bluuebunny/crossref_metadata_2025 huggingface dataset:
VERGİ USUL KANUNU’NUN 11. MADDESİNİN 3. VE DEVAMI FIKRALARINDA DÜZENLENEN MÜTESELSİL SORUMLULUK ESASININ DEĞERLENDİRİLMESİ
Authors: ARIKAN Zeynep , ARIKAN Abdullah
Published: July 2023

Vergi alacağının zamanında ve eksiksiz bir biçimde hazineye intikal ettirilmesinin doğrudan kamu yararını hedef aldığı hususu açıktır. Fakat vergilendirme yetkisinin kullanımıyla vergi alacaklısı ile vergi yükümlüsü ve sorumlusu arasında kurulan vergi ilişkisinde hukuka uygunluk sahası dışına çıkılmaması gerekir. Aksi takdirde vergi hukukunun temel ilkelerinin ihlal edilmesi kaçınılmaz hale gelecektir. Buraya kadar değinilen çerçevenin olumsuz mahiyette somutlaşan bir örneğini 213 sayılı Vergi Usul Kanunu (VUK)’un 11. maddesinin 3. ve devamı fıkralarında düzenlenen müteselsil sorumluluk esası meydana getirmektedir. Bu saptamanın berraklaştırılabilmesi için çalışmada öncelikle sorumluluğun detayları ortaya konulmaya çalışılmıştır. Bu yapılırken idareye tanınan yetkinin kullanımı ile gelir vergisinde zirai kazançların vergilendirilmesinde ve katma değer vergisinde vergiye tabi işlemler yönünden tatbik edilen sorumluluğa dair öğreti ve yargı kararlarında beliren tartışmalar ele alınmıştır. Akabinde ise anlam ve kapsamı saptanmaya gayret edilen sorumluluğun Anayasaya uygunluğu irdelenmiş ve Anayasa Mahkemesinin benzer bir konuda verdiği karar da göz önünde bulundurularak çalışma konusunu meydana getiren kanuni düzenlemelerin Yüksek Mahkemenin önüne tekrar getirilmesi halinde iptal edilmesi gerektiği savunulmuştur.
6284 SAYILI AİLENİN KORUNMASI VE KADINA KARŞI ŞİDDETİN ÖNLENMESİNE DAİR KANUN’DAKİ DESTEK HİZMETLERİNİN DÖNÜŞTÜRÜCÜ ADALET BAĞLAMINDA DEĞERLENDİRİLMESİ
Authors: BİRİNCİ Nevin , ÖZDEMİR Nadire
Published: July 2023

Günümüzde aile içi şiddeti önlemeye ve şiddetle mücadele etmeye yönelik yaklaşımlar şiddetin sadece bireysel değil, toplumsal boyutlarını da hesaba katmakta ve tarafların sorumluluk almalarını ve değişmelerini teşvik etmeye yönelik araçlar ve programlar öngörmektedir. Bu amaca uygun bir şekilde 6284 Sayılı Ailenin Korunması ve Kadına Karşı Şiddetin Önlenmesine Dair Kanun, koruyucu ve önleyici tedbirlerin yanı sıra, uygulamada ve literatürde daha az bilinen ‘destekleyici’ tedbirleri de öngörmektedir. 6284 Sayılı Kanun’un 15 inci maddesi uyarınca düzenlenmiş olan bu destek hizmetleri, şiddet olgusuna yönelik dönüştürücü araçları sunması adına önem arz etmektedir. Bu çalışma, söz konusu destek hizmetlerinde amaçlanan hedefleri dönüştürücü adaletin bağlamsallık ve ilişkisellik vurgusu taşıyan ilkeleri eşliğinde ele alacaktır. Söz konusu ilkeler ‘özgürleştirme’, ‘gücü değiştirme’, ‘hesap verilebilirlik’, ‘kültürel duyarlılık’, ‘sürdürebilirlik’ ve ‘esneklik’tir. Bu ilkeler temelinde korunan kişiye, şiddet uygulayana ve çocuklara yönelik verilecek destekleyici tedbirler ayrı başlıklarda değerlendirilecektir. Teorik açıklamaları somutlaştırmak adına yargı kararlarına başvurulacak ve verilmiş tedbir kararları örnekleriyle çalışmanın temel iddiası açıklanacaktır.
YARGI KARARLARI IŞIĞINDA NEW YORK SÖZLEŞMESİ’NE GÖRE YABANCI HAKEM KARARLARININ TÜRKİYE’DE TENFİZİ ENGELİ OLARAK HUKUKİ DİNLENİLME HAKKI ÜZERİNE BAZI DEĞERLENDİRMELER
Authors: BÖRÜ Levent
Published: July 2023

