarks clustered together to form protons.
How to be happy
Authors: Annas Julia
Published: November 2023

This chapter introduces the ancient philosophy behind happiness. It starts with the Choice of Heracles and the role of Virtue and Pleasure, which is widespread in ancient Greek and Roman culture. Compared to modern discussions of happiness, ancient ethics primarily revolve around the notion of happiness is about having a happy life. The overall end must be complete and self-sufficient in order to be happy. Moreover, pleasure is a short-term joy that only satisfies for a while, while happiness is expected to last for a long time. The chapter then explores the concepts of eudaimonia and hedonism, while also considering how virtue ethics moved to the foreground of contemporary moral thinking.
Logic and reality
Authors: Annas Julia
Published: November 2023

This chapter focuses on the ancient notions of logic and reality. Logic is one of Aristotle’s more impressive achievements after he systematized the notion of valid argument and constructed an extensive logical system. The chapter mentions how students of philosophy in the ancient world could expect to study Aristotelian or Stoic logic unless they were Epicureans. Moreover, the emergence of physics and metaphysics solved several scientific inquiries on nature. The chapter also explores the concept of teleology as presented by Aristotle and Plato. It cites that the legacy of ancient disputes became greatly simplified, explaining how new learning of the Renaissance replaced the system of Aristotelianism.
Intragastric administration of cinnamaldehyde induces changes in body temperature via TRPA1
Authors: Mori Noriyuki , Urata Tomomi
Published: November 2023

The transient receptor potential (TRP) channel family, including TRPA1, is known to be involved in temperature sensing and response. Previous studies have shown that intragastric administration of cinnamaldehyde (a typical TRPA1 agonist) can change body temperature, but the role of TRPA1 in this response is not clear. In this study, we found that intragastric administration of cinnamaldehyde increased in the intrascapular brown adipose tissue (IBAT) and rectal temperatures. However, this effect was not observed in TRPA1 knockout mice, suggesting that TRPA1 is involved in these temperature changes. Intravenous cinnamaldehyde also increased IBAT and rectal temperatures, only in the presence of TRPA1. We also explored the contribution of the vagus nerve to these temperature changes and found that it played a limited role. These results suggest that cinnamaldehyde can affect body temperature through TRPA1 activation, with the vagus nerve having a minor influence.
Regulations and functions of proline utilization in yeast Saccharomyces cerevisiae
Authors: Nishimura Akira
Published: November 2023

The quality of alcoholic beverages strongly depends on the metabolic characteristics of the yeast cells being used. To control the aroma and the taste of alcoholic beverages, as well as the production of ethanol in them, it is thus crucial to select yeast cells with the proper characteristics. Grape must contain a high concentration of proline, an amino acid that can potentially be a useful nitrogen source. However, Saccharomyces cerevisiae cannot utilize proline during the wine-making process, resulting in the elevated levels of proline in wine and consequent negative effects on wine quality. In this article, I review and discuss recent discoveries about the inhibitory mechanisms and roles of proline utilization in yeast. The information can help in developing novel yeast strains that can improve fermentation and enhance the quality and production efficiency of wine.
The fluid factor OVGP1 provides a significant oviductal microenvironment for the reproductive process in golden hamster
Authors: Yamatoya Kenji , Kurosawa Masaru , Hirose Michiko , Miura Yoshiki , Taka Hikari , Nakano Tomoyuki , Hasegawa Akiko , Kagami Kyosuke , Yoshitake Hiroshi , Goto Kaoru , Ueno Takashi , Fujiwara Hiroshi , Shinkai Yoichi , Kan Frederick W K , Ogura Atsuo , Araki Yoshihiko
Published: November 2023

The mammalian oviductal lumen is a specialized chamber that provides an environment that strictly regulates fertilization and early embryogenesis, but the regulatory mechanisms to gametes and zygotes are unclear. We evaluated the oviductal regulation of early embryonic development using Ovgp1 (encoding an oviductal humoral factor, OVGP1)-knockout golden hamsters. The experimental results revealed the following: (1) female Ovgp1-knockout hamsters failed to produce litters; (2) in the oviducts of Ovgp1-knockout animals, fertilized eggs were sometimes identified, but their morphology showed abnormal features; (3) the number of implantations in the Ovgp1-knockout females was low; (4) even if implantations occurred, the embryos developed abnormally and eventually died; and (5) Ovgp1-knockout female ovaries transferred to wild-type females resulted in the production of Ovgp1-knockout egg-derived OVGP1-null litters, but the reverse experiment did not. These results suggest that OVGP1-mediated physiological events are crucial for reproductive process in vivo, from fertilization to early embryonic development. This animal model shows that the fate of the zygote is determined not only genetically, but also by the surrounding oviductal microenvironment.
Validating the risk of hypoparathyroidism after total thyroidectomy in a population-based cohort: plea for improved follow-up
Authors: Annebäck Matilda , Osterman Carolina , Arlebrink Jesper , Mellerstedt Simon , Papathanasakis Nicolas , Wallin Göran , Hessman Ola , Annerbo Maria , Norlén Olov
Published: November 2023

