bluuebunny/crossref_metadata_2025 huggingface dataset:
Rabbit IgA Hinges That Resist IgA1 Protease Action Provide Options for Improved IgA-Based Therapeutic Agents
Authors: de Sousa-Pereira Patrícia , Lanning Dennis K. , Esteves Pedro J. , Spoerry Christian , Woof Jenny M. , Pinheiro Ana
Published: June 2022

Immunoglobulin A provides a major line of defence against pathogens and plays a key role in the maintenance of the commensal microbiota in the intestinal tract. Having been shown to be more effective at tumour cell killing than IgG and strongly active against pathogens present in the mucosae, IgA antibodies have been attracting significant attention in recent years for use as therapeutic antibodies. To improve their therapeutic potential, bioengineered IgA forms with increased serum half-life and neutralizing abilities have been developed but the IgA hinge, which impacts susceptibility to bacterial proteases and ability to bridge between target and effector cells, has not yet been explored. The European rabbit has 15 IgA subclasses with exclusive hinge region motifs and varying lengths, constituting a unique model to evaluate the functional capabilities offered by incorporation of longer IgA hinges into immunoglobulins. Hinge regions from rabbit IgAs, featuring different lengths and sequences, were inserted into human IgA1 heavy chain to substitute the IgA1 hinge. These hinges did not appear to affect antigen binding nor the ability of the engineered chimeric IgA1 to bind and trigger FcαRI, as detected by IgA-mediated cell agglutination and release of superoxide by neutrophils. All rabbit hinge-human IgA1 hybrids were resistant toClostridrum ramosumIgA protease enzyme digestion, as predicted by the lack of the cleavage site in the rabbit hinges. Some IgA1s featuring long rabbit hinges were cleaved byNeisseria meningitidisIgA1 protease cleavage type 1 or 2 enzymes, despite the lack of the predicted cleavage sites. More interestingly, the hybrid featuring the rabbit IgA15 hinge was not affected by any of the IgA proteases. The IgA15 hinge is longer than that found in human IgA1 and is composed by a unique motif with a stretch of nine consecutive Ser residues. These characteristics allow the preservation of a long hinge, with associated ability to bridge distantly spaced antigens and provide higher avidity binding, while remaining resistant to IgA protease degradation. The data suggest that the rabbit Cα15 hinge represents an interesting alternative hinge sequence for therapeutic human IgA antibodies that remains resistant to proteolytic cleavage.
Towards an Ecosystem Approach to Management in Areas Beyond National Jurisdiction: REMPs for Deep Seabed Mining and the Proposed BBNJ Instrument
Authors: Christiansen Sabine , Durussel Carole , Guilhon Maila , Singh Pradeep , Unger Sebastian
Published: June 2022

The ocean plays a key role in sustaining life on our planet and is inextricably linked to biodiversity, climate, human well-being, and health. However, the governance of the ocean is primarily pursued through sectoral-based legal and institutional frameworks that falls short in ensuring the long-term protection of the marine environment and the sustainability of marine resources. This is especially concerning in areas beyond the limits of national jurisdiction (ABNJ) where human activities continue to expand. The existence of two distinct regimes in ABNJ, namely the High Seas (applicable to the water column, which is a global common) and the Area (applicable to the international seabed and its mineral resources, which are the common heritage of mankind), that have been largely regulated separately, impede the development and implementation of integrated marine environmental governance and biodiversity conservation in ABNJ. On the one hand, the International Seabed Authority (ISA), which is mandated to administer the mineral resources of the Area, is currently discussing a set of regulations to enable future exploitation activities. On the other hand, multilateral negotiations are taking place for the development of an internationally legally binding instrument for the conservation and sustainable use of marine biodiversity in areas beyond national jurisdiction (referred to as the proposed ‘BBNJ’ Instrument). Both processes offer a unique opportunity to foster an ecosystem approach to management (EAM) in ABNJ. In this article, we elaborate on options for stronger governance integration and the development of a coherent and collaborative interplay between these two processes. To this end, we explore the potential of Regional Environmental Management Plans (REMPs) established by the ISA as a case study to contribute to global biodiversity conservation, and the opportunity for the proposed BBNJ Instrument to promote overarching coherence to biodiversity conservation in ABNJ, premised on EAM. We conclude that the proposed BBNJ Instrument could have a pivotal role to streamline multilateral action for the conservation of biodiversity in ABNJ by adopting an ambitious, overarching environmental vision and strategic goals, accompanied by strong implementation and enforcement mechanisms.
High Coral Recruitment Despite Coralline Algal Loss Under Extreme Environmental Conditions
Authors: Tanvet Clément , Benzoni Francesca , Peignon Christophe , Thouzeau Gérard , Rodolfo-Metalpa Riccardo
Published: June 2022