Yabancı hakem kararlarının tanınması ve tenfizi konusunda Türkiye’de geçerli olan iki düzenleme vardır: Bunlardan ilki 5718 sayılı Milletlerarası Özel Hukuk ve Usul Hukuku Hakkında Kanun’dur. Diğeri ise Yabancı Hakem Kararlarının Tanınması ve İcrasına İlişkin New York Sözleşmesi’dir. 10.06.1958 tarihli Yabancı Hakem Kararlarının Tanınması ve İcrasına İlişkin New York Sözleşmesi (New York Konvansiyonu) hükümleri Anayasa m. 90 çerçevesinde bir kanunla onaylanarak Türk iç hukukunun bir parçası durumuna getirilmiştir. New York Sözleşmesi, hukukî dinlenilme hakkını hakem kararının tenfizine engel olabilecek bir sebep olarak V/1-b maddesinde düzenleme konusu yapmıştır. New York Sözleşmesi’nde açıkça “iddia ve savunma hakkı” ifadesi kullanılmış olsa da modern zamandaki gelişmeler dikkate alındığında artık bunun yerine “hukuki dinlenilme hakkı” kavramının daha yerinde olması sebebiyle makalemizde bu kavramın kullanılması tercih edilmiştir. Makalemizde hukuki dinlenilme hakkının, bilgilenme, açıklama-ispat hakkı ve dikkate alınma-değerlendirme hakkı unsurlarının New York Sözleşmesi m. V/1-b uyarınca bazı özel kavramlarla (kamu düzeni, silahların eşitliği ilkesi, somutlaştırma yükü, gerekçe ve sürpriz karar verme yasağı ile) ilişkisi Türkiye’deki yargı kararları kapsamında değerlendirilmesi yapılmıştır.
SEÇİMLİK YARIŞMA KAVRAMI VE BUNA DUYULAN İHTİYAÇ ÜZERİNE
Authors: GÖKA Emir
Published: July 2023

Seçimlik yarışma, hak sahibinin, aralarından yalnızca birini kullanmak üzere birden fazla hakkının bulunduğu durumları, yani seçimlik hak çokluklarını ifade etmektedir. Alman öğretisindeki hakim görüş bunu hem hukuki yapısı hem de bazı sonuçları itibariyle seçimlik borç ve yetkiden ayırmakta, bağımsız bir kavram olarak ele almaktadır. Ancak bu kavramı, ifade ettiği durumlardaki sorunlara yeknesak çözümler sunamadığı sebebiyle eleştiren yazarlar olduğu gibi tamamen reddeden yazarlar da vardır. Bu tartışmalar henüz Türk ve İsviçre öğretisini etkilememiştir. Hatta burada seçimlik yarışma kavramına da oldukça az sayıda yazar tarafından yer verilmektedir. Fakat bu kavramı kullanmayan yazarlar da bununla ifade edilen durumları çoğunlukla seçimlik borç, yetki veya başka bir kavramla açıklamamakta, sadece hak sahibinin “seçimlik hakları” bulunduğundan söz etmektedir. Bu çalışmada önce Alman hukukunda seçimlik borç, yetki ve yarışma kavramları ele alınmış ve seçimlik yarışmayla ilgili tartışmalar açıklanmıştır. Sonrasında Türk ve İsviçre hukukunda aynı kavramlar incelenmiş, seçimlik yarışmanın bağımsız bir kavram olarak kabul edilmesi ihtiyacını arka planda bırakan sebeplere değinilmiş ve böyle bir kabulün isabetli olup olmadığı tartışılmıştır.
DINAMIKA PERDAGANGAN EMAS DAN BUDAK DI GORONTALO ABAD XVIII-XIX
Authors: Sekarningrum Retno , Hasanuddin Hasanuddin
Published: July 2023

As a hub between major ports such as Malacca, Singapore, Ternate, and Makassar, Gorontalo plays a crucial role in the shipping and trade networks of the northern region of Sulawesi. This condition was strengthened by the availability of numerous commodities, especially gold, and enslaved people. These two essential commodities had been exported, mainly by Bugis and Mandar traders, to the international market since the 16th century. Studies on the development of the Gorontalo port have received less attention from historians who only focused on the role of large ports. This paper focuses on the development of Gorontalo port in exporting gold and enslaved people in the 18th to 19th centuries. By implementing the historical method, which comprises heuristics, criticism, interpretation, and historiography, this paper points out that the development had its dynamics. Bugis and Mandar traders reflected this dynamic when they lost access to trade in gold and the enslaved people in Gorontalo since the VOC trade monopoly in the seventeenth century. The monopoly led to the vulnerability of shipping-trade activities around Gorontalo to rampant piracy by pirates and smuggling.
PERUBAHAN EKONOMI DAN POLITIK SURABAYA DI BAWAH HEGEMONI VOC PADA ABAD KE-18
Authors: Nugroho Andri Setyo
Published: July 2023

The establishment of the VOC fortress on the north coast of Java originated from a political contract between Mataram and the Company. Its presence has indirectly led to economic and political changes in Surabaya. The fort, which initially served as a means of defense, shifted to become a center for trade and government. Discussions about the early development of Surabaya mainly stem from the colonial settlements that mushroomed in the 19th century. Even though changes had already emerged when the VOC was based in Surabaya, which started with constructing a fort and infrastructure improvements, subsequently generating economic growth, and encouraging massive political change. The study aims to describe the economic and political changes in Surabaya under VOC hegemony. It used historical research, which sources are taken from archives, maps, and VOC letters from the 18th century. The study results show that the fort has an economic impact, namely increasing trading activities and triggering the formation of Chinese settlements. Political development grew from the fortress, which became the center of Java’s Oosthoek government. Surabaya was chosen as the location for the gezaghebber’s official residence, the seat of government, and the place for the inauguration of the regents in the vicinity.
A CRÔNICA CANTADA E A VERSÃO ABSURDA DO PERFEITO IDIOTA LATINO-AMERICANO
Authors:   Universidade do Estado de Minas Gerais - Unidade Frutal, PESSOA MARCELO
Published: July 2023