Background

A previous nationwide study from Sweden showed that the rate of permanent hypoparathyroidism is high and under-rated in the Swedish Quality Register. This retrospective population-based study aimed to validate the rate and diagnosis of permanent hypoparathyroidism found in the previous study. A secondary aim was to assess the relationship between the rate of low parathyroid hormone (PTH) levels within 24 h after surgery and the rate of permanent hypoparathyroidism.

Methods

All patients who underwent total thyroidectomy from 2005 to 2015 in a region of Sweden were included. Data were retrieved from local health records, the National Patient Registry, the Swedish Prescribed Drug Registry, and the Swedish Quality Register. A strict definition of permanent hypoparathyroidism was used, including biochemical data and attempts to stop the treatment.

Results

A total of 1636 patients were included. Altogether, 143 patients (8.7 per cent) developed permanent hypoparathyroidism. Of these, 102 (6.2 per cent) had definitive permanent hypoparathyroidism, whereas 41 (2.5 per cent) had possible permanent hypoparathyroidism, because attempts to stop the treatment were lacking (28) or patients were lost to follow-up (13). The agreement between the Swedish Quality Register and the chart review was 29.3 per cent. A proportion of 23.2 per cent with a PTH level below the reference value corresponded to a 6.7 per cent rate of permanent hypoparathyroidism.

Conclusion

The risk of permanent hypoparathyroidism after total thyroidectomy is high. Some patients are overtreated because attempts to stop the treatment are lacking. Quality registers might underestimate the risk of permanent hypoparathyroidism. Approximately one-quarter of all patients with low PTH levels immediately after surgery developed permanent hypoparathyroidism.
A Battle of the Big Three?—Competing Conceptualizations of Personal Data Shaping Transnational Data Flows
Authors: Gao Raymond Yang
Published: November 2023

In the unfolding digital era, personal data has increasingly been conceptualized in a hybrid way, primarily drawing on notions of economics, privacy, and national security. Such a sui generis nature makes personal data something of its own category, opening the door to different conceptualizations by different actors. This article identifies three primary conceptualizations of personal data adopted by three major powers (the US, the EU, and China) with respect to cross-border data transfers—namely, a factor of production, an embodiment of fundamental rights, and an element of national security. Highlighting different attributes of personal data, these conceptualizations differ in what they understand personal data to be, how they address the relationship between individuals, their data, and the governments, as well as what they frame as the most important normative goals for regulatory interventions. Moreover, these conceptualizations are embedded in different philosophies and ideologies, ranging from neo-liberalism to human rights and to sovereignty. These irreducible normative elements render the contestations among such conceptualizations unable to be easily resolved. Further, divergent conceptualizations of personal data mandate and justify different legal paradigms to institutionalize their basic logics and policy choices. Built on different primary conceptualizations of personal data, three major legal paradigms compete to regulate cross-border personal data flows: a trade paradigm, a privacy paradigm, and a security paradigm. Aligned with its major conceptual framing of personal data, a great power often embraces a particular paradigm as its dominant approach to regulate cross-border transfers of personal data. These paradigms strive to provide legal and regulatory solutions (including legal prescriptions, regulatory institutions, and enforcement tools) to address the salient problems identified and framed by different conceptualizations of personal data.
Associations between body composition and the risk of fracture according to bone mineral density in postmenopausal women: a population-based database cohort study
Authors: Lee Jeongmin , Jung Jin-Hyung , Kim Jinyoung , Jeong Chaiho , Ha Jeonghoon , Kim Min-Hee , Lee Jung-Min , Chang Sang-Ah , Baek Ki-Hyun , Han Kyungdo , Lim Dong-Jun
Published: November 2023

Objective

We aimed to investigate the associations of body composition and the risk of fracture in postmenopausal women, stratified based on bone mineral density.

Methods

A population-based cohort study using the database of the National Screening Program for Transitional Ages with women aged 66 years was performed. Bone mineral density was categorized as normal, osteopenia, and osteoporosis. The following body mass index (BMI) categories for general obesity were used: underweight (<18.5), normal (18.5-22.9), overweight (23-24.9), obese (25-29.9), and severely obese (≥30 kg/m2). Waist circumference (WC) used for central obesity assessment was categorized into 5 groups. Newly diagnosed fracture during the follow-up period defined based on ICD-10 codes was the primary outcome.