The crucial role of crustose coralline algae (CCA) in inducing hard coral larval settlement and ensuring the replenishment of coral reefs is widely accepted, and so are the negative effects of anthropogenic CO2 emissions on both CCA abundance and coral development. However, diversified and well-developed coral reef communities have been recently discovered in natural conditions where CCA and corals would not be expected to thrive. Back-reef pools, volcanic CO2 vents, mangrove estuaries, and semi-enclosed lagoons systems can present seawater pH, temperature, and dissolved oxygen values reaching or even exceeding the conditions currently predicted by the Inter Panel on Climate Change (IPCC) for 2100. In the semi-enclosed lagoon of Bouraké (New Caledonia, southwest Pacific Ocean), seawater pHT, dissolved oxygen, and temperatures regularly fluctuate with the tide reaching respectively minimum values of 7.23 pHT units, 2.28 mg O2 L-1, and maximum of 33.85°C. This study reports the effect of such extreme environmental conditions on hard coral recruitment and CCA originally settled at a forereef on artificial substrates that were transplanted over two years in two fringing reef and at the Bouraké lagoon. Our data emphasize the negative effects of the extreme conditions in our study sites on the CCA, which decreased in cover by ca. 80% and lost in the competition with turf algae, which, in turn, increased up to 162% at the end of the two years. Conversely, hard coral recruitment remained high at Bouraké throughout the study, three-fold higher than at two sites located outside Bouraké where environmental conditions were typical for coastal fringing reefs. Our findings show that while such extreme, climate change like-conditions have a direct and adverse effect on CCA abundance, and despite a certain persistence, coral larvae settlement was not affected. Based on previous findings from Bouraké, and the present observations, both coral recruits and adults seem to be unaffected despite the extreme environmental conditions. This study supports previous research illustrating how extreme natural and variable environments may reveal unexpected and positive insights on the processes underlying coral acclimatization and adaptation to global change.
Local And Deep-Ocean Forcing Effects on the West Florida Continental Shelf Circulation and Ecology
Authors: Weisberg Robert H. , Liu Yonggang
Published: June 2022

We review the evolution of knowledge on the forcing of the west Florida continental shelf by a combination of local winds and deep-ocean influences, and we provide application examples regarding the relationships between the shelf responses to these forcing functions and certain ecological phenomena, including blooms of the harmful alga,Karenia brevis, recruitment of gag juveniles and how Deepwater Horizon hydrocarbons may have affected west Florida reef fish and the shoreline. Our approach employs a coordinated set of observations and numerical circulation model simulations, wherein the observations, by providing reasonable veracity checks on the model simulations, allow for further dynamical analyses that would otherwise be unavailable from the observations alone. For the case of local forcing only, we provide two dynamically consistent definitions of the inner-shelf and outer-shelf regions, and for the case of deep-ocean forcing, we show how the west Florida shelf geometry (with regard to certain geophysical fluid dynamics principles) can result in the entire shelf region being impacted by the Gulf of Mexico Loop Current. Thus, we help to explain why the west Florida shelf experiences large inter-annual variations in shelf ecology, providing impetus for further interdisciplinary study.
Microscopic Stages of North Atlantic Laminaria digitata (Phaeophyceae) Exhibit Trait-Dependent Thermal Adaptation Along Latitudes
Authors: Schimpf Nele M. , Liesner Daniel , Franke Kiara , Roleda Michael Y. , Bartsch Inka
Published: June 2022

Kelp forests in the North Atlantic are at risk of decline at their warm temperature distribution margins due to anthropogenic temperature rise and more frequent marine heat waves. To investigate the thermal adaptation of the cold-temperate kelpLaminaria digitata, we sampled six populations, from the Arctic to Brittany (Spitsbergen, Tromsø, Bodø [all Norway], Helgoland [Germany], Roscoff and Quiberon [both France]), across the species’ entire distribution range, spanning 31.5° latitude and 12-13°C difference in mean summer sea surface temperature. We used pooled vegetative gametophytes derived from several sporophytes to approximate the genetic diversity of each location. Gametophytes were exposed to (sub-) lethal high (20-25°C) and (sub-) optimal low (0-15°C) temperature gradients in two full-factorial, common-garden experiments, subjecting subsets of populations from different origins to the same conditions. We assessed survival of gametophytes, their ability to develop microscopic sporophytes, and subsequent growth. We hypothesized that the thermal performance of gametophytes and microscopic sporophytes corresponds to their local long-term thermal history. Integrated gametophyte survival revealed a uniform upper survival temperature (UST) of 24°C among five tested populations (Tromsø to Quiberon). In contrast, following two weeks of thermal priming of gametophytes at 20-22°C, sporophyte formation at 15°C was significantly higher in southern populations (Quiberon and Roscoff) compared to the high-latitude population of Tromsø. Between 0-15°C, survival of the Arctic population (Spitsbergen) was negatively correlated with increasing temperatures, while the southern-most population (Quiberon) showed the opposite. Thus, responses of survival at low, and sporophyte formation at high temperatures, support the concept of local adaption. On the other hand, sporophyte formation between 0-15°C peaked at 6-9°C in the Quiberon and at 9-12°C in the Spitsbergen population. Sporophyte growth rates (GR) both in length and width were similar for Spitsbergen, Tromsø and Quiberon; all had maximum GRs at 12-15°C and low GRs at 0-6°C. Therefore, responses of sporophyte formation and growth at low temperatures do not reflect ecotypic adaptation. We conclude thatL. digitatapopulations display trait-dependent adaptation, partly corresponding to their local temperature histories and partly manifesting uniform or unpredictable responses. This suggests differential selection pressures on the ontogenetic development of kelps such asL. digitata.
Coral Reef Coupling to the Atmospheric Boundary Layer Through Exchanges of Heat, Moisture, and Momentum: Case Studies From Tropical and Desert Fringing Coral Reefs
Authors: McGowan Hamish , Lensky Nadav G. , Abir Shai , Saunders Melissa
Published: June 2022