The present chapter of the book aims to make public an interview, still unpublished, carried out with the poet-composer Caetano Veloso, in November 1998. As an immediate result of this historical rescue, the scientific production now publicized can contribute to helping to fill some gaps in the criticism related to Brazilian chronic-musical production.. As a fundamental bibliographic contribution of this revisited writing, we have those by Pessoa (2013 and 2014). The methodology used in this weaving was the bibliographic review of collections arranged in physical and digital repositories.
Advances on mechanical designs for assistive ankle-foot orthoses
Authors: Lora-Millan Julio S. , Nabipour Mahdi , van Asseldonk Edwin , Bayón Cristina
Published: July 2023

Assistive ankle-foot orthoses (AAFOs) are powerful solutions to assist or rehabilitate gait on humans. Existing AAFO technologies include passive, quasi-passive, and active principles to provide assistance to the users, and their mechanical configuration and control depend on the eventual support they aim for within the gait pattern. In this research we analyze the state-of-the-art of AAFO and classify the different approaches into clusters, describing their basis and working principles. Additionally, we reviewed the purpose and experimental validation of the devices, providing the reader with a better view of the technology readiness level. Finally, the reviewed designs, limitations, and future steps in the field are summarized and discussed.
Disentangling the “net” from the “offset”: learning for net-zero climate policy from an analysis of “no-net-loss” in biodiversity
Authors: McLaren Duncan P. , Carver Louise
Published: July 2023

Net-zero has proved a rapid and powerful convening concept for climate policy. Rather than treating it as a novel development from the perspective of climate policy, we examine net-zero in the context of the longer history and experience of the “no-net-loss” framing from biodiversity policy. Drawing on material from scholarly, policy and activist literature and cultural political economy theory, we interpret the turn to “net” policies and practices as part of the political economy of neoliberalism, in which the quantification and commodification of the environment, and in particular—trading through an offset market, enable continued ideological dominance of economic freedoms. This analysis highlights the ways in which the adoption of a “net” framing reconstructs the goals, processes and mechanisms involved. It is the neoliberal commitment to markets that drives the adoption of net framings for the very purpose of validating offsetting markets. Understanding the making of “net” measures in this way highlights the potential to disentangle the “net” from the “offset”, and we discuss the various obfuscations and perversities this entanglement affords. We argue that the delivery of net outcomes might be separated from the mechanism of offsetting, and the marketization of compensation it is typically presumed to involve, but may yet remain entangled in neoliberal political ideology. In conclusion we suggest some conditions for more effective, fair and sustainable delivery of “net-zero” climate policy.
Magnetocardiography for the detection of myocardial ischemia
Authors: Her Ae-Young , Dischl Dominic , Kim Yong Hoon , Kim Sang-Wook , Shin Eun-Seok
Published: July 2023

Ischemic heart disease (IHD) continues to be a significant global public health concern and ranks among the leading causes of mortality worldwide. However, the identification of myocardial ischemia in patients suspected of having coronary artery disease (CAD) remains a challenging issue. Functional or stress testing is widely recognized as the gold standard method for diagnosing myocardial ischemia, but it is hindered by low diagnostic accuracy and limitations such as radiation exposure. Magnetocardiography (MCG) is a non-contact, non-invasive method that records magnetic fields produced by the electrical activity of the heart. Unlike electrocardiography (EKG) and other functional or stress testing, MCG offers numerous advantages. It is highly sensitive and can detect early signs of myocardial ischemia that may be missed by other diagnostic tools. This review aims to provide an extensive overview of the available evidence that establishes the utility of MCG as a valuable diagnostic tool for identifying myocardial ischemia, accompanied by a discussion of potential future research directions in this domain.
Midlife body mass index, central adiposity and neuropsychological performance over 10 years in women living with and without HIV
Authors: Vásquez Elizabeth , Kuniholm Mark H. , Appleton Allison A. , Rubin Leah H. , Adimora Ada A. , Fischl Margaret A. , Fox Ervin , Mack Wendy J. , Holman Susan , Moran Caitlin Anne , Minkoff Howard , Plankey Michael W. , Sharma Anjali , Tien Phyllis C. , Weber Kathleen M. , Gustafson Deborah R.
Published: July 2023

Background and objective

Observations of overweight and obesity in association with neuropsychological performance (NP) vary over the adult life course depending on baseline levels, biological sex, age, race, temporality of measurements, and other factors. Therefore, similar published analyses across cohorts are inconsistent. In our sample of women living with HIV (WLWH) and women without HIV (WWOH), we conducted comparable analyses as those published in men with and without HIV. We examined cross-sectional and longitudinal associations between body mass index (BMI) and waist circumference (WC) and NP.

Methods

Four hundred thirty two 432 virologically-suppressed WLWH and 367 WWOH, ≥40 years in the Women’s Interagency HIV Study (WIHS) with anthropometry and NP assessments every two years from 2009-2019 were included in the study. Demographically-adjusted T-scores were calculated for six NP domains: learning, memory, executive function, processing speed, attention and working memory, and motor function. Multivariable linear regression models stratified by HIV status were used to examine cross-sectional associations of BMI and WC by NP domain; repeated measures analyses assessed baseline BMI and WC in association with longitudinal change in NP. Covariates included sociodemographic, behavioral, and HIV-related characteristics.