Results

During 7.7 ± 1.4 years of follow-up, 41 672 (17.9%) participants experienced any fracture, 20 326 (8.7%) experienced vertebral fractures (VFs), and 2883 (1.2%) experienced hip fractures (HFs). The adjusted hazard ratios (aHRs) for any fracture showed a progressive increase with higher BMI and WC categories in individual with osteopenia and osteoporosis. Regarding VF, aHR was highest in severely obese individuals with osteoporosis (aHR [95% CI], 3.45 [2.99-3.97]) and in individuals with WC ≥ 95 cm with osteoporosis (4.79 [4.09-5.60]). The aHR [95% CI] for HF was highest in the underweight group with osteopenia (1.94 [1.16-3.27]) and osteoporosis (2.96 [2.15-4.10]). In central obesity individuals with WC ≥ 95 cm, aHR [95% CI] for HF was 2.80 [1.91-4.91].

Conclusions

General obesity and central obesity are not protective against any fracture, VF and HF in postmenopausal women with osteopenia or osteoporosis.
Justice implications of health and food security policies for Indigenous peoples facing COVID-19: a qualitative study and policy analysis in Peru
Authors: Chicmana-Zapata Victoria , Arotoma-Rojas Ingrid , Anza-Ramírez Cecilia , Ford James , Galappaththi Eranga K , Pickering Kerrie , Sacks Emma , Togarepi Cecil , Perera Chrishma D , van Bavel Bianca , Hyams Keith , Akugre Francis A , Nkalubo Jonathan , Dharmasiri Indunil , Nakwafila Olivia , Mensah Adelina , Miranda Jaime J , Zavaleta-Cortijo Carol
Published: November 2023

The spread of COVID-19 in Peru resulted in the declaration of a national health emergency, in which Indigenous peoples were identified as being particularly vulnerable due to their pre-existing poor health indicators and disadvantaged social conditions. The aim of this paper is to examine how the Peruvian government responded to the health and food needs of the Shawi and Ashaninka Indigenous peoples of Peru during the first 18 months of the pandemic (March 2020–August 2021). This study uses both official policy documents and real-world experiences to evaluate policy responses in terms of their immediate impact and their longer-term sustainability and contribution to the improvement of health, well-being and justice for Indigenous communities. Four health and food security responses were evaluated: the Amazon Health Plan and Indigenous Command; food aid; cash aid; and COVID-19 vaccination. We employed the Multidimensional Injustice Framework to analyse the justice implications of the design and implementation of responses. Data collection included 71 interviews with government officials (n = 7), Indigenous leaders (n = 31) and community members (n = 33). The results show how national and regional governments released policies to address the health and food needs of Indigenous peoples directly or indirectly, as part of a broader focus on vulnerable people. However, justice implications were not sufficiently addressed in the design or implementation of the responses. On the distributive dimension, Indigenous communities were prioritized to receive health goods and services, nevertheless, the distribution had shortcomings that impeded their collection and Indigenous food systems and livelihoods were largely overlooked. On the procedural dimension, Indigenous representatives were included to provide culturally sensitive feedback on health interventions, but without funding, and furthermore, the community members had only passive participation. This paper points out the importance of considering and addressing justice implications for more effective and fairer health and food policy responses to current and future health crises.
Policy and practices shaping the delivery of health services to pregnant adolescents in informal urban settlements in Kenya
Authors: Okoth Linet , Steege Rosie , Ngunjiri Anne , Theobald Sally , Otiso Lilian
Published: November 2023

In Kenya, the pregnancy rate of 15% among adolescents aged 15–19 years is alarmingly high. Adolescent girls living in informal urban settlements are exposed to rapid socio-economic transitions and multiple intersecting health risks and may be particularly disadvantaged in accessing sexual reproductive health services. Understanding vulnerabilities and service-seeking behaviours from different perspectives is important in order to support the development and implementation of progressive policies and services that meet adolescents’ unique needs within urban informal settlements. This study explored policy makers, community health service providers’ and community members’ perceptions of access to, and delivery of, sexual reproductive health services for pregnant adolescents in one informal urban settlement in Nairobi. We employed qualitative methods with respondents throughout the health system, purposively sampled by gender and diversity of roles. We conducted focus group discussions with community members (n = 2 female-only; n = 2 male-only), key informant interviews with policy makers (n = 8), traditional birth attendants (n = 12), community health volunteers (CHVs) (n = 11), a nutritionist (n = 1), social workers (n = 2) and clinical officers (n = 2). We analysed the data using thematic analysis. Government policies and strategies on sexual and reproductive health for adolescents exist in Kenya and there are examples of innovative and inclusive practice within facilities. Key factors that support the provision of services to pregnant adolescents include devolved governance, and effective collaboration and partnerships, including with CHVs. However, inadequate financing and medical supplies, human resource shortages and stigmatizing attitudes from health providers and communities, mean that pregnant adolescents from informal urban settlements often miss out on critical services. The provision of quality, youth-friendly reproductive health services for this group requires policies and practice that seek to achieve reproductive justice through centring the needs and realities of pregnant adolescents, acknowledging the complex and intersecting social inequities they face.
Pretreatment prediction for IVF outcomes: generalized applicable model or centre-specific model?
Authors: Cai Jiali , Jiang Xiaoming , Liu Lanlan , Liu Zhenfang , Chen Jinghua , Chen Kaijie , Yang Xiaolian , Ren Jianzhi
Published: November 2023

