And those who were seen dancing: Human interactions with fungi and vice versa

Abstract

This issue of the Biomedical Journal features a special section exploring mycobiota. Three articles examine the role of fungi in common metabolic disorders in, Clostridium difficile infection, and in immunocompromised patients. Additionally, the potential and challenges of the metaverse in healthcare are reviewed, alongside a holistic approach to improve patient outcomes in pancreatic cancer. In this issue also possible mechanism contributing to long COVID are discussed, as well as biomarkers that effectively predict sepsis outcomes, and key targets in osteosarcoma progression. Moreover, factors leading to peri-intubation cardiac arrest are analyzed, healthcare strategies from various regions are employed to predict cardiovascular events in Asian populations, two approaches to cavernous sinus dural arteriovenous fistula are compared, and a combination therapy against soft tissue sarcoma is presented.

1. Spotlight on reviews

“And those who were seen dancing, were thought to be insane by those who could not hear the music.“1 In 1518, a woman in Strasbourg began dancing uncontrollably and seemingly unwillingly for days until she collapsed from exhaustion. After shortly resting, she resumed dancing. Within a few days, dozens joined her, and eventually, hundreds of Strasbourg's citizens, then part of the Roman Empire, danced beyond the point of physical injury. Civic and religious leaders concluded that more dancing was the solution, hence opted for engaging musicians and professional dancers to assist the afflicted. Despite or because of those efforts, many of those affected died from exertion. The exact stressors causing this outbreak remain uncertain. One hypothesis suggests food poisoning from rye bread contaminated with the ergot fungus, Claviceps purpurea, might have caused the convulsions, possibly enhanced through stress-induced mass hysteria.2

Originating from the historical region of Mesopotamia, that includes parts of modern-day Iraq, Turkey, Syria, and Kuwait, rye spread to Europe, and became a predominantly cultivated grain. Along with it came its parasite, the ergot fungus, which produces poisonous alkaloids harmful to humans.3 [1]

Claviceps purpurea is part of the ascomycota division, one of the five phyla of the fungi kingdom. Ascomycetes may be both beneficial and harmful to humans, providing antibiotics, aiding in the fermentation of grains, and serving as biocatalysts in waste biorefineries, while some, like ergot fungi and Candida albicans, are pathogenic [[2], [3], [4]].

A special section of this issue of the Biomedical Journal provides a fascinating insight into the influence of mycobiota in human disease. Fungi are crucial constituents of the gut microbiome, participating in protective immune responses and modulating local inflammatory reactions. Their interactions with bacterial microbiota can be synergistic, symbiotic, or antagonistic. The genus Candida, often termed opportunistic pathogens, illustrates this complexity. Fungal dysbiosis, closely linked to bacterial dysbiosis, is for instance observed in patients with chronic kidney disease, who show a lower abundance of Candida, decreased Lactobacillus and Bifidobacterium, and higher levels of Saccharomyces, E. coli, and Enterococcus. C. albicans, a prominent fungus able to colonize the human gut, mouth, and skin, can spread into the bloodstream and invade nearly every organ, potentially causing life-threatening infections [5,6]. A number of fungi is involved in human diseases including cancer [Fig. 1].

Fig. 1.

A selection of diseases influenced by the mycobiome across different organs and tissues. Species labeled in red play a role in cancer [7].

In their review, Zhou, Zhang, and Yu's elucidate the influence of the gut mycobiome on obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver disease, emphasizing its unique role in these prevalent metabolic disorders [8].

In another article of this issue, Wang et al. set out to highlight the composition and key characteristics of gut fungal communities and their contribution to Clostridium difficile infection (CDI) [9]. CDI remains one of the leading causes of nosocomial infections worldwide, with previous broad-spectrum antibiotic use identified as a major risk factor [10,11]. Wang et al. advocate for an interdisciplinary approach encompassing genomics, proteomics, metagenomics, and metabolomics to not merely acknowledge the connection between mycobiota and CDI, but to also establish detailed insights into the relationships between gut fungi, gut bacteria, and CDI. This comprehensive approach could foster understanding underlying mechanisms and open opportunities for tackling CDI through novel treatment strategies [9].

Fungi do not only shape our inner landscapes, but are in many regards essential in influencing our environment. Some fungi may for instance act as rainmakers since water droplets can form on mushroom spores. This sets the spores into motion, and floating through the air they attract even more water droplets, promoting cloud condensation and raindrop formation [12]. Rainfall then further increases communication among forest mushrooms and enhances their symbiotic relationship with soil and plants.4

Indigenous traditions of rain-making, once commonly practiced by Native American, African, and Asian tribes, are notable for their specific and intricate elements. So-called rain dances often involved detailed instructions for formations like dancers spinning in circles or squares. Dance rituals included pre-defined choreographies, intense stomping and jumping on the ground for extended periods. Additionally, depending on the region, elaborate ritualistic attire was part of the ceremony, featuring elements like animal hair and feathers swiping in large movements across the floor and through the air with the dancer. The dancers adhered to strict rules, such as designated locations where rain dances could or could not be performed. In some tribes, dedicated musical instruments were used to create specific frequencies. Those instruments were otherwise stored in places considered sacred like caves.,5,6,7,8,9,10,11 The specificity of these rituals raises the intriguing possibility that they might have served as early ways of cloud seeding, as attempts to influence weather patterns by dispersing spores from the ground into the atmosphere.