Results

At baseline among all women, the median age was 45 years, 65% were Non-Latinx Black women, and 45% were obese women. Obese WLWH (BMI≥30.0 kg/m2) had poorer executive function (β=-2.27, 95%CI [-4.46, -0.07]) versus WLWH with healthy BMI (18.5–24.9 kg/m2). Longitudinally over ~8 years, obese versus overweight WWOH improved on memory (β=2.19, 95%CI [0.13, 4.26]), however overweight versus healthy WWOH experienced declining memory (β= -2.67, 95%CI [-5.40, -0.07]). Increasing WC was associated with declining executive, processing speed, and motor function (p’s<0.05); an at-risk WC was associated with improved memory (β=1.81, 95%CI [0.19, 3.44]) among WWOH. Among WLWH, increasing BMI was associated with improved learning (β=0.07, 95%CI [0.00, 0.15].

Conclusion

Our cross-sectional and longitudinal analyses evaluating the associations of BMI and WC and NP were mixed compared to previous reports. This illustrates the importance of sociodemographic characteristics, baseline levels of exposures and outcomes, HIV status, temporality of measurements, and other factors when evaluating aging HIV epidemiology study results.
Clitoral preputial edema can be mistaken for clitoromegaly: a clinical analysis of ten cases
Authors: Mitani-Konno Marie , Saito Reiko , Narumi-Wakayama Hiroko , Sakai Yuki , Suzuki Shuichi , Satoh Hiroyuki , Hasegawa Yukihiro
Published: July 2023

Background and objectives

We herein reported ten, female neonates with transient clitoral preputial edema, which was mistaken for clitoromegaly. Although it is well known that the clitoris is prominent in premature, female neonates, there are as of yet no reports of clitoral preputial edema in full-term neonates. The present study was conducted to clarify the clinical course of clitoral preputial edema.

Methods

Seventeen, Japanese patients aged < 6 months with suspected clitoromegaly were enrolled, and their clinical course was analyzed retrospectively. Clitoral preputial edema was defined by 1) a normal clitoral glans despite edema; and 2) the absence of established differences of sexual development, such as 21-hydroxylase deficiency.

Results

Ten of the 17 patients with suspected clitoromegaly had clitoral preputial edema; eight of the ten patients were full-term, and the remaining two were preterm neonates. The median age at the first visit was 8 days. Edema of the labia minora and labia majora, rugosity of the labia majora, and hymenal polyps often accompanied the clitoral preputial edema. Seven patients were examined at our division during the neonatal period, and three patients were examined in the post-neonatal period. Age at reduction of the clitoral width to < 7 mm ranged from 8 to 74 days in four of the seven neonatal patients. In the three post-neonatal patients, age to reduction in the clitoral width ranged from 107 to 243 days.

Conclusions

Transient clitoral preputial edema is often mistaken for clitoromegaly. The key to diagnosing clitoral preputial edema lies in its characteristic appearance and improvement course.
Case Report: Chemoimmunotherapy in microsatellite-instability-high advanced goblet cell carcinoma of the colon
Authors: Mutlu Arda Ulaş , Aytaç Erman , Gülmez Mehmet , Erdamar Sibel , Özer Leyla
Published: July 2023

Background

Mismatch repair (MMR) deficiency is a fundamental factor affecting the management treatment outcomes of colorectal cancer (CRC). MMR status can be diagnosed by both immunohistochemistry (IHC) polymerase chain reaction (PCR). Since tumors with MMR deficiency are prone to respond to immunotherapy immune checkpoint inhibitors are used to treat such tumors.

Case presentation

A 69-year-old male patient presented to an outside clinic with weight loss and abdominal pain. Radiological investigations detected a mesenteric mass of 10 cm, peritoneal implants, and mediastinal lymphadenopathy. The eventual biopsy result from the mesenteric mass was mucinous adenocarcinoma with a goblet cell pattern. Since the IHC result was unclear for deficiency in mismatch repair (dMMR) metastatic CRC (mCRC), the diagnosis was confirmed with PCR. The patient received 8 cycles of FOLFIRINOX + bevacizumab followed by FOLFOX combined with pembrolizumab. No adverse effect was reported related to immunotherapy which resulted in radiologic and metabolic regression. The patient underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). The final pathology results revealed a pathological complete response and R0 resection. In the 6th month follow-up, no recurrence or metastasis was reported.

Conclusion

Chemotherapy and immunotherapy combination is a promising treatment modality which can also be used for mCRC. This is the index case who received chemotherapy in combination with immunotherapy for mucinous adenocarcinoma of the colon with a goblet cell pattern and had pCR.
Integrated analyses of single-cell transcriptomics identify metastasis-associated myeloid subpopulations in breast cancer lung metastasis
Authors: Huang Zhen , Bu Dawei , Yang Nan , Huang Wenwen , Zhang Liyin , Li Xiaoxue , Ding Bi-Sen
Published: July 2023