Coral reefs represent abrupt changes in surface roughness, temperature, and humidity in oceanic and coastal locations. This leads to formation of internal atmospheric boundary layers that grow vertically in response to turbulent mixing which conveys changes in surface properties into the prevailing wind. As a result, coral reefs under favourable conditions couple to the overlying atmosphere. Here we present rare observations of coral reef – atmospheric interactions during summer monsoon conditions on the Great Barrier Reef, Australia, and a desert fringing coral reef in the Gulf of Eilat, Israel. We show that in the hyper-arid location of the Gulf of Eilat where air temperatures are greater than water temperatures, a stable atmospheric boundary inhibits coupling of the reef to the atmosphere. In contrast, under monsoon conditions on the Great Barrier Reef, the coral reef is shown to couple to the overlying atmosphere leading to the formation of a convective internal boundary layer in which convective exchange of heat and moisture influences cloud and possibly precipitation. We conclude that understanding these processes is essential for determining the role of coral reefs in coastal meteorology, and whether through coupling with the overlying atmosphere coral reefs may regulate their meteorology by triggering formation of cloud and/or vertical exchange on aerosols and their precursor gases such as Dimethyl sulphide.
The Abundance and Persistence of Temperate and Tropical Seagrasses at Their Edge-of-Range in the Western Atlantic Ocean
Authors: Bartenfelder Amy , Kenworthy William Judson , Puckett Brandon , Deaton Charles , Jarvis Jessie C.
Published: June 2022

Species, including seagrasses, at their range limits are uniquely vulnerable to climate change. In the western Atlantic Ocean, the biogeographic transition zone between temperate and tropical ecosystems is recognized as one of several global hotspots where poleward-flowing western boundary currents are forecast to warm faster than the global average. In this region seagrass ecosystem services are primarily supplied by two species, Zostera marina, a temperate seagrass at its southern range limit and Halodule wrightii, a tropical seagrass at its northern limit. Water temperatures in the study location in Back Sound, North Carolina, USA have gradually increased the length of the stressful summer season for Z. marina (beginning after 3 consecutive days of daily mean water temperatures >23°C, ending after 3 consecutive days <25°C) from 84 days in 1962 to 156 days in 2019. The occurrence of extreme water temperatures also increased resulting in temperatures ≥30°C occurring more frequently in the last decade (2009-2019) than the previous 10 years. Biomass and aerial imagery collected periodically from 1981-2019 indicate that Z. marina biomass remained stable until 2008 but declined to 30-year low levels by 2019. Meadow area estimated from imagery collected during peak Z. marina biomass did not show a significant trend over time; however, lowest meadow area during the time series was recorded in 2019. Despite summer warming, H. wrightii biomass remained steady between 1979-2019 but did not replace Z. marina as the dominant species in the cooler months. We hypothesize that persistence of temperate Z. marina populations under stressful water temperatures is positively influenced by water clarity, life history, and meadow stability, due in part to the consistent presence of tropical H. wrightii maintaining meadow biomass and area. However, temperate species in edge-of-range tropicalized meadows, are still limited by physiological thresholds, and when these limits are exceeded, related declines in meadow biomass and area may not be fully replaced by tropical species immediately. Therefore, while tropicalization of seagrass meadows may result in greater resilience to abiotic stressors in the short-term, declines in biomass and area during the process of tropicalization may have significant impacts on meadow function.
Regulation of the Cell Cycle, Apoptosis, and Proline Accumulation Plays an Important Role in the Stress Response of the Eastern Oyster Crassostrea Virginica
Authors: Li Cui , Wang Haiyan , Guo Ximing
Published: June 2022

Background

Understanding how organisms respond and adapt to environmental changes is central to evolutionary biology. As a sessile organism that has adapted to life in estuaries and intertidal zones, the eastern oyster Crassostrea virginica can tolerate wide fluctuations in temperature and salinity and survive for weeks out of water. To understand the molecular mechanisms underlying the remarkable stress tolerance of the eastern oyster, we studied the transcriptomic changes induced by exposure to air and cold stress. Eastern oysters were maintained for 7 days under four conditions, namely, in seawater (normal) at 22°C, in air at 22°C, in seawater at 5°C and in air at 5°C, and then sampled for RNA sequencing.

Results

Transcriptomic analysis revealed that many genes involved in cell cycle progression and DNA replication were downregulated in oysters exposed to air and cold, which indicates that stress inhibits cell division. Exposure to air at 22°C induced a concerted inhibition of apoptosis through the upregulation of expanded inhibitors of apoptosis and the downregulation of caspases. Interactions between TNF and NF-κB signalling implied a reduction in the inflammatory response and immune functions. Key genes for proline production, fatty acid synthesis and chromosomal proteins were upregulated during exposure to low temperatures, which suggested that proline accumulation, energy conservation, and epigenetic modification of chromosomes are important for coping with cold stress. The upregulation of melatonin, FMRFamide, and neural acetylcholine receptors indicate the significance of the neurohormonal regulation of homeostasis.