STUDY QUESTION

What was the performance of different pretreatment prediction models for IVF, which were developed based on UK/US population (McLernon 2016 model, Luke model, Dhillon model, and McLernon 2022 model), in wider populations?

SUMMARY ANSWER

For a patient in China, the published pretreatment prediction models based on the UK/US population provide similar discriminatory power with reasonable AUCs and underestimated predictions.

WHAT IS KNOWN ALREADY

Several pretreatment prediction models for IVF allow patients and clinicians to estimate the cumulative probability of live birth in a cycle before the treatment, but they are mostly based on the population of Europe or the USA, and their performance and applicability in the countries and regions beyond these regions are largely unknown.

STUDY DESIGN, SIZE, DURATION

A total of 26 382 Chinese patients underwent oocyte pick-up cycles between January 2013 and December 2020.

PARTICIPANTS/MATERIALS, SETTING, METHODS

UK/US model performance was externally validated according to the coefficients and intercepts they provided. Centre-specific models were established with XGboost, Lasso, and generalized linear model algorithms. Discriminatory power and calibration of the models were compared as the forms of the AUC of the Receiver Operator Characteristic and calibration curves.

MAIN RESULTS AND THE ROLE OF CHANCE

The AUCs for McLernon 2016 model, Luke model, Dhillon model, and McLernon 2022 model were 0.69 (95% CI 0.68–0.69), 0.67 (95% CI 0.67–0.68), 0.69 (95% CI 0.68–0.69), and 0.67 (95% CI 0.67–0.68), respectively. The centre-specific yielded an AUC of 0.71 (95% CI 0.71–0.72) with key predictors including age, duration of infertility, and endocrine parameters. All external models suggested underestimation. Among the external models, the rescaled McLernon 2022 model demonstrated the best calibration (Slope 1.12, intercept 0.06).

LIMITATIONS, REASONS FOR CAUTION

The study is limited by its single-centre design and may not be representative elsewhere. Only per-complete cycle validation was carried out to provide a similar framework to compare different models in the sample population. Newer predictors, such as AMH, were not used.

WIDER IMPLICATIONS OF THE FINDINGS

Existing pretreatment prediction models for IVF may be used to provide useful discriminatory power in populations different from those on which they were developed. However, models based on newer more relevant datasets may provide better calibrations.

STUDY FUNDING/COMPETING INTEREST(S)

This work was supported by the National Natural Science Foundation of China [grant number 22176159], the Xiamen Medical Advantage Subspecialty Construction Project [grant number 2018296], and the Special Fund for Clinical and Scientific Research of Chinese Medical Association [grant number 18010360765].

TRIAL REGISTRATION NUMBER

N/A.
The Microfoundations of Nuclear Proliferation: Evidence from South Korea
Authors: Lee Kyung Suk
Published: November 2023

How do South Koreans shape their nuclear proliferation beliefs? Despite growing scholarly research on public attitudes toward nuclearization, we do not fully understand the underlying factors that influence mass opinion on nuclear weapon acquisition. This study tests the effects of structural- and individual-level factors on South Korean public support for nuclear weapon acquisition by creating a novel time-series dataset. Contrary to conventional wisdom, structural variables did not immediately shift South Koreans’ proliferation beliefs. Instead, the effects accumulated over time. North Korea’s ballistic missile launches and nuclear tests gradually increased South Koreans’ support for proliferation. Also, within a short time period, South Korea–U.S. summits had null effects but progressively dampened the armament preferences. Interestingly, North Korea’s denuclearization summits instantly reduced the proliferation beliefs, but, the support for nuclearization surged over time. Regarding individual-level factors, South Koreans’ fear of nuclear imbalance, desire to decide on their own nuclear war, and conservative party identification were positively associated with the support for proliferation. This study enriches existing literature by offering new empirical evidence and contributes to the scholarly debate on the impact of U.S. security assurances on South Koreans’ nuclear proliferation attitudes.
Pattern formation and travelling waves in a multiphase moving boundary model of tumour growth
Authors: Jepson Jacob M , O’Dea Reuben D , Billingham John , Fadai Nabil T
Published: November 2023