Lung metastasis of breast cancer is closely associated with patient morbidity and mortality, which correlates with myeloid cells in the lung microenvironment. However, the heterogeneity and specificity of metastasis-associated myeloid cells have not been fully established in lung metastasis. Here, by integrating and analyzing single-cell transcriptomics, we found that myeloid subpopulations (Tppp3+ monocytes, Isg15+ macrophages, Ifit3+ neutrophils, and Il12b+ DCs) play critical roles in the formation and development of the metastatic niche. Gene enrichment analyses indicate that several tumor-promoting pathways should be responsible for the process, including angiogenesis (Anxa1 and Anxa2 by Tppp3+ monocytes), immunosuppression (Isg15 and Cxcl10 by Isg15+ macrophages; Il12b and Ccl22 by Il12b+ DCs), and tumor growth and metastasis (Isg15 and Isg20 by Ifit3+ neutrophils). Furthermore, we have validated these subpopulations in lung microenvironment of MMTV-PyVT transgenic mice and verified their association with poor progression of human breast cancer. Also, our results elucidated a crosstalk network among four myeloid subpopulations by cell-cell communication analysis. This study, therefore, highlights the crucial role of myeloid cells in lung metastasis and provides insights into underlying molecular mechanisms, which pave the way for therapeutic interventions in breast cancer metastasis to lung.
Expression of targets of the RNA-binding protein AUF-1 in human airway epithelium indicates its role in cellular senescence and inflammation
Authors: Salvato Ilaria , Ricciardi Luca , Dal Col Jessica , Nigro Annunziata , Giurato Giorgio , Memoli Domenico , Sellitto Assunta , Lamparelli Erwin Pavel , Crescenzi Maria Assunta , Vitale Monica , Vatrella Alessandro , Nucera Francesco , Brun Paola , Caicci Federico , Dama Paola , Stiff Thomas , Castellano Leandro , Idrees Sobia , Johansen Matt D. , Faiz Alen , Wark Peter A. , Hansbro Philip M. , Adcock Ian M. , Caramori Gaetano , Stellato Cristiana
Published: July 2023

Introduction

The RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss.

Results

RNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3’-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets’ steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression.

Discussion

Loss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells.
Intracellular DNA sensing by neutrophils and amplification of the innate immune response
Authors: Mankan Arun K. , Czajka-Francuz Paulina , Prendes Maria , Ramanan Sriram , Koziej Marcin , Vidal Laura , Saini Kamal S.
Published: July 2023

As the first responders, neutrophils lead the innate immune response to infectious pathogens and inflammation inducing agents. The well-established pathogen neutralizing strategies employed by neutrophils are phagocytosis, the action of microbicide granules, the production of ROS, and the secretion of neutrophil extracellular traps (NETs). Only recently, the ability of neutrophils to sense and respond to pathogen-associated molecular patterns is being appreciated. This review brings together the current information about the intracellular recognition of DNA by neutrophils and proposes models of signal amplification in immune response. Finally, the clinical relevance of DNA sensing by neutrophils in infectious and non-infectious diseases including malignancy are also discussed.
Robust spike-specific CD4+ and CD8+ T cell responses in SARS-CoV-2 vaccinated hematopoietic cell transplantation recipients: a prospective, cohort study
Authors: Federico Lorenzo , Tvedt Tor Henrik Anderson , Gainullin Murat , Osen Julie Røkke , Chaban Viktoriia , Lund Katrine Persgård , Tietze Lisa , Tran Trung The , Lund-Johansen Fridtjof , Kared Hassen , Lind Andreas , Vaage John Torgils , Stratford Richard , Tennøe Simen , Malone Brandon , Clancy Trevor , Myhre Anders Eivind Leren , Gedde-Dahl Tobias , Munthe Ludvig André
Published: July 2023

Poor overall survival of hematopoietic stem cell transplantation (HSCT) recipients who developed COVID-19 underlies the importance of SARS-CoV-2 vaccination. Previous studies of vaccine efficacy have reported weak humoral responses but conflicting results on T cell immunity. Here, we have examined the relationship between humoral and T cell response in 48 HSCT recipients who received two doses of Moderna’s mRNA-1273 or Pfizer/BioNTech’s BNT162b2 vaccines. Nearly all HSCT patients had robust T cell immunity regardless of protective humoral responses, with 18/48 (37%, IQR 8.679-5601 BAU/mL) displaying protective IgG anti-receptor binding domain (RBD) levels (>2000 BAU/mL). Flow cytometry analysis of activation induced markers (AIMs) revealed that 90% and 74% of HSCT patients showed reactivity towards immunodominant spike peptides in CD8+ and CD4+ T cells, respectively. The response rate increased to 90% for CD4+ T cells as well when we challenged the cells with a complete set of overlapping peptides spanning the entire spike protein. T cell response was detectable as early as 3 months after transplant, but only CD4+ T cell reactivity correlated with IgG anti-RBD level and time after transplantation. Boosting increased seroconversion rate, while only one patient developed COVID-19 requiring hospitalization. Our data suggest that HSCT recipients with poor serological responses were protected from severe COVID-19 by vaccine-induced T cell responses.
Genetic support of the causal association between gut microbiome and COVID-19: a bidirectional Mendelian randomization study
Authors: Li Zengbin , Zhu Guixian , Lei Xiangye , Tang Liqiong , Kong Guangyao , Shen Mingwang , Zhang Lei , Song Lingqin
Published: July 2023

Background

The association between gut microbiome and coronavirus disease 2019 (COVID-19) has attracted much attention, but its causality remains unclear and requires more direct evidence.