Conclusion

These results show that air exposure and cold stress alter the expression of key genes for cell division, apoptosis, proline accumulation, fatty acid metabolism, neurohormonal signalling, and epigenetic modifications, suggesting regulation of these processes plays an important role in the stress response of the eastern oyster and possibly other marine molluscs. This study provides new insights into molecular mechanisms of stress response that are essential for understanding the adaptive potential of marine organisms under climate change.
Bio-Evaluation of 99mTc-Labeled Homodimeric Chalcone Derivative as Amyloid-β-Targeting Probe
Authors: Mann Garima , Chauhan Kanchan , Kumar Vikas , Daksh Shivani , Kumar Nikhil , Thirumal M. , Datta Anupama
Published: June 2022

Chalcone derivatives have been successfully utilized for a range of biological applications and can cross the blood–brain barrier easily. β-amyloid-specific bis-chalcone derivative, 6,9-bis(carboxymethyl)-14-(4-[(E)-3-(4-(dimethylamino)phenyl)acryloyl]phenoxy)-3-(2-[(2-(4-[(E)-3-(4-(dimethylamino)phenyl)acryloyl]phenoxy)ethyl)amino]-2-oxoethyl)-11-oxo-3,6,9,12-tetraazatetradecanoic acid, DT(Ch)2, was analyzed using molecular modeling to explain the binding modes of the ligand with amyloid fibril and monomer followed by 99mTc-complexation in 95% yield and 98.7% efficiency. High-binding specificity of the radiocomplex was established following in vitro evaluation against 100-fold excess of DT(Ch)2. 99mTc–DT(Ch)2 exhibited <3% trans-complexation in human serum after 24 h, indicating high stability. A fast clearance rate in pharmacokinetics studies displayed a biphasic pattern with t1/2(F) = 30 min ± 0.09 and t1/2(S) = 4 h 20 min ± 0.06. In vivo single-photon emission computed tomography (SPECT) imaging in rabbits reiterated the pharmacokinetics data with initially high brain uptake followed by rapid washout. Biodistribution studies confirmed the initial brain uptake as 1.16 ± 0.02% ID/g after 2 min and the brain2min/brain30min ratio was 3.74. Radioactivity distribution in the brain was >40% in the cingulate cortex followed by >25% in the hippocampus, a distribution pattern aligned to Alzheimer’s affected brain regions. Radiocomplex also displayed rapid plasma clearance followed by hepatobolic and renal modes of excretion.
Rhino-Orbital-Cerebral Mycosis and Extranodal Natural Killer or/and T-Cell Lymphoma, Nasal Type
Authors: Li Dong Ming , Lun Li De
Published: June 2022

Background

Extranodal natural killer/T-cell lymphoma, nasal type is a syndrome of middle face destruction with an association to Epstein-Barr virus. Fungi have been recovered from the diseased tissue now and then but were often seen as a lymphoma-associated secondary infection. However, there are ENKTL-NT cases with the recoveries of fungi and complete recovery with antifungal therapy, which are quite similar to rhino-orbital-cerebral mycosis (ROCM) that often confuses the physicians.

Methods

We searched Medline for English-language manuscripts limited to “human” and “case reports,” “letters,” “reviews,” and “clinical conferences” from 1966 to 2022. We used MeSH terms “lymphoma, extranodal nk-t-cell” [MeSH Terms] or “lethal midline granuloma” [MeSH Terms], in combination with MeSH terms “microbiology” [subheading] or “microbiology” [all fields] or “fungi” [all fields] or “fungi” [MeSH Terms] for ENKTL-NT with infections. We used MeSH terms “Mycoses” in combination with “Nose” [Mesh] OR “Orbital Diseases” [Mesh] for rhino-orbital-cerebral fungal infections.

Results

We appraised 149 included articles and extracted references related to ENKTL-NT and/or ROCM. Themes and subcategories were subsequently derived. Our findings revealed that ROCM and ENKTL-NT are characterized by progressive and destructive ulcers in the midline face or rhino-orbital structures. ROCM is mainly caused by fungi in the order of Mucorales, and ENKTL-NT is usually associated with Epstein-Barr virus and sometimes fungi. Radiologically, both are characterized by non-specific features of sinusitis, soft tissue infection, and necrosis. Pathologically, ROCM and ENKTL-NT share the same characteristics of inflammation, necrosis, and granuloma. ROCM is characterized by the detection of fungi in tissue, while ENKTL-NT is typically positive for NK/T-cell markers and cytotoxic granule-associated proteins, proliferation, and vascular damage of angioinvasion, which could be incited by Mucor irregularis and Rhizopus arrhizus in patients and mice.

Conclusion

ENKTL-NT and ROCM share many similarities in clinical presentations, radiology, and histopathology, and might have the same etiology. This may explain why the two diseases are tangled together in the reported cases, and suggests the role that the fungi may play in the development of these ENKTL-NT/ROCM diseases. The reason why ENKTL-NT and ROCM are sometimes confused is that the main pathogens of ROCM, Mucor irregularis and Rhizopus arrhizus, are the fungal causative agents of ENKTL-NT.
Efficacy of Pirfenidone vs. Placebo in Unclassifiable Interstitial Lung Disease, by Surgical Lung Biopsy Status: Data From a post-hoc Analysis
Authors: Molina-Molina Maria , Kreuter Michael , Cottin Vincent , Corte Tamera J. , Gilberg Frank , Kirchgaessler Klaus-Uwe , Axmann Judit , Maher Toby M.
Published: June 2022