We employ the multiphase, moving boundary model of Byrne et al. (2003, Appl. Math. Lett., 16, 567–573) that describes the evolution of a motile, viscous tumour cell phase and an inviscid extracellular liquid phase. This model comprises two partial differential equations that govern the cell volume fraction and the cell velocity, together with a moving boundary condition for the tumour edge, and here we characterize and analyse its travelling-wave and pattern-forming behaviour. Numerical simulations of the model indicate that patterned solutions can be obtained, which correspond to multiple regions of high cell density separated by regions of low cell density. In other parameter regimes, solutions of the model can develop into a forward- or backward-moving travelling wave, corresponding to tumour growth or extinction, respectively. A travelling-wave analysis allows us to find the corresponding wave speed, as well as criteria for the growth or extinction of the tumour. Furthermore, a stability analysis of these travelling-wave solutions provides us with criteria for the occurrence of patterned solutions. Finally, we discuss how the initial cell distribution, as well as parameters related to cellular motion and cell-liquid drag, control the qualitative features of patterned solutions.
The 3-Isogeny Selmer Groups of the Elliptic Curves y2=x3+n2
Authors: Chan Stephanie
Published: November 2023

Consider the family of elliptic curves $E_{n}:y^{2}=x^{3}+n^{2}$, where $n$ varies over positive cubefree integers. There is a rational $3$-isogeny $\phi $ from $E_{n}$ to $\hat {E}_{n}:y^{2}=x^{3}-27n^{2}$ and a dual isogeny $\hat {\phi }:\hat {E}_{n}\rightarrow E_{n}$. We show that for almost all $n$, the rank of $\operatorname {Sel}_{\phi }(E_{n})$ is $0$, and the rank of $\operatorname {Sel}_{\hat {\phi }}(\hat {E}_{n})$ is determined by the number of prime factors of $n$ that are congruent to $2\bmod 3$ and the congruence class of $n\bmod 9$.
Berberine inhibitsCandida albicansgrowth by disrupting mitochondrial function through the reduction of iron absorption
Authors: Zheng Dongming , Yue Daifan , Shen Jinyang , Li Dongmei , Song Zhen , Huang Yifu , Yong Jiangyan , Li Yan
Published: November 2023

Aims

This study aimed to investigate whether berberine (BBR) can inhibit the iron reduction mechanism of Candida albicans, lowering the iron uptake of the yeast and perhaps having antimicrobial effects.

Methods and results

We determined that BBR may cause extensive transcriptional remodeling in C. albicans and that iron permease Ftr1 played a crucial role in this process through eukaryotic transcriptome sequencing. Mechanistic research showed that BBR might selectively inhibit the iron reduction pathway to lower the uptake of exogenous iron ions, inhibiting C. albicans from growing and metabolizing. Subsequent research revealed that BBR caused significant mitochondrial dysfunction, which triggered the process of mitochondrial autophagy. Moreover, we discovered that C. albicans redox homeostasis, susceptibility to antifungal drugs, and hyphal growth are all impacted by the suppression of this mechanism by BBR.

Conclusions

The iron reduction mechanism in C. albicans is disrupted by BBR, which disrupts mitochondrial function and inhibits fungal growth. These findings highlight the potential promise of BBR in antifungal applications.
Targeting the PD-L1 cytoplasmic domain and its regulatory pathways to enhance cancer immunotherapy
Authors: Chai Fangni , Li Pan , Liu Xin , Zhou Zhihui , Ren Haiyan
Published: November 2023

As a significant member of the immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) plays a critical role in cancer immune escape and has become an important target for cancer immunotherapy. Clinically approved drugs mainly target the extracellular domain of PD-L1. Recently, the small cytoplasmic domain of PD-L1 has been reported to regulate PD-L1 stability and function through multiple pathways. Therefore, the intracellular domain of PD-L1 and its regulatory pathways could be promising targets for cancer therapy, expanding available strategies for combined immunotherapy. Here, we summarize the emerging roles of the PD-L1 cytoplasmic domain and its regulatory pathways. The conserved motifs, homodimerization, and posttranslational modifications of the PD-L1 cytoplasmic domain have been reported to regulate the membrane anchoring, degradation, nuclear translocation, and glycosylation of PD-L1. This summary provides a comprehensive understanding of the functions of the PD-L1 cytoplasmic domain and evaluates the broad prospects for targeted therapy.
Coughing up blood: Massive hemoptysis
Authors: Garrison Jeremiah , Hypes Cameron
Published: November 2023