Methods

In this study, we conducted the bidirectional Mendelian randomization (MR) analysis to assess the causal association between gut microbiome and COVID-19 based on the summary statistics data of genome-wide association studies (GWASs). Over 1.8 million individuals with three COVID-19 phenotypes (severity, hospitalization and infection) were included. And 196 bacterial taxa from phylum to genus were analyzed. The inverse-variance weighted (IVW) analysis was chosen as the primary method. Besides, false discovery rate (FDR) correction of p-value was used. To test the robustness of the causal relationships with p-FDR < 0.05, sensitivity analyses including the secondary MR analyses, horizontal pleiotropy test, outliers test, and “leave-one-out” analysis were conducted.

Results

In the forward MR, we found that 3, 8, and 10 bacterial taxa had suggestive effects on COVID-19 severity, hospitalization and infection, respectively. The genus Alloprevotella [odds ratio (OR) = 1.67; 95% confidence interval (95% CI), 1.32–2.11; p = 1.69×10−5, p-FDR = 2.01×10−3] was causally associated with a higher COVID-19 severity risk. In the reverse MR, COVID-19 severity, hospitalization and infection had suggestive effects on the abundance of 4, 8 and 10 bacterial taxa, respectively. COVID-19 hospitalization causally increased the abundance of the phylum Bacteroidetes (OR = 1.13; 95% CI, 1.04–1.22; p = 3.02×10−3; p-FDR = 2.72×10−2). However, secondary MR analyses indicated that the result of COVID-19 hospitalization on the phylum Bacteroidetes required careful consideration.

Conclusion

Our study revealed the causal association between gut microbiome and COVID-19 and highlighted the role of “gut-lung axis” in the progression of COVID-19.
Diabetic complications and prospective immunotherapy
Authors: Reynolds Lewis , Luo Zhengkang , Singh Kailash
Published: July 2023

The incidence of Diabetes Mellitus is increasing globally. Individuals who have been burdened with diabetes for many years often develop complications as a result of hyperglycemia. More and more research is being conducted highlighting inflammation as an important factor in disease progression. In all kinds of diabetes, hyperglycemia leads to activation of alternative glucose metabolic pathways, resulting in problematic by-products including reactive oxygen species and advanced glycation end products. This review takes a look into the pathogenesis of three specific diabetic complications; retinopathy, nephropathy and neuropathy as well as their current treatment options. By considering recent research papers investigating the effects of immunotherapy on relevant conditions in animal models, multiple strategies are suggested for future treatment and prevention of diabetic complications with an emphasis on molecular targets associated with the inflammation.
Multispecies probiotic supplementation in diet with reduced crude protein levels altered the composition and function of gut microbiome and restored microbiome-derived metabolites in growing pigs
Authors: Vasquez Robie , Kim Sang Hoon , Oh Ju Kyoung , Song Ji Hoon , Hwang In-Chan , Kim In Ho , Kang Dae-Kyung
Published: July 2023

Both crude protein (CP) and probiotics can modulate the gut microbiome of the host, thus conferring beneficial effects. However, the benefits of low CP diet supplemented with multispecies probiotics on gut microbiome and its metabolites have not been investigated in pigs. Thus, we investigated the combinatory effects of low CP diet supplemented with multispecies probiotics on gut microbiome composition, function, and microbial metabolites in growing pigs. In total, 140 6 week-old piglets (Landrace × Yorkshire × Duroc) were used in this study. The pigs were divided into four groups with a 2 × 2 factorial design based on their diets: normal-level protein diet (16% CP; NP), low-level protein diet (14% CP; LP), NP with multispecies probiotics (NP-P), and LP with multispecies probiotics (LP-P). After the feeding trial, the fecal samples of the pigs were analyzed. The fecal scores were improved by the probiotic supplementation, especially in LP-P group. We also observed a probiotic-mediated alteration in the gut microbiome of pigs. In addition, LP-P group showed higher species richness and diversity compared with other groups. The addition of multispecies probiotics in low CP diet also enhanced gut microbiota metabolites production, such as short-chain fatty acids (SCFAs) and polyamines. Correlation analysis revealed that Oscillospiraceae UCG-002, Eubacterium coprostanoligenes, Lachnospiraceae NK4A136 group, and Muribaculaceae were positively associated with SCFAs; and Prevotella, Eubacterium ruminantium, Catenibacterium, Alloprevotella, Prevotellaceae NK3B31 group, Roseburia, Butyrivibrio, and Dialister were positively correlated with polyamines. Supplementation with multispecies probiotics modulated the function of the gut microbiome by upregulating the pathways for protein digestion and utilization, potentially contributing to enriched metabolite production in the gut. The results of this study demonstrate that supplementation with multispecies probiotics may complement the beneficial effects of low CP levels in pig feed. These findings may help formulate sustainable feeding strategies for swine production.
Structural determinants underlying high-temperature adaptation of thermophilic xylanase from hot-spring microorganisms
Authors: Li Yi , Peng Hong-Qian , Yang Li-Quan
Published: July 2023

Thermophilic xylanases from hot-spring microorganisms play potential biological and industrial applications for renewable and sustainable social development. However, high-temperature adaptation mechanisms of these thermophilic xylanases remain elusive at the molecular and evolutionary levels. Here, two recently reported xylanases, named XynDRTY1 and XynM1, from hot springs were subjected to molecular dynamics (MD) simulations at a series of temperature gradients and comparatively analyzed in comparison with the evolutionary background of the xylanase family. Comparative analysis of MD trajectories revealed that the XynM1 exhibits smaller structural dynamics and greater thermal stability than the XynDRTY1, although both share a similar fold architecture with structural differences in the βα_loops. Local regions whose conformational flexibility and regular secondary structure exhibited differences as temperature increases were closely related to the high-temperature adaptation of xylanase, implying that stabilization of these regions is a feasible strategy to improve the thermal stability of xylanases. Furthermore, coevolutionary information from the xylanase family further specified the structural basis of xylanases. Thanks to these results about the sequence, structure, and dynamics of thermophilic xylanases from hot springs, a series of high-temperature-related structural determinants were resolved to promote understanding of the molecular mechanism of xylanase high-temperature adaptation and to provide direct assistance in the improvement of xylanase thermal stability.
Seasonality of the bacterial and archaeal community composition of the Northern Barents Sea
Authors: Thiele Stefan , Vader Anna , Thomson Stuart , Saubrekka Karoline , Petelenz Elzbieta , Müller Oliver , Bratbak Gunnar , Øvreås Lise
Published: July 2023

The Barents Sea is a transition zone between the Atlantic and the Arctic Ocean. The ecosystem in this region is highly variable, and a seasonal baseline of biological factors is needed to monitor the effects of global warming. In this study, we report the results from the investigations of the bacterial and archaeal community in late winter, spring, summer, and early winter along a transect through the northern Barents Sea into the Arctic Ocean east of Svalbard using 16S rRNA metabarcoding. Winter samples were dominated by members of the SAR11 clade and a community of nitrifiers, namely Cand. Nitrosopumilus and LS-NOB (Nitrospinia), suggest a prevalence of chemoautotrophic metabolisms. During spring and summer, members of the Gammaproteobacteria (mainly members of the SAR92 and OM60(NOR5) clades, Nitrincolaceae) and Bacteroidia (mainly Polaribacter, Formosa, and members of the NS9 marine group), which followed a succession based on their utilization of different phytoplankton-derived carbon sources, prevailed. Our results indicate that Arctic marine bacterial and archaeal communities switch from carbon cycling in spring and summer to nitrogen cycling in winter and provide a seasonal baseline to study the changes in these processes in response to the effects of climate change.
Green synthetic natural carbon dots derived from Fuligo Plantae with inhibitory effect against alcoholic gastric ulcer
Authors: Zhao Yusheng , Cheng Guoliang , Gao Yushan , Cui Luming , Zhao Yafang , Zhang Yifan , Tian Yu , Zhao Yan , Zhang Yue , Qu Huihua , Kong Hui
Published: July 2023

Introduction:Fuligo Plantae (FP), the ash that sticks to the bottom of pots or chimneys after weeds burn, has long been used for its hemostatic effects and treatment of gastrointestinal bleeding. Nevertheless, the active ingredient of FP still needs to be further explored.

Methods: The microstructure, optical and chemical properties of FP-CDs were characterized. An alcohol-induced gastric ulcer model was utilized to evaluate whether pre-administration of FP-CDs alleviated gastric bleeding symptoms and ameliorated gastric mucosal barrier disruption. In addition, the feces of each group of rats were extracted for 16S rDNA genome sequencing of intestinal flora.

Results: FP-CDs with a diameter ranging from 1.4–3.2 nm had abundant chemical groups, which may be beneficial to the exertion of inherent activity. FP-CDs alleviated alcohol-induced gastric ulcer, as demonstrated by activating the extrinsic coagulation pathway, alleviating inflammation, and suppressing oxidative stress levels. More interestingly, FP-CDs can improve the diversity and dysbiosis of intestinal flora in rats with alcohol-induced gastric ulcer.

Conclusion: These comes about illustrate the momentous inhibitory effects of FP-CDs on alcoholic gastric ulcer in rats, which give a modern methodology for investigating the effective ingredient of FP, and lay an experimental basis for the application of FP-CDs in the clinical treatment of alcoholic gastric ulcer.
Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery
Authors: Novorolsky Robyn J. , Kasheke Gracious D. S. , Hakim Antoine , Foldvari Marianna , Dorighello Gabriel G. , Sekler Israel , Vuligonda Vidyasagar , Sanders Martin E. , Renden Robert B. , Wilson Justin J. , Robertson George S.
Published: July 2023

The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+and stimulating energy production. However, excessive mitochondrial Ca2+uptake causes toxic mitochondrial Ca2+overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+uptake and efflux in the brain are mediated by the mitochondrial Ca2+uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcxinhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+overloading. These findings suggest that combining MCUcxinhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcxinhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.
Assessment of cochlear synaptopathy by electrocochleography to low frequencies in a preclinical model and human subjects
Authors: Haggerty Raymond A. , Hutson Kendall A. , Riggs William J. , Brown Kevin D. , Pillsbury Harold C. , Adunka Oliver F. , Buchman Craig A. , Fitzpatrick Douglas C.
Published: July 2023

Cochlear synaptopathy is the loss of synapses between the inner hair cells and the auditory nerve despite survival of sensory hair cells. The findings of extensive cochlear synaptopathy in animals after moderate noise exposures challenged the long-held view that hair cells are the cochlear elements most sensitive to insults that lead to hearing loss. However, cochlear synaptopathy has been difficult to identify in humans. We applied novel algorithms to determine hair cell and neural contributions to electrocochleographic (ECochG) recordings from the round window of animal and human subjects. Gerbils with normal hearing provided training and test sets for a deep learning algorithm to detect the presence of neural responses to low frequency sounds, and an analytic model was used to quantify the proportion of neural and hair cell contributions to the ECochG response. The capacity to detect cochlear synaptopathy was validated in normal hearing and noise-exposed animals by using neurotoxins to reduce or eliminate the neural contributions. When the analytical methods were applied to human surgical subjects with access to the round window, the neural contribution resembled the partial cochlear synaptopathy present after neurotoxin application in animals. This result demonstrates the presence of viable hair cells not connected to auditory nerve fibers in human subjects with substantial hearing loss and indicates that efforts to regenerate nerve fibers may find a ready cochlear substrate for innervation and resumption of function.
Effects of neurofeedback on standing postural control task with combined imagined and executed movements
Authors: Sawai Shun , Fujikawa Shoya , Ohsumi Chihiro , Ushio Ryu , Tamura Kosuke , Yamamoto Ryosuke , Kai Yoshihiro , Murata Shin , Shima Keisuke , Nakano Hideki
Published: July 2023

Introduction

Motor imagery (MI) is a method of imagining movement without actual movement, and its use in combination with motor execution (ME) enhances the effects of motor learning. Neurofeedback (NFB) is another method that promotes the effects of MI. This study aimed to investigate the effects of NFB on combined MI and ME (MIME) training in a standing postural control task.

Methods

Sixteen participants were randomly divided into MIME and MIME + NFB groups and performed 10 trials of a postural control task on an unstable board, with nine trials of MI in between. Electroencephalogram was assessed during MI, and the MIME + NFB group received neurofeedback on the degree of MI via auditory stimulation. A postural control task using an unstable board was performed before and after the MIME task, during which postural instability was evaluated.

Results

Postural instability was reduced after the MIME task in both groups. In addition, the root mean square, which indicates the sway of the unstable board, was significantly reduced in the MIME + NFB group compared to that in the MIME group.

Conclusion

Our results indicate that MIME training is effective for motor learning of standing postural control. Furthermore, when MI and ME are combined, the feedback on the degree of MI enhances the learning effect.
Streptococcus pneumoniae nasal carriage patterns with and without common respiratory virus detections in households in Seattle, WA, USA before and during the COVID-19 pandemic
Authors: Bennett Julia C. , Emanuels Anne , Heimonen Jessica , O'Hanlon Jessica , Hughes James P. , Han Peter D. , Chow Eric J. , Ogokeh Constance E. , Rolfes Melissa A. , Lockwood Christine M. , Pfau Brian , Uyeki Timothy M. , Shendure Jay , Hoag Samara , Fay Kairsten , Lee Jover , Sibley Thomas R. , Rogers Julia H. , Starita Lea M. , Englund Janet A. , Chu Helen Y.
Published: July 2023

Background

Respiratory viruses might influence Streptococcus pneumoniae nasal carriage and subsequent disease risk. We estimated the association between common respiratory viruses and semiquantitative S. pneumoniae nasal carriage density in a household setting before and during the COVID-19 pandemic.

Methods

From November 2019–June 2021, we enrolled participants in a remote household surveillance study of respiratory pathogens. Participants submitted weekly reports of acute respiratory illness (ARI) symptoms. Mid-turbinate or anterior nasal swabs were self-collected at enrollment, when ARI occurred, and, in the second year of the study only, from household contacts after SARS-CoV-2 was detected in a household member. Specimens were tested using multiplex reverse-transcription PCR for respiratory pathogens, including S. pneumoniae, rhinovirus, adenovirus, common human coronavirus, influenza A/B virus, respiratory syncytial virus (RSV) A/B, human metapneumovirus, enterovirus, and human parainfluenza virus. We estimated differences in semiquantitative S. pneumoniae nasal carriage density, estimated by the inverse of S. pneumoniae relative cycle threshold (Crt) values, with and without viral detection for any virus and for specific respiratory viruses using linear generalized estimating equations of S. pneumoniae Crt values on virus detection adjusted for age and swab type and accounting for clustering of swabs within households.

Results

We collected 346 swabs from 239 individuals in 151 households that tested positive for S. pneumoniae (n = 157 with and 189 without ≥1 viruses co-detected). Difficulty breathing, cough, and runny nose were more commonly reported among individuals with specimens with viral co-detection compared to without (15%, 80% and 93% vs. 8%, 57%, and 51%, respectively) and ear pain and headache were less commonly reported (3% and 26% vs. 16% and 41%, respectively). For specific viruses among all ages, semiquantitative S. pneumoniae nasal carriage density was greater with viral co-detection for enterovirus, RSV A/B, adenovirus, rhinovirus, and common human coronavirus (P < 0.01 for each). When stratified by age, semiquantitative S. pneumoniae nasal carriage density was significantly greater with viral co-detection among children aged <5 (P = 0.002) and 5–17 years (P = 0.005), but not among adults aged 18–64 years (P = 0.29).

Conclusion

Detection of common respiratory viruses was associated with greater concurrent S. pneumoniae semiquantitative nasal carriage density in a household setting among children, but not adults.