bluuebunny/crossref_metadata_2025 huggingface dataset:
The AU and Disputed Presidential Elections
Authors: Yemisi Omorogbe Eki
Published: May 2022

This chapter considers the response of the African Union (AU) to two types of unconstitutional change: fraudulent electoral practices and the refusal of incumbent presidents to step down from office following electoral defeat. The chapter addresses the AU’s legal and policy framework for intervention on the occurrence of unconstitutional change of government. In addressing these issues, the chapter considers AU response to election crises in Kenya (2007), Zimbabwe (2008), Cote d’Ivoire (2010), and Gambia (2016). With the exception of Gambia, the AU preference is for power sharing. The chapter concludes that the AU is making positive progress but that in each case the AU’s ultimate support for an incumbent undermines any deterrent and regulatory effect which AU law and policy may have. It also concludes that a revision of the definition of unconstitutional change coupled with firmer responses against perpetrators, including through criminal prosecution, would better advance peace, security, democracy, and development in Africa.
Human Rights, Statelessness, and the Right to Nationality (R2N) in Africa: What Can Vertical Structures Achieve?
Authors: Nwankwo Chidebe Matthew
Published: May 2022

Africa contributes a substantial percentage to the global population of stateless people. Groups most affected by statelessness in Africa include descendants of colonial-era migrants, nomadic pastoralists, populations separated by arbitrary colonial borders or affected by nascent states, and internally displaced persons. These groups are further increased by the rise in climate change induced migration and Africa’s continuous ethnic conflicts. These persons are denied the right to nationality by a combination of systematic discrimination through bad policies, weak administrative systems, and laws that effectually provide limited rights based on nationality through jus soli and restrict nationality through jus sanguinis on discriminatory grounds. At national level, laws and policies on the right to nationality are fragmented and discriminatory. This is perhaps a reflection of the colonial origins of citizenship laws in post-colonial African states and a dismissive political attitude to the issue. Regardless of this, there appears to be an appreciation of the danger of statelessness and the need to formulate regional standards to guide national approaches to the right to nationality. This chapter analyses the emerging jurisprudence of African regional courts and argues that the African human rights system offers considerable potential to tackle the problem.
The Contribution of AU Human Rights Agreements to an Emergent AU Law
Authors: Naldi Gino
Published: May 2022

The adoption of the African Charter on Human and Peoples’ Rights has attracted considerable attention, and much negative comment, for its distinctive approach to human rights, with its stress on socio-economic and group rights. Notwithstanding the conventional Western stance that such rights are aspirational and non-justiciable, the African Commission on Human and Peoples’ Rights maintains that parties have assumed obligations under the Charter which are enforceable. The African understanding of human rights is replicated in a number of later treaties on vulnerable groups. Human rights form an integral part of the African Union which its organs are charged to uphold. This chapter will argue that human rights agreements adopted by the AU pave the way for an AU law to emerge based on a body of jurisprudence giving effect to a uniquely African conceptualization of human rights.
Six Concepts of Legality and their Disambiguation
Authors: Yip Ka Lok
Published: May 2022

This chapter performs a conceptual under-labouring by identifying, clarifying and differentiating six concepts of legality under public international law. Three of these concepts can be further categorized as ‘vertical legality’ as they measure the ‘entrenching’ quality of the legal norms across varying depths of permissiveness—Neutral Legality, Negative Legality, and Positive Legality. The other three of these concepts can be further categorized as ‘Horizontal Legality’ as they measure the ‘covering’ quality of the legal norms across different subject areas—Simple Legality, Compounding Legality, and System-wide Legality. The new vocabulary is designed to clearly demarcate the different notions of something being ‘legal’, properly name their differences, and use these differences to precisely locate the roots of disagreement over the legality of use of force against individuals in war.
Verticalizing and Horizontalizing the Notion of ‘Legality’ under International Human Rights Law
Authors: Yip Ka Lok
Published: May 2022