Even though exploring the mycobiota's influence on human health and disease might have once seemed far-fetched, it is about time to grant it the same extensive attention that other members of the microbiota have received over the past decade. Maybe, those that were seen dancing were not as insane as others might have previously assumed. Furthering our comprehension of the mycobiota and its impact on our inner ecosystem could usher in an evolution in healthcare strategies once we are able to fully leverage the unique skills offered by fungi.

2. VSI: mycobiota

Iyer and Ojcius introduce this virtual special issue to mycobiota with an emphasis on the interconnectedness of bacteria, and their extensively studied microbial communities alongside their often neglected sibling, the fungal communities. Historically, the challenge in analyzing the full diversity of mycobiota stemmed inter alia from a lack of specialized tools. However, recent advancements now enable us to gain further insights into fungal communities in their native environments [7].

3. A hidden threat to immunocompromised patients

The incidences of invasive fungal infections (IFIs) surge particularly in immunocompromised individuals. This group of those especially prone to an opportunistic fungal infection includes organ transplant recipients, hematologic patients requiring stem cell transplants, AIDS patients, diabetics, burn patients, neoplastic disease patients, and those with chronic respiratory diseases. These infections may quickly become life-threatening, therefore necessitating prompt and precise diagnosis and treatment [13,14].

Mahmoud et al. provide an extensive overview highlighting that IFIs are a major cause of mortality and morbidity among solid-organ transplant and hematopoietic stem cell transplant recipients. Their research details involved prominent yeast and mold species, outlines associated risk factors, and offers valuable insights into the latest basic research advancements in the field [15].

4. Also in this issue

4.1. Review articles

4.1.1. Metaverse medicine

The metaverse, envisioned as the next evolution of the internet, integrates artificial intelligence (AI), augmented reality (AR), virtual reality (VR), and advanced connectivity like 5G networks to create highly immersive online environments. Telemedicine became a prime example when it peaked in popularity due to the COVID-19 pandemic. The metaverse for example could easily enable consultations with top specialists worldwide, help address regional shortages of medical professionals, and offer personalized virtual environments for patient treatment.12 However, some of the almost utopian visions of metaverse healthcare face fundamental challenges. Issues such as racial and gender biases in AI, the impact of the “coded gaze” - the inherent priorities, preferences, and prejudices of those who shape technology - and the potential for exacerbating mental health problems through addictive algorithms in virtual spaces, present substantial hurdles.,13,14,15

Li et al. have reviewed the burgeoning potential of the metaverse, exploring the technological framework required for an immersive experience, its possible applications, and the current obstacles [16].

4.1.2. Unlocking new potential

In 2018, a youth soccer team went missing for 10 days after unexpected heavy rain caught them while exploring Thailand's fourth largest cave system. Rising water levels blocked the entry and flooded the caves, forcing the group deeper underground. The situation became highly complex due to impending monsoon conditions, challenging terrain, and the difficulty of rescuing individuals inexperienced in cave diving alive. The successful rescue of all 13 boys was deemed miraculous and was made possible by a multidisciplinary effort involving experts in cave diving, medicine, engineering, geology, logistics, and military operations.,16,17

Furthermore, the efficacy of multidisciplinary teams extends beyond crisis scenarios. Su et al. discuss in their study on pancreatic cancer, notorious for its poor prognosis, how a multidisciplinary approach incorporating tailored chemotherapy and innovative treatments involving systemic therapy could strikingly enhance patient outcomes [17].

4.2. Original articles

4.2.1. The lingering long shadow of COVID

Long COVID, or Post-COVID Conditions (PCC), encompasses a spectrum of symptoms that some individuals endure for weeks, months, persistently or recurrently after an acute COVID-19 illness. These symptoms range from mild to debilitating and can affect multiple organs.18

Rodríguez et al. observed that certain sarbecovirus, a lineage of coronaviruses, seem to infect lymphocytes through mechanisms independent of the spike protein, leading to a considerable immune deficiency over time [18]. In addition to the angiotensin-converting enzyme 2 (ACE2), the cluster of differentiation 147 (CD147) facilitates SARS-CoV-2 entry into human cells [19]. The team's in silico assay identified the interaction between the N-RBD protein and CD147 as a critical factor in lymphocyte infection, supporting the hypothesis that this interaction may contribute to acquired immune deficiency and enable the virus to persist latently in the host [18].

4.2.2. Navigating sepsis biomarkers

Originally it was hypothesized, that the two stages involved in sepsis consist of an initial hyperinflammation, followed by a compensatory anti-inflammatory response which aimed at restoring homeostasis. However, these stages can occur concurrently, and dysregulation of this systemic deactivation can lead to persistent immune suppression and additionally a high risk of recurring infections. The complexity of the cellular processes involved in sepsis complicates the identification of reliable diagnostic biomarkers [20]. Furthermore, the dynamic nature of biomarkers and the limitations of static measurements hinder accurate sepsis outcome predictions. To evaluate the performance of 15 novel biomarkers in predicting sepsis outcomes, Yen et al. conducted a receiver operating characteristic curve analysis. They identified four markers with excellent predictive accuracy in the early stages of illness and found the Sequential Organ Failure Assessment (SOFA) score consistently effective in predicting sepsis-associated mortality throughout the course of the illness [21].