This chapter reviews the presentation and management of hemoptysis in the emergency department. The most common causes of hemoptysis are infection, malignancy, and trauma. Airway hemorrhage can cause significant hypoxic respiratory failure, and this will require modification of typical routine airway management. Care for the patient presenting with hemoptysis first involves stratifying the bleeding as mild, moderate, or massive. Initial management is to assess for airway patency, adequacy of gas exchange, and work of breathing. The mainstays of treatment of a patient with severe airway hemorrhage are early intubation, correction of coagulopathy, administration of positive end-expiratory pressure on mechanical ventilation, positioning with the affected side down, and early consultation for computed tomographic angiography and bronchoscopic-guided therapies.
I still can’t breathe: ARDS and advanced ventilation strategies
Authors: Miller Ashley , Dahn Cassidy
Published: November 2023

Acute respiratory distress syndrome (ARDS) is a disease process with an insidious onset associated with high morbidity and mortality. It is most often seen in patients with sepsis, pneumonia, and aspiration. Appropriate ventilation management is the mainstay of treatment, with a focus on low tidal volumes of less than or equal to 6 cc/kg of predicted body weight. Additional ventilation strategies include utilizing high peak end-expiratory pressure (PEEP) and limiting inspired oxygen content (FiO2) while maintaining oxygen saturation and low plateau airway pressures. For refractory ARDS, other options include proning, neuromuscular blockade, recruitment maneuvers, and extracorporeal membrane oxygenation.
It’s getting harder to breathe: Refractory ARDS and VV-ECMO
Authors: Mackay Fraser
Published: November 2023

Severe acute respiratory distress syndrome (ARDS) can present abruptly and needs aggressive management. A small number of patients who have refractory ARDS are salvageable with the use of veno-venous extracorporeal membrane oxygenation (VV-ECMO), which bypasses the patient’s injured lungs to provide temporary gas exchange. Patients should undergo timely evaluation and transfer to capable centers, with the understanding that evidence-based and aggressive ARDS care will set these patients up for the best chance of success for salvage. Patient selection is key to good VV-ECMO outcomes, and teams should weigh the possible benefit of the therapy against its high resource utilization, cost, and invasive nature.
The engine isn’t working: Cardiogenic shock states
Authors: Rowan Daniel J.
Published: November 2023

Cardiogenic shock is defined as systemic hypoperfusion with impaired tissue oxygen delivery as a result of reduced cardiac output and may quickly spiral into multisystem organ failure. While acute coronary syndrome (ACS) is still the leading etiology, a growing percentage of cases result from progression of baseline cardiomyopathy. The clinical exam can be augmented by ultrasonographic assessment focusing on cardiac function, volume status, and presence of pulmonary edema or pleural effusions. Early treatment should focus on supporting a patient’s hemodynamics, guided by ultrasound findings, along with provision of ventilatory support. Definitive treatment relies upon reversing the underlying cause, with particular emphasis on early culprit lesion–guided percutaneous coronary intervention for ACS. Patients with refractory cardiogenic shock should undergo urgent evaluation for candidacy for mechanical circulatory support devices as a bridge to recovery, ventricular assist device, or heart transplant.
A pump replacement: The bleeding LVAD patient
Authors: Gordon Alexandra June , Phillips Andrew W.
Published: November 2023

If a patient with a left ventricular assist device (LVAD) presents to the ED with a gastrointestinal bleed, the management can be complicated. LVAD patients are anticoagulated and often coagulopathic from the device itself, so gastrointestinal bleeding is a common presentation. Assessment of hemodynamics in an LVAD patient requires a Doppler to assess the mean arterial pressure as well as an interrogation of the LVAD controller. These patients are sensitive to decreases in preload and increases in afterload, so resuscitation should be tailored accordingly. Special consideration should be given to reversing anticoagulation in these patients, and the LVAD team should be contacted early and communicated with frequently.
Choked off: Tamponade
Authors: Krieger Josh , Jain Ashika
Published: November 2023

Cardiac tamponade can present insidiously with nonspecific symptoms of dyspnea and tachycardia. Findings on exam can include cool extremities and peripheral edema with elevated jugular venous pressure. Chest radiography may demonstrate clear lungs with an enlarged cardiac silhouette. ECG may show low-amplitude QRS complexes with beat-to-beat variability in amplitude. Pericardial effusions are diagnosed with transthoracic echocardiography, and the first sign of tamponade is right atrial collapse during systole, followed by diastolic collapse of the right ventricle. Severity of tamponade can be judged by the presence of hypotension as well as the duration of right atrial collapse throughout the cardiac cycle. Tamponade can be temporized by administration of intravenous volume and is treated with pericardiocentesis.
Brain plumbing problems: Ischemic versus hemorrhagic strokes
Authors: Lentz Skyler , Marcolini Evie
Published: November 2023