Approximately 12–13% of patients with interstitial lung disease (ILD) are diagnosed with unclassifiable ILD (uILD), often despite thorough evaluation. A recent Phase 2 study (NCT03099187) described a significant effect of pirfenidone vs. placebo on forced vital capacity (FVC) measured by site spirometry in patients with progressive fibrosing uILD (hereafter referred to as the pirfenidone in uILD study). Here, we present the results from a post-hoc analysis of this study to assess patient baseline characteristics and the efficacy of pirfenidone vs. placebo analyzed by surgical lung biopsy (SLB) status. Mean FVC (mL) change over 24 weeks was included as a post-hoc efficacy outcome. Of 253 randomized patients, 88 (34.8%) had a SLB and 165 (65.2%) did not. Baseline characteristics were generally similar between SLB subgroups; however, patients who had a SLB were slightly younger and had a higher 6-min walk distance than those without a SLB. Mean FVC change over 24 weeks for pirfenidone vs. placebo was −90.9 vs. −146.3 mL, respectively, in patients who had a SLB, and 8.2 vs. −85.3 mL, respectively, in patients without a SLB. Overall, the results from the post-hoc analysis identified that pirfenidone may be an effective treatment in progressive fibrosing uILD over 24 weeks, irrespective of SLB status; however, caution should be taken when interpreting these data due to several limitations. There are differences in the treatment effect of pirfenidone between the subgroups that require further pathological and radiological investigation. In this manuscript, we also descriptively compared baseline characteristics from the overall pirfenidone in uILD study population with other uILD populations reported in the literature, with the aim of understanding if there are any similarities or differences within these cohorts. Most baseline characteristics for patients in the pirfenidone in uILD study were within the ranges reported in the literature; however, ranges were wide, highlighting the heterogeneity of uILD populations.

Clinical Trial Registration

ClinicalTrials.gov, identifier: NCT03099187.
Helicobacter pylori Infection in Cirrhotic Patients With Portal Hypertensive Gastropathy: A New Enigma?
Authors: Alarfaj Sumaiah J. , Abdallah Mostafa Sally , Abdelsalam Ramy A. , Negm Walaa A. , El-Masry Thanaa A. , Hussein Ismail A. , El Nakib Ahmed Mohamed
Published: June 2022

The relationship between Helicobacter pylori (H. pylori) infection and Portal hypertensive gastropathy (PHG) is still a debatable matter. The aim of this study is to find out how common H. pylori infection is in cirrhotic patients with PHG and to see if there’s a link between H. pylori infection and PHG severity. Out of 340 cirrhotic patients who had upper Gastrointestinal Tract (GIT) endoscopy for early varices screening, 160 cirrhotic patients were selected and divided into 2 groups; 80 cirrhotic patients with PHG (cases) and 80 cirrhotic patients without PHG (controls). Gastric biopsies were taken from all enrolled patients for histological evaluation for the presence or absence of H. pylori infection. H. pylori was found in 44 cirrhotic patients (55%) who had PHG (cases), compared to 22 cirrhotic patients (27.5%) who did not have PHG (controls). The prevalence of H. pylori infection was significantly higher in patients with PHG (p < 0.001). The severity of PHG was associated with H. pylori infection (p < 0.001). The response to eradication therapy of H. pylori infection was must better in patients without PHG (p = 0.045). By multi-variant analysis, H. pylori infection, splenic diameter, and portal vein diameter were independent predictors for PHG presence. After treating H. pylori infection in patients who tested positive for H. pylori, there was a significant reduction in PHG severity (p < 0.001). Patients with PHG have a greater prevalence of H. pylori infection. PHG is more severe in patients infected with H. pylori. To improve PHG severity, cirrhotic patients must have their H. pylori infection eradicated.
Combined Preimplantation Genetic Testing for Genetic Kidney Disease: Genetic Risk Identification, Assisted Reproductive Cycle, and Pregnancy Outcome Analysis
Authors: Xiao Min , Shi Hua , Rao Jia , Xi Yanping , Zhang Shuo , Wu Junping , Zhu Saijuan , Zhou Jing , Xu Hong , Lei Caixia , Sun Xiaoxi
Published: June 2022

Background

Genetic kidney disease is a major cause of morbidity and mortality in neonates and end-stage renal disease (ESRD) in children and adolescents. Genetic diagnosis provides key information for early identification of congenital kidney disease and reproductive risk counseling. Preimplantation genetic testing for monogenic disease (PGT-M) as a reproductive technology helps prospective parents to prevent passing on disease-causing mutations to their offspring.

Materials and Methods

A retrospective cohort of couples counseled on PGT who had a risk to given birth to a child with genetic kidney disease or had a history of prenatal fetal kidney and urinary system development abnormalities from 2011 to 2021. Through a combination of simultaneously screening for aneuploidy and monogenic kidney disease, we achieved reproductive genetic intervention.

Results

A total of 64 couples counseled on PGT for monogenic kidney disease in a single reproductive center during the past 10 years, of whom 38 different genetic kidney diseases were identified. The most frequent indications for referral were autosomal recessive disease (54.7%), then autosomal dominant disease (29.7%), and X-linked disease (15.6%). Polycystic kidney disease was the most common diseases counted for 34.4%. After oocyte-retrieval in all of 64 females, a total of 339 embryos were diagnosed and 63 embryos were transferred in succession. Among 61 cycles of frozen-embryo transfer (FET), ongoing pregnancy/live birth rate (OP/LBR) reached 57.38%. The cumulative OP/LBR in our cohort for the 64 couples was 54.69%. In addition, we have carried out expanded carrier screening (ECS) in all the in vitro fertilization (IVF) couples performed PGT covering 7,311 individuals. The carrier frequency of the candidate genes for monogenic kidney diseases accounted for 12.19%.

Conclusion

Overall, the customization PGT-M plan in our IVF center is pivotal to decreasing the morbidity and implementing reproductive genetic intervention of genetic kidney disease.
Cow Farmers’ Homes Host More Diverse Airborne Bacterial Communities Than Pig Farmers’ Homes and Suburban Homes
Authors: Amin Hesham , Šantl-Temkiv Tina , Cramer Christine , Vestergaard Ditte V. , Holst Gitte J. , Elholm Grethe , Finster Kai , Bertelsen Randi J. , Schlünssen Vivi , Sigsgaard Torben , Marshall Ian P. G.
Published: June 2022

Living on a farm has been linked to a lower risk of immunoregulatory disorders, such as asthma, allergy, and inflammatory bowel disease. It is hypothesized that a decrease in the diversity and composition of indoor microbial communities is a sensible explanation for the upsurge in immunoregulatory diseases, with airborne bacteria contributing to this protective effect. However, the composition of this potentially beneficial microbial community in various farm and suburban indoor environments is still to be characterized. We collected settled airborne dust from stables and the associated farmers’ homes and from suburban homes using electrostatic dust collectors (EDCs) over a period of 14 days. Then, quantitative PCR (qPCR) was used to assess bacterial abundance. The V3–V4 region of the bacterial 16S rRNA gene was amplified and sequenced using Ilumina MiSeq in order to assess microbial diversity. The Divisive Amplicon Denoising Algorithm (DADA2) algorithm was used for the inference of amplicon sequence variants from amplicon data. Airborne bacteria were significantly more abundant in farmers’ indoor environments than in suburban homes (p < 0.001). Cow farmers’ homes had significantly higher bacterial diversity than pig farmers’ and suburban homes (p < 0.001). Bacterial taxa, such as Firmicutes, Prevotellaceae, Lachnospiraceae, and Lactobacillus were significantly more abundant in farmers’ homes than suburban homes, and the same was true for beneficial intestinal bacterial species, such as Lactobacillus amylovorus, Eubacterium hallii, and Faecalibacterium prausnitzii. Furthermore, we found a higher similarity between bacterial communities in individual farmers’ homes and their associated cow stables than for pig stables. Our findings contribute with important knowledge on bacterial composition, abundance, and diversity in different environments, which is highly valuable in the discussion on how microbial exposure may contribute to the development of immune-mediated diseases in both children and adults.
Fundamental Differences in Inactivation Mechanisms of Escherichia coli O157:H7 Between Chlorine Dioxide and Sodium Hypochlorite
Authors: Bridges David F. , Lacombe Alison , Wu Vivian C. H.
Published: June 2022

Chlorine dioxide (ClO2) and sodium hypochlorite (NaClO) are two chlorinated oxidizing agents that are implemented in water treatment and postharvest processing of fresh produce. While the antibacterial mechanisms of NaClO have been investigated, there are comparatively few studies that have looked at how ClO2 kills bacteria. Therefore, the objective of this study was to compare the inactivation pathways of ClO2 and NaClO against Escherichia coli O157:H7. Treatments consisted of 2.5, 5, and 10 ppm ClO2 or 50, 100, and 200 ppm NaClO for 5, 10, and 15 min. Maximum log reductions of E. coli O157:H7 were 5.5 and 5.1 after treatment with ClO2 or NaClO, respectively. Bacterial inactivation was measured using log reductions, intracellular reactive oxygen species (ROS) using with 2′,7′–dichlorofluorescin diacetate (DCFDA) or aminophenyl fluorescein (APF) probes, relative values of NAD+, NADH, NADP+, and NADPH cofactors. Additionally, the expression of three key genes involved in ROS stress was measured via RT-PCR. Levels of intracellular ROS measured by DCFDA after ClO2 treatment were significantly higher than those found after treatment in NaClO. Additionally, NaClO treatment resulted in upregulation of ROS-defense genes, while expression of the same genes was typically at base levels or downregulated after ClO2 treatment. As the concentrations of both treatments increased, the NADP+:NADPH ratio shifted to the cofactor being predominantly present as NADP+. These data indicate that ClO2 and NaClO damage E. coli O157:H7 via measurably different mechanisms and that ClO2 does not appear to cause substantial oxidative stress to E. coli O157:H7 directly.
Thicker Ice Improves the Integrity and Angular Distribution of CDC48A Hexamers on Cryo-EM Grids
Authors: Huntington Brandon , Zhao Lingyun , Bron Patrick , Shahul Hameed Umar F. , Arold Stefan T. , Qureshi Bilal M.
Published: June 2022

Many cryogenic electron microscopy (cryo-EM) single particle analyses are constrained by the sample preparation step upon which aggregation, dissociation, and/or preferential orientation of particles can be introduced. Here, we report how we solved these problems in the case of CDC48A, a hexameric AAA ATPase from Arabidopsis thaliana. CDC48A hexamers are well preserved under negative staining conditions but disassemble during grid freezing using the classical blotting method. Vitrification of grids using the blot-free Chameleon method preserved the integrity of particles but resulted in their strong preferential orientation. We then used a strategy where we improved in parallel the purification of CDC48A and the conditions for cryo-EM data acquisition. Indeed, we noted that images taken from thicker ice presented an even distribution of intact particles with random orientations, but resulted in a lower image resolution. Consequently, in our case, distribution, orientation, image resolution, and the integrity of particles were tightly correlated with ice thickness. By combining the more homogeneous and stable CDC48A hexamers resulting from our improved purification protocol with an iterative search across different ice thicknesses, we identified an intermediate thickness that retained sufficiently high-resolution structural information while maintaining a complete distribution of particle orientations. Our approach may provide a simple, fast, and generally applicable strategy to record data of sufficient quality under standard laboratory and microscope settings. This method may be of particular value when time and resources are limited.
Towards Understanding the Relationship Between ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis
Authors: Zhao Chenxuan , Liao Yong , Rahaman Abdul , Kumar Vijay
Published: June 2022