4.2.3. Energizing cancer research

Energy drinks have become a major part of the beverage market, and leading brands often featuring high doses of caffeine and the amino acid taurine. It is suggested that age plays a crucial role in the toxicity of both caffeine and taurine, with adolescents particularly prone to adverse effects from chronic consumption of energy drinks [22].

The German anatomist and physiologist Friedrich Tiedemann was one of the earliest scientists to challenge racism. He faced significant criticism for his paper on the brain sizes of humans from different genetic backgrounds, advocating for equality and the abolition of enslaving specific groups of people [23]. Notably, Tiedemann was among the first to isolate taurine from ox bile.19

Taurine may exert potent anti-inflammatory properties. Its haloamines, along with taurine upregulated gene 1 (TUG1) long non-coding RNA (lncRNA), could offer beneficial effects in both cancer and inflammation [24]. An et al. investigated in vitro as well as in vivo the specific roles and key targets involved in osteosarcoma (OS) progression in the context of dysregulated lncTUG1 expression, suggesting that lncTUG1 may promote OS progression [25].

4.2.4. The suffering heart

The 7th century poet Qais ibn Al-Mulawah vividly wrote about his love for Lila, recounting his tears, sleeplessness, lack of appetite, racing heart, palpitations, and fainting spells after her departure. It is said that he died immediately after writing the famous poem “Majnoon Lila”, where he repeatedly declares, “My body is tightly bound.” While coronary heart disease is often attributed to modern lifestyles, atherosclerosis has been found in mummies from populations spanning more than 4000 years, and it seems that clinical symptoms of various forms of heart disease were known in Ancient Egypt medicine. An Arab cardiologist suggested that “Majnoon Lila” represents the first clear description of angina pectoris in medical history, concluding from the poem and other symptoms that Qais died of a myocardial infarction [26,27].

Yang et al.'s meta-analysis investigated the risk factors of peri-intubation cardiac arrest (PICA), aiming to support care physicians in identifying at-risk patients in acute settings. The team concluded that pre-intubation hypotension, possibly due to unstable hemodynamic status or poor cardiac function, hypoxemia, and repeated intubation attempts are major risk factors for PICA [28].

4.2.5. From regional to universal healthcare strategies

The Health Belief Model posits that an individual's health behavior is influenced by their perception of the severity of a disease and their susceptibility to it, alongside the perceived benefits and barriers to taking action. Developed in the 1950s to explain low participation in Public Health Service programs, this model remains relevant today [29,30]. Considering that enhancing patient health literacy could positively impact health behaviors, Hsiao et al. drew inspiration from this model. Their study aimed to utilize a straightforward, well-established Western model to predict risk of cardiovascular event within Asian populations. The research team was motivated by the idea whether a robust model can overcome cultural and regional differences, and thus eventually contribute to universally applicable healthcare strategies [31].

4.2.6. Endovascular therapy against abnormal fistula

A cavernous sinus dural arteriovenous fistula consists of an abnormal connection between the dura mater and branches of the carotid arteries. Various surgical strategies are available, though their safety and effectiveness may vary [32,33]. Wu et al. conducted a study comparing the effectiveness and peri-procedural complications of two endovascular treatment methods: transvenous coiling and transarterial embolization. Their data comparison provided valuable insights into the different occlusion rates, similar complication rates, and overall success rates of both approaches [34].

4.3. Brief communication

4.3.1. Bright discoveries

“Plus lucis”, more light, was the motto of the Austrian scientist and innovator Carl Auer von Welsbach. He introduced the first metallic filament for incandescent lamps, setting the stage for modern light bulbs. In 1907/1908, Welsbach and French chemist Georges Urbain independently discovered the rare earth element Lutetium. After a prolonged dispute, Urbain was credited with the discovery, since he had published his findings first.,20,21,22 In medical application, ¹⁷⁷Lu gained popularity over other isotopes because of several advantages including its low toxicity as well as its potential use for both primary tumors and metastatic cancers [35].

For years, the combination of diagnostics and therapeutics has been used in imaging and selectively treating various cancers. Theranostics is a rapidly evolving field with great potential for transforming clinical practice through radionuclide therapy [36].

Tseng et al. explored the synergy of ¹⁷⁷Lu-FAPI-046 with Pazopanib in treating soft tissue sarcoma, a rare and heterogeneous cancer. The combination therapy provided insights for future clinical treatments, demonstrating reduced fibroblast activation protein (FAP) expression in patient-derived xenograft animal models and slowed tumor proliferation [37].

Disclaimer

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Conflicts of interest

The author declares no conflict of interests.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the author used ChatGPT Open AI in order to improve readability and language of the work. After using this tool/service, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.