Stroke symptoms can vary and change over time, so the emergency physician must determine the timing of onset, perform a thorough neurologic exam (using the National Institutes of Health Stroke Scale), and obtain initial CT imaging to determine whether the stroke is of ischemic or hemorrhagic origin. Treatments, including reaching blood pressure targets, potential referral for mechanical thrombectomy (ischemic strokes), and reversal or initiation of anticoagulation, are all predicated on accurate timing and diagnosis. Emergency clinicians must also be familiar with the care of ischemic and hemorrhagic stroke patients beyond the first few hours in case there are delays in transfer.
The worst headache of my life: Subarachnoid hemorrhage
Authors: Fontenette Roderick W. , Branting Andrew J.
Published: November 2023

Spontaneous subarachnoid hemorrhage (SAH) is an uncommon neurologic emergency afflicting 1% of patients presenting to EDs with an acute headache. Despite being a low-frequency diagnosis, it requires a high index of suspicion and a thoughtful practitioner’s care as the disease carries a variety of presentations and the associated morbidity and mortality is high. Specifically with aneurysmal SAH, the mortality nears 50% on initial presentation and increases to 80% if rebleeding occurs. A substantial proportion of survivors suffer residual functional impairments. Morbidity and mortality associated with aneurysmal SAH can be greatly impacted with timely detection and appropriate management. The goal is to secure the source of bleeding within 24 hours, and it is recommended to do so with early consideration of transfer to a high-volume comprehensive stroke center equipped with neurovascular interventionalists and familiarity with vasospasm management.
Stop the bleed: Procedures for hemostatic control
Authors: Ramzy Mark M.
Published: November 2023

Hemorrhage control is a vital skill that all emergency physicians will use frequently and must master. When left untreated, acute blood loss and the ensuing hypovolemic shock is the leading cause of preventable death following trauma. The degree of complexity can vary based on the location and source of the bleeding. Whether the bleeding is due to epistaxis or a traumatic injury, all emergency physicians must have a well-devised strategy that includes stepwise interventions to achieve hemostatic control. Approaches should include an arsenal of combined treatments such as direct pinpoint pressure, chemically infused gauze, pharmacotherapy, and tampon or balloon inflation.
Transplant troubles: Managing post-transplant complications
Authors: Murali Shyam , Owyang Clark G.
Published: November 2023

Patients who have received solid organ transplants are at risk for rejection of the transplanted organ as well as adverse effects of the immunosuppressant medications they are taking to prevent rejection. Transplant rejection occurs when the recipient’s immune system destroys the tissue that has been transplanted. To prevent this, many patients are on a lifelong regimen of immunosuppressive medications. The adverse effects of these medications are numerous but notably include infections, which can lead to severe illness and organ failure. Emergency physicians must understand the approach to recognizing complications of transplantation early and must be equipped to treat the acute problems.
Thalamus and Prethalamus Cell Types and Their Interconnections
Authors: Bickford Martha
Published: November 2023

The interconnected neurons of the thalamus and prethalamus can be divided into 3 basic categories: (1) glutamatergic thalamic projection neurons that innervate the cortex and prethalamic reticular nucleus (TRN), and often other forebrain regions such as the striatum, and amygdala; (2) GABAergic intrinsic interneurons that form synaptic connections only within their nucleus of origin; and (3) GABAergic TRN neurons that are reciprocally connected with each thalamic nucleus. As briefly reviewed in this chapter, these 3 basic categories of neurons can be further subdivided based on gene and protein expression, developmental origin, soma size, dendritic morphology, physiological properties, axonal projection patterns, and synaptic connections. Nonetheless, the fundamental circuit patterns formed between these 3 categories of neurons are shared across thalamic nuclei. For example, intrinsic interneurons form dendrodendritic synaptic connections with projection neurons and interneurons in tightly entwined synaptic arrangements termed glomeruli, while TRN neurons are connected to projection neurons via reciprocal axonal projections to and from each thalamic nucleus. A description of these 3 essential thalamic elements sets the stage for the subsequent chapters of this book that describe wide-ranging features that underlie the dynamic interplay between the thalamus and the cortex.
Biophysical Properties of Cortical Excitatory Neurons
Authors: Palmer Lucy M.
Published: November 2023

The capability of the cortex to receive and integrate information from various sources is at the core of brain function. As the most abundant cell type in the cortex, excitatory pyramidal neurons are critical for cortical function. Cortical neurons have specialized input/output patterns and biophysical properties which enhance their integrative and computational capabilities. In this chapter, the properties of cortical excitatory neurons will be explored, detailing the morphology, ion channel distribution, and firing modes. The dendritic integration of input will also be discussed, focusing on the integration of different thalamic input in cortical dendrites. Understanding overall brain function requires detailed knowledge of cortical functioning, including detailed knowledge about the biophysical properties of cortical excitatory neurons and how synaptic input is integrated within their dendrites.
Functional Roles of Cortical Inhibitory Interneurons
Authors: Shin Hyeyoung , Adesnik Hillel
Published: November 2023