Biological stress due to the aberrant buildup of misfolded/unfolded proteins in the endoplasmic reticulum (ER) is considered a key reason behind many human neurodegenerative diseases. Cells adapted to ER stress through the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by degeneration of the motor system. It has largely been known that ER stress plays an important role in the pathogenesis of ALS through the dysregulation of proteostasis. Moreover, accumulating evidence indicates that ER stress and UPR are important players in TDP-43 pathology. In this mini-review, the complex interplay between ER stress and the UPR in ALS and TDP-43 pathology will be explored by taking into account the studies from in vitro and in vivo models of ALS. We also discuss therapeutic strategies to control levels of ER stress and UPR signaling components that have contrasting effects on ALS pathogenesis.
Identification of miRNA–mRNA Pairs in the Alzheimer’s Disease Expression Profile and Explore the Effect of miR-26a-5p/PTGS2 on Amyloid-β Induced Neurotoxicity in Alzheimer’s Disease Cell Model
Authors: Xie Tao , Pei Yongyan , Shan Peijia , Xiao Qianqian , Zhou Fei , Huang Liuqing , Wang Shi
Published: June 2022

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common type of dementia. MicroRNAs (miRNAs) have been extensively studied in many diseases, including AD. To identify the AD-specific differentially expressed miRNAs and mRNAs, we used bioinformatics analysis to study candidate miRNA–mRNA pairs involved in the pathogenesis of AD. These miRNA–mRNAs may serve as promising biomarkers for early diagnosis or targeted therapy of AD patients. In this study, based on the AD mRNA and miRNA expression profile data in Gene Expression Omnibus (GEO), through differential expression analysis, functional annotation and enrichment analysis, weighted gene co-expression network analysis, miRNA–mRNA regulatory network, protein–protein interaction network, receiver operator characteristic and Least absolute shrinkage and selection operator (LASSO) regression and other analysis, we screened the key miRNA–mRNA in the progress of AD: miR-26a-5p/PTGS2. Dual-luciferase and qPCR experiments confirmed that PTGS2 is a direct target gene of miR-26a-5p. The expression of miR-26a-5p in the peripheral blood of AD patients and AD model cells (SH-SY5Y cells treated with Aβ25–35) was up-regulated, and the expression of PTGS2 was down-regulated. Functional gain -loss experiments confirmed that PTGS2 protects AD model cells from damage by inhibiting proliferation and migration. However, the expression of miR-26a-5p promotes the proliferation of AD model cells. It is further found that PTGS2 is involved in the regulation of miR-26a-5p and can reverse the effect of miR-26a-5p on the proliferation of AD model cells. In addition, through network pharmacology, qPCR and CCK-8, we found that baicalein may affect the progression of AD by regulating the expression of PTGS2. Therefore, PTGS2 can be used as a target for AD research, and miR-26a-5p/PTGS2 can be used as an axis of action to study the pathogenesis of AD.
Distinct Brain Dynamic Functional Connectivity Patterns in Schizophrenia Patients With and Without Auditory Verbal Hallucinations
Authors: Zhang Yao , Wang Jia , Lin Xin , Yang Min , Qi Shun , Wang Yuhan , Liang Wei , Lu Huijie , Zhang Yan , Zhai Wensheng , Hao Wanting , Cao Yang , Huang Peng , Guo Jianying , Hu Xuehui , Zhu Xia
Published: June 2022

Schizophrenia patients with auditory verbal hallucinations (AVHs) are diseased groups of serious psychosis with still unknown etiology. The aim of this research was to identify the neurophysiological correlates of auditory verbal hallucinations. Revealing the neural correlates of auditory hallucination is not merely of great clinical significance, but it is also quite essential to study the pathophysiological correlates of schizophrenia. In this study, 25 Schizophrenia patients with AVHs (AVHs group, 23.2 ± 5.35 years), 52 Schizophrenia patients without AVHs (non-AVHs group, 25.79 ± 5.63 years) and 28 healthy subjects (NC group, 26.14 ± 5.45 years) were enrolled. Dynamic functional connectivity was studied with a sliding-window method and functional connectivity states were then obtained with the k-means clustering algorithm in the three groups. We found that schizophrenia patients with AVHs were characterized by significant decreased static functional connectivity and enhanced variability of dynamic functional connectivity (non-parametric permutation test, Bonferroni correction, p < 0.05). In addition, the AVHs group also demonstrated increased number of brain states, suggesting brain dynamics enhanced in these patients compared with the non-AVHs group. Our findings suggested that there were abnormalities in the connection of brain language regions in auditory verbal hallucinations. It appears that the interruption of connectivity from the language region might be critical to the pathological basis of AVHs.
An Argument in Favor of Deep Brain Stimulation for Uncommon Movement Disorders: The Case for N-of-1 Trials in Holmes Tremor
Authors: Mendonça Marcelo , Cotovio Gonçalo , Barbosa Raquel , Grunho Miguel , Oliveira-Maia Albino J.
Published: June 2022