This chapter conducts a systematic analysis of this layered notion of ‘legality’ under IHRL using the various concepts of Vertical Legality and Horizontal Legality developed in the previous chapter and is divided into three substantive sections. The first section illustrates the ‘layered’ nature of the legality requirements embedded in IHRL for the right to life and the right to liberty by surveying their formulation. The second section explores the vertical dimension of these legality requirements and demonstrates the vision for Positive Legality. The third section explores the horizontal dimension of these legal requirements and demonstrates the vision for System-wide Legality.
Agents and Structures in the Field of Via Dolorosa
Authors: Yip Ka Lok
Published: May 2022

This chapter presents a case study on the use of force against individuals in the context of the Israeli–Palestinian conflict, using both archival research and field research conducted in Israel and the occupied West Bank between 2015 and 2016. It is divided into three substantive sections. The first section describes the social structures, understood in a Durkheimian sense of collective consciousness and representations and the morphological facts of society, that influence the use of force in the context of the Israeli–Palestinian conflict. The second section conceptualizes the role of human agency, respectively as a pre-legal notion, a legal construction, and a relative concept to signify greater or lesser degree of human autonomy, in the use of force against individuals in war. Adopting a relative conception of human agency, the third section establishes the relative distinction between structural and agential factors through examining their interaction in different instances of use of force in the Israeli–Palestinian conflict. It demonstrates how the purported convergence of the laws governing these factors leads to a conflation of ontologies in practice.
Repression and Conspiracy
Authors: Najemy John M.
Published: May 2022

Machiavelli believed the 1466 Medici victory made constitutional opposition impossible. With power concentrated in one family’s faction, dissent could manifest itself only through conspiracy. Machiavelli relates two early challenges to Lorenzo: an actual conspiracy in Prato; and a dispute with Volterra (1472) over control of an alum mine. This was not a conspiracy, but Lorenzo, determined to assert unquestioned leadership of the party, decided, against the advice of Medici elder Tommaso Soderini, on a military solution that turned into a sack and massacre. Lorenzo saw plots everywhere and responded with humiliations and insults against the Pazzi and Pope Sixtus, thus provoking the attack that wounded Lorenzo and killed his brother Giuliano. Machiavelli highlights the regime’s confusion of public and private rights and wrongs in Lorenzo’s speech (8.10) in which he claims to be only a private citizen but also that his family “rules” the city by authority of the people’s “unito consenso.” The war that Sixtus and King Ferdinand launched against Lorenzo alone, as they insisted, generated dissatisfaction in Florence. Without authorization, Lorenzo went to Naples and negotiated a separate peace. Because of the rumblings during the war and unhappiness with aspects of the treaty, in 1480 Lorenzo imposed reforms that completed the regime’s seizure of power. Machiavelli emphasizes the regime’s precariousness and its drastic reaction to dissent. The phrase (8.36) about Lorenzo keeping his patria “sempre in festa” paraphrases verses from Juvenal’s tenth satire, and, when read together with passages from Discourses 3.6, hints at his underlying tyrannical ambitions.
(Re)designing the Future
Authors: Geraci Robert M.
Published: May 2022

The conclusion of the book describes how the rise and dissemination of artificial intelligence (AI) and ideas about it produce a certain kind of world. The visions of technology that give strength to AI will bear partial responsibility for what kind of world emerges. So we must think with care about the technological values that are already present or emerging in our time and consider how best to ensure those values are productive. Shared responsibility and shared values can emerge through global collaboration. To build a single vision that accommodates every human culture is inconceivable; nevertheless, to advance AI in clear awareness of the religious and cultural contexts in which we deploy it offers opportunities to use AI to advance human flourishing.
First Report of Pucciniastrum boehmeriae in North America, Causing Rust Disease in Bog Hemp
Authors: Gomez-Zapata Paula A. , Smith Matthew E. , Frank Marc S. , Aime Mary Catherine
Published: May 2022

Bog hemp ( Boehmeria cylindrica) is a perennial herbaceous plant widely distributed across the Americas. In September of 2016, a rust disease was observed on leaves of bog hemp in Florida, U.S.A. The specimen was sent to the Arthur Fungarium at Purdue University for further identification and long-term deposit. Based on morphological characteristics and sequence analysis, the rust species was identified as  Pucciniastrum boehmeriae. To our knowledge, this is the first report of  P. boehmeriae in North America from any host.
Enterobacter cloacae Keratitis: Clinicomicrobiological Profiles, Risk Factors, and Outcomes
Authors: Rajarajan Mugundhan , Madduri Bhagyasree , Mohan Nitin , Fernandes Merle
Published: May 2022

Purpose:

The purpose of the study was to report the clinical features, risk factors, antibiotic susceptibility, and treatment outcomes in a series of Enterobacter cloacae keratitis.