This chapter describes how distinct classes of cortical inhibitory interneurons (INs) mediate unique aspects of cortical computation. First, it details how INs can be classified into discrete cell types based on their morphology, cellular physiology, gene expression, and synaptic connectivity. Next, it discusses how different IN classes shape cortical dynamics through their control of excitation-inhibition balance, their role in generating neural oscillations, and their modulation by brain state and arousal. Finally, it surveys INs’ functional role in neocortical computations, with a primary focus on sensory processing. While a series of exciting discoveries in the past decade have linked specific IN classes to specific cortical computations, more recent experimental and theoretical work suggests that most cortical computations are carried out by the interactions between multiple types of INs. The chapter highlights a specific computation that has been heavily researched and yet remains unsolved: the question of how inhibition shapes excitatory principal cells’ feature selectivity. The chapter concludes with a proposal for a general approach to understanding IN contributions in light of the complexity, and highlight several key unanswered questions in cortical function that could be solved by employing a more holistic approach to understanding IN roles in cortical computations.
Thalamic Output Pathways
Authors: Clasca Francisco
Published: November 2023

An accurate cell-level of description of the thalamic output circuits is key for modeling the interactions between thalamus and cortex. Until recently, however, it was not technically possible to delineate the full morphology of individual projection neurons, from their parent cell bodies to all their distant terminal branches. Thus, thalamic output pathways remained loosely defined as cell or axon populations. New single-cell labeling methods have in recent years made it possible to delineate individual thalamic projection neuron morphologies in full. Applied to date almost exclusively in rodents, these new methods are revealing an unsuspected cell diversity. While differences in axon wiring motifs are the most prominent, relevant variations have also been observed in the projection neuron somatodendritic architecture. Other studies are exploring projection neuron gene expression and membrane properties at the single-cell level. Together, these data provide the basis for a robust classification of thalamic projection neurons into several high-level cell classes.
Structure and Function of Corticothalamic Pathways of Layer 6 Neurons
Authors: Murphy Allison J. , Briggs Farran
Published: November 2023

Throughout the brain, corticothalamic (CT) neurons project from layer 6 of the cerebral cortex to various regions of the thalamus, including first-order thalamic nuclei that receive input from the sensory periphery and higher-order thalamic nuclei that derive their inputs mainly from cortical areas. Layer 6 CT neurons are diverse in terms of their cellular morphology and physiological properties, and they likely subserve a number of heterogeneous functions. While the number of synapses originating from layer 6 CT neurons onto thalamic cells is large, their terminals are distally located, small in size, and produce small, facilitating excitatory postsynaptic potentials, all characteristics that define these synaptic interactions as “modulatory” rather than “driving.” Importantly, layer 6 CT circuits often include axon collaterals that target inhibitory neuronal populations within the thalamus, enabling CT feedback to dynamically regulate the balance of excitation and inhibition among thalamic neurons. Although much is yet to be learned about the function of layer 6 CT feedback in the thalamus, current evidence from sensory systems suggests that CT feedback can shape the tuning properties of thalamic neurons as well as influence the timing and precision with which thalamic cells encode incoming sensory information. Other functions of layer 6 CT feedback include regulating arousal state, attention, and sleep. Overall, layer 6 CT pathways provide diverse inputs to thalamus that are likely critical for multiple aspects of brain function.
A Comparative Approach to Parallel Geniculocortical Pathways
Authors: Solomon Samuel G.
Published: November 2023

The dorsal lateral geniculate nucleus of the thalamus (LGN) occupies a central locus in both the passage of visual signals from retina to cortex and in the development of theories for vision. Six decades of research, in several mammalian species, have allowed deep empirical understanding of the structure, connections, and functional properties of the LGN. This work supports the idea that LGN is organized into compartments with different afferent inputs, projections, and functional properties; that is, signals are conveyed from retina to cortex through parallel channels. The aim of this chapter is to develop a comparative, historical overview of this work, and to help the reader understand some of the key debates.
Thalamic Contributions to Visual Cortical Receptive Fields
Authors: O’Shea Ronan , Severson Mandi C. , Priebe Nicholas J.
Published: November 2023

The thalamocortical projection has been linked to many of the canonical computations in primary visual cortex (V1). Across mammals, functionally segregated thalamocortical projections provide the basis for parallel processing streams of visual information in the cortex. The emergent selectivities for orientation and motion direction are shaped by the spatiotemporal response properties of geniculate afferents converging onto single V1 cells. At the population level, the pattern of thalamocortical convergence may also play a role in the formation of the columnar architecture characteristic of V1. The thalamocortical pathways therefore provide essential scaffolds that guide the emergence of novel visual representations in V1.