Deep brain stimulation (DBS) is part of state-of-the-art treatment for medically refractory Parkinson’s disease, essential tremor or primary dystonia. However, there are multiple movement disorders that present after a static brain lesion and that are frequently refractory to medical treatment. Using Holmes tremor (HT) as an example, we discuss the effectiveness of currently available treatments and, performing simulations using a Markov Chain approach, propose that DBS with iterative parameter optimization is expected to be more effective than an approach based on sequential trials of pharmacological agents. Since, in DBS studies for HT, the thalamus is a frequently chosen target, using data from previous studies of lesion connectivity mapping in HT, we compared the connectivity of thalamic and non-thalamic targets with a proxy of the HT network, and found a significantly higher connectivity of thalamic DBS targets in HT. The understanding of brain networks provided by analysis of functional connectivity may thus provide an informed framework for proper surgical targeting of individual patients. Based on these findings, we argue that there is an ethical imperative to at least consider surgical options in patients with uncommon movement disorders, while simultaneously providing consistent information regarding the expected effectiveness and risks, even in a scenario of surgical-risk aversion. An approach based on n-of-1 DBS trials may ultimately significantly improve outcomes while informing on optimal therapeutic targets and parameter settings for HT and other disabling and rare movement disorders.
Reducing Behavioral Detection Thresholds per Electrode via Synchronous, Spatially-Dependent Intracortical Microstimulation
Authors: Kunigk Nicolas G. , Urdaneta Morgan E. , Malone Ian G. , Delgado Francisco , Otto Kevin J.
Published: June 2022

Intracortical microstimulation (ICMS) has shown promise in restoring quality of life to patients suffering from paralysis, specifically when used in the primary somatosensory cortex (S1). However, these benefits can be hampered by long-term degradation of electrode performance due to the brain’s foreign body response. Advances in microfabrication techniques have allowed for the development of neuroprostheses with subcellular electrodes, which are characterized by greater versatility and a less detrimental immune response during chronic use. These probes are hypothesized to enable more selective, higher-resolution stimulation of cortical tissue with long-term implants. However, microstimulation using physiologically relevant charges with these smaller-scale devices can damage electrode sites and reduce the efficacy of the overall device. Studies have shown promise in bypassing this limitation by spreading the stimulation charge between multiple channels in an implanted electrode array, but to our knowledge the usefulness of this strategy in laminar arrays with electrode sites spanning each layer of the cortex remains unexplored. To investigate the efficacy of simultaneous multi-channel ICMS in electrode arrays with stimulation sites spanning cortical depth, we implanted laminar electrode arrays in the primary somatosensory cortex of rats trained in a behavioral avoidance paradigm. By measuring detection thresholds, we were able to quantify improvements in ICMS performance using a simultaneous multi-channel stimulation paradigm. The charge required per site to elicit detection thresholds was halved when stimulating from two adjacent electrode sites, although the overall charge used by the implant was increased. This reduction in threshold charge was more pronounced when stimulating with more than two channels and lessened with greater distance between stimulating channels. Our findings suggest that these improvements are based on the synchronicity and polarity of each stimulus, leading us to conclude that these improvements in stimulation efficiency per electrode are due to charge summation as opposed to a summation of neural responses to stimulation. Additionally, the per-site charge reductions are seen regardless of the cortical depth of each utilized channel. This evocation of physiological detection thresholds with lower stimulation currents per electrode site has implications for the feasibility of stimulation regimes in future advanced neuroprosthetic devices, which could benefit from reducing the charge output per site.
Effects of Rhythmic Transcranial Magnetic Stimulation in the Alpha-Band on Visual Perception Depend on Deviation From Alpha-Peak Frequency: Faster Relative Transcranial Magnetic Stimulation Alpha-Pace Improves Performance
Authors: Coldea Andra , Veniero Domenica , Morand Stephanie , Trajkovic Jelena , Romei Vincenzo , Harvey Monika , Thut Gregor
Published: June 2022

Alpha-band oscillatory activity over occipito-parietal areas is involved in shaping perceptual and cognitive processes, with a growing body of electroencephalographic (EEG) evidence indicating that pre-stimulus alpha-band amplitude relates to the subjective perceptual experience, but not to objective measures of visual task performance (discrimination accuracy). The primary aim of the present transcranial magnetic stimulation (TMS) study was to investigate whether causality can be established for this relationship, using rhythmic (alpha-band) TMS entrainment protocols. It was anticipated that pre-stimulus 10 Hz-TMS would induce changes in subjective awareness ratings but not accuracy, in the visual hemifield contralateral to TMS. To test this, we administered 10 Hz-TMS over the right intraparietal sulcus prior to visual stimulus presentation in 17 participants, while measuring their objective performance and subjective awareness in a visual discrimination task. Arrhythmic and 10 Hz sham-TMS served as control conditions (within-participant design). Resting EEG was used to record individual alpha frequency (IAF). A study conducted in parallel to ours with a similar design but reported after we completed data collection informed further, secondary analyses for a causal relationship between pre-stimulus alpha-frequency and discrimination accuracy. This was explored through a regression analysis between rhythmic-TMS alpha-pace relative to IAF and performance measures. Our results revealed that contrary to our primary expectation, pre-stimulus 10 Hz-TMS did not affect subjective measures of performance, nor accuracy, relative to control-TMS. This null result is in accord with a recent finding showing that for influencing subjective measures of performance, alpha-TMS needs to be applied post-stimulus. In addition, our secondary analysis showed that IAF was positively correlated with task accuracy across participants, and that 10 Hz-TMS effects on accuracy—but not awareness ratings—depended on IAF: The slower (or faster) the IAF, relative to the fixed 10 Hz TMS frequency, the stronger the TMS-induced performance improvement (or worsening), indicating that 10 Hz-TMS produced a gain (or a loss) in individual performance, directly depending on TMS-pace relative to IAF. In support of recent reports, this is evidence for alpha-frequency playing a causal role in perceptual sensitivity likely through regulating the speed of sensory sampling.