Methods:

A retrospective analysis was performed of the electronic medical records of microbial keratitis caused by E. cloacae identified by the Vitek 2 system (BioMerieux, Craponne, France). We collected data pertaining to demographics, risk factors, ulcer characteristics, antibiogram, visual acuity at presentation and final follow-up, and management outcome. The main outcome measure was resolution of infection. The final visual acuity was the secondary outcome measure.

Results:

Ten episodes of E. cloacae keratitis in 9 patients were identified between January 2009 and December 2019. Nine (90%) cases had undergone penetrating keratoplasty and 8 were failed grafts. Other risk factors included topical steroid use and irregular ocular surface due to epithelial bullae. The mean ulcer size was 17.55 ± 13.99 mm2. More than 80% of isolates were sensitive to chloramphenicol, gentamicin, and colistin. Nine (90%) cases healed on medical management within 56.55 ± 26.74 days (range 9–120 d), although almost all required adjunctive procedures: tissue adhesive application (n = 6) and/or tarsorrhaphy (n = 4). One case with a near total infiltrate had a mixed infection with Kocuria kristinae requiring therapeutic penetrating keratoplasty. One case developed endophthalmitis and phthisis after the corneal infiltrate resolved.

Conclusions:

E. cloacae keratitis is a rare clinical entity seen more often in immunocompromised host conditions such as failed corneal transplants with concomitant topical steroids. Most cases healed with medical management.
Diffuse Synaptophysin Expression in Aggressive Recurrent Castration-Resistant Acinar (Usual) Prostate Cancer: Case Report and Review of Prostatic Neuroendocrine Tumors
Authors: Russell Daniel H. , Mignano Salvatore E.
Published: May 2022

Metastatic or locally advanced prostate cancer in a majority of men recurs within two to three years. The literature contains ample evidence that locally advanced and metastatic prostate cancers are associated with increased neuroendocrine expressing tumor cells, as is castration resistance. Usual (acinar) prostatic adenocarcinoma with neuroendocrine features is a high-grade malignant acinar tumor with neuroendocrine expression, which can be mistaken for neuroendocrine carcinoma, in particular large cell neuroendocrine carcinoma. We present a case of metastatic acinar prostatic adenocarcinoma with neuroendocrine features with strong and diffuse synaptophysin expression, mimicking a metastatic neuroendocrine tumor. We review recognized prostatic neuroendocrine tumors, tumors with neuroendocrine differentiation requiring further investigation, relevant differential considerations, and recommended ancillary workup of challenging cases.
Adenosquamous Carcinoma of the Prostate: A Unique Presentation of a Rare Entity and Review of the Literature
Authors: Long James O. , Moncur Joel T.
Published: May 2022

Adenosquamous carcinoma of the prostate is an exceedingly rare and aggressive histologic variant of prostate cancer, which is composed of glandular and squamous components. Up to two-thirds of these cases are identified in patients with a history of adenocarcinoma after treatment with androgen deprivation therapy or radiation therapy; however, multiple cases have been reported arising de novo. Patients frequently present with obstructive urinary complaints and bony osteolytic metastases. Serum prostate-specific antigen is usually normal or slightly elevated. We describe a rare case of de novo metastatic adenosquamous carcinoma in a patient presenting with a markedly elevated serum prostate-specific antigen and multiple osteoblastic lesions. The prognosis for patients with adenosquamous carcinoma of the prostate has historically been dismal, with death occurring within 12 to 24 months of diagnosis.
Association of PTSD With Longitudinal COVID-19 Burden in a Mixed-Serostatus Cohort of Men and Women: Weathering the Storm
Authors: Jones Deborah L. , Zhang Yuehan , Rodriguez Violeta J. , Haberlen Sabina , Ramirez Catalina , Adimora Adaora A. , Merenstein Daniel , Aouizerat Bradley , Sharma Anjali , Wilson Tracey , Mimiaga Matthew J. , Sheth Anandi N. , Plankey Michael , Cohen Mardge H. , Stosor Valentina , Kempf Mirjam-Colette , Friedman M. Reuel
Published: May 2022

Objectives:

This study of people with HIV (PWH) and those without HIV conducted during the COVID-19 pandemic in the United States in 2020 examines the impact of posttraumatic stress disorder (PTSD) on COVID-19 burden, defined as pandemic-related disruptions.

Methods:

Data consisted of survey responses on PTSD among participants (N = 2434) enrolled in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV (WIHS) cohorts. Unadjusted and adjusted regression models were used to examine the association of PTSD with COVID-19 burden (overall and domain-specific burdens). Quasi-Poisson regression models were used to assess associations with the COVID-19 burden score and 2 domain-specific burdens: (1) changes in resources and (2) interruptions in health care. Analyses was adjusted for age, race/ethnicity, HIV serostatus, current smoking status, number of comorbidities, education, and study regions.

Results:

Study participants were a median age of 58 (interquartile range, 52–65) years. In both bivariate and multivariable models, PTSD severity was associated with greater overall COVID-19 burden. PTSD severity was associated with the number of resource changes and number of interruptions in medical care. These findings were also consistent across cohorts (MACS/WIHS) and across HIV serostatus, suggesting a greater risk for COVID-19 burden with greater PTSD severity, which remained significant after controlling for covariates.

Conclusions:

This study builds on emerging literature demonstrating the impact of mental health on the burden and disruption associated with the COVID-19 pandemic, providing context specific to PWH. The ongoing pandemic requires structural and social interventions to decrease disruption to resources and health resource needs among these vulnerable populations.
JMM Profile: Achromobacter xylosoxidans: the cloak-and-dagger opportunist
Authors: Bonis Benjamin M. , Hunter Ryan C.
Published: May 2022

Achromobacter xylosoxidans

is associated with resilient nosocomial infections, with bacteraemia, pneumonia and chronic cystic fibrosis lung infection being the most common clinical presentations. Innate multi-drug resistance and a suite of virulence factors select for

A. xylosoxidans

infection during long-term antibiotic therapy, contributing to its persistence, treatment recalcitrance, association with poor clinical outcomes and emergence as a problematic pathogen. Horizontal gene transfer and maintenance of large genomes underpin the resilience and cosmopolitan lifestyle of

A. xylosoxidans

, and complicate its phylogenetic characterization.
Optimization of ultrasound-assisted extraction of bioactive
compounds from peony root (Paeonia japonica)
Authors: Park Gwang Deok , Park Jong Jin , Olawuyi Ibukunoluwa Fola , Yun Jun Hyun , Lee So Hyeon , Choi Won Seok , Lee Chang Ho , Lee Won Young
Published: May 2022

Peony root is a medicinal plant containing potent bioactive compounds. This study
used response surface methodology (RSM) to optimize ultrasonic-assisted
extraction (UAE) conditions of antioxidant compounds from peony roots. A central
composite design consisting of extraction temperature (30-70°C), ethanol
concentration (20-100% v/v), and extraction time (15-55 min) was used to
determine the significance of each extraction condition on the total polyphenol,
paeoniflorin, and myricetin contents and
2,2¢-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)- scavenging
activity of the extracts. The ABTS-scavenging activity and myricetin content
increased with an increasing extraction temperature. Further, at low ethanol
concentrations, paeoniflorin and myricetin contents increased. Superimposition
of 4D graphs revealed that an extraction temperature of 60-65°C, ethanol
concentration of 40-50%, and extraction time of 40-50 min were optimal
extraction conditions for peony root. A validation experiment was conducted
using 45% ethanol at 63°C for 45 min. Under these UAE conditions, the
experimental values of total polyphenol, paeoniflorin, and myricetin contents,
and ABTS-scavenging activity were 101.80 mg GAE/g, 46.87 mg/g, 184.30 mg/g, and
23.13%, respectively. The validation experiment revealed slight differences
between the experimental and predicted values (less than 10%), confirming the
optimal UAE conditions for obtaining peony root antioxidant compounds via RSM.
This study provides valuable information in developing functional food,
medicine, and cosmetic using peony root extracts.
The structural basis of long-term potentiation in hippocampal synapses, revealed by EM-imaging of lanthanum-induced synaptic vesicle recycling
Authors: Heuser John E.
Published: May 2022

Hippocampal neurons in tissue-culture were exposed to the trivalent cation lanthanum for short periods (15 to 30 minutes) and prepared for electron microscopy (EM), to evaluate the stimulatory effects of this cation on synaptic ultrastructure. Not only were characteristic ultrastructural changes of exaggerated synaptic vesicle turnover seen within the presynapses of these cultures - - including synaptic vesicle depletion and proliferation of vesicle-recycling structures - - but the overall architecture of a large proportion of the synapses in the cultures was dramatically altered, due to large postsynaptic ‘bulges’ or herniations into the presynapses. Moreover, in most cases these postsynaptic herniations or protrusions produced by lanthanum were seen by EM to distort or break or ‘perforate’ the so-called postsynaptic densities (PSD’s) that harbor receptors and recognition-molecules essential for synaptic function. These dramatic EM-observations lead us to postulate that such PSD-breakages or ‘perforations’ could very possibly create essential substrates or ‘tags’ for synaptic growth, simply by creating fragmented free-edges around the PSD’s, into which new receptors and recognition-molecules could be recruited more easily, and thus they could represent the physical substrate for the important synaptic-growth process known as “long-term potentiation” (LTP). All of this was created simply in hippocampal tissue-cultures, and simply by pushing synaptic vesicle recycling way beyond its normal limits with the trivalent cation lanthanum; but we argue in this report that such fundamental changes in synaptic architecture - - given that they can occur at all - - could also occur at the extremes of normal neuronal activity, which are presumed to lead to learning and memory.
A Computational Theory of Learning Flexible Reward-Seeking Behavior with Place Cells
Authors: Gao Yuanxiang
Published: May 2022

An important open question in computational neuroscience is how various spatially tuned neurons, such as place cells, are used to support the learning of reward-seeking behavior of an animal. Existing computational models either lack biological plausibility or fall short of behavioral flexibility when environments change. In this paper, we propose a computational theory that achieves behavioral flexibility with better biological plausibility. We first train a mixture of Gaussian distributions to model the ensemble of firing fields of place cells. Then we propose a Hebbian-like rule to learn the synaptic strength matrix among place cells. This matrix is interpreted as the transition rate matrix of a continuous time Markov chain to generate the sequential replay of place cells. During replay, the synaptic strengths from place cells to medium spiny neurons (MSN) are learned by a temporal-difference like rule to store place-reward associations. After replay, the activation of MSN will ramp up when an animal approaches the rewarding place, so the animal can move along the direction where the MSN activation is increasing to find the rewarding place. We implement our theory into a high-fidelity virtual rat in the MuJoCo physics simulator. In a complex maze, the rat shows significantly better learning efficiency and behavioral flexibility than a rat that implements a neuroscience-inspired reinforcement learning algorithm, deep Q-network.
Anticodon Table of the Chloroplast Genome and Identification of Putative Quadruplet Anticodons in Chloroplast tRNAs
Authors: Mohanta Tapan Kumar , Mohanta Yugal Kishore , Al-Harrasi Ahmed , Sharma Nanaocha
Published: May 2022

The chloroplast genome of 5959 species was analyzed to construct the anticodon table of the chloroplast genome. Analysis of the chloroplast transfer ribonucleic acid (tRNA) revealed the presence of a putative quadruplet anticodon containing tRNAs in the chloroplast genome. The tRNAs with putative quadruplet anticodons were UAUG, UGGG, AUAA, GCUA, and GUUA, where the GUUA anticodon putatively encoded tRNAAsn. The study also revealed the complete absence of tRNA genes containing ACU, CUG, GCG, CUC, CCC, and CGG anticodons in the chloroplast genome from the species studied so far. The chloroplast genome was also found to encode tRNAs encoding N-formylmethionine (fMet), Ile2, selenocysteine, and pyrrolysine. The chloroplast genomes of mycoparasitic and heterotrophic plants have had heavy losses of tRNA genes. Furthermore, the chloroplast genome was also found to encode putative spacer tRNA, tRNA fragments (tRFs), tRNA-derived, stress-induced RNA (tiRNAs), and group I introns. An evolutionary analysis revealed that chloroplast tRNAs had evolved via multiple common ancestors and the GC% had more influence toward encoding the tRNA number in the chloroplast genome compared to the genome size.
Changes in prefrontal GABA and glutamate through adolescence supports excitation/inhibition balance
Authors: Perica Maria I. , Calabro Finnegan J. , Larsen Bart , Foran Will , Yushmanov Victor E. , Hetherington Hoby , Tervo-Clemmens Brenden , Moon Chan-Hong , Luna Beatriz
Published: May 2022

Animal and human postmortem studies provide evidence for changes in gamma-aminobutyric acid (GABA) and glutamate in prefrontal cortex (PFC) during adolescence, suggesting shifts in excitation and inhibition balance consistent with critical period plasticity. However, how GABA and glutamate change through adolescence and how the balance of these inhibitory and excitatory neurotransmitters changes is not well understood in vivo in humans. High field (7 Tesla) Magnetic Resonance Spectroscopic Imaging was used to investigate age-related changes in the balance of GABA/creatine (Cr) and glutamate/Cr in multiple developmentally-relevant regions of PFC in 144 10 to 30-year-olds. Results indicated a homogenous pattern of age-related Glu/Cr decreases across PFC regions, while age-related changes in GABA/Cr were heterogenous, with a mix of stable and decreasing age effects. Importantly, balance between glutamate/Cr and GABA/Cr in areas of prefrontal cortex increased through adolescence, suggesting the presence of critical period plasticity in PFC at this significant time of development when adult trajectories are established.
Heme-deficient metabolism and impaired cellular differentiation as an evolutionary trade-off for human infectivity in Trypanosoma brucei gambiense
Authors: Horáková Eva , Lecordier Laurence , Cunha Paula , Sobotka Roman , Changmai Piya , Langedijk Catharina J. M. , Van Den Abbeele Jan , Vanhollebeke Benoit , Lukeš Julius
Published: May 2022

Resistance to African trypanosomes in humans relies in part on the high affinity targeting of a trypanosome lytic factor 1 (TLF1) to a trypanosome haptoglobin-hemoglobin receptor (HpHbR). While TLF1 avoidance by the inactivation of HpHbR contributes to Trypanosoma brucei gambiense human infectivity, the evolutionary trade-off of this adaptation is unknown, as the physiological function of the receptor remains to be elucidated. Here we show that uptake of hemoglobin via HpHbR constitutes the sole heme import pathway in the trypanosome bloodstream stage. T. b. gambiense strains carrying the inactivating mutation in HpHbR, as well as genetically engineered T. b. brucei HpHbR knock-out lines show only trace levels of intracellular heme and lack hemoprotein-based enzymatic activities, thereby providing an uncommon example of aerobic parasitic proliferation in the absence of heme. We further show that HpHbR facilitates the developmental progression from proliferating long slender forms to cell cycle-arrested stumpy forms in T. b. brucei. Accordingly, T. b. gambiense was found to be poorly competent for slender-to-stumpy differentiation unless a functional HpHbR receptor derived from T. b. brucei was genetically restored. Altogether, we identify heme-deficient metabolism and disrupted cellular differentiation as two distinct HpHbR-dependent evolutionary trade-offs for T. b. gambiense human infectivity.
ABL1 Kinase plays an important role in spontaneous and chemotherapy-induced genomic instability in multiple myeloma
Authors: Kumar Subodh , Talluri Srikanth , Zhao Jiangning , Liao Chengcheng , Potluri Lakshmi B. , Buon Leutz , Mu Shidai , Shi Jialan , Chakraborty Chandraditya , Tai Yu-Tzu , Samur Mehmet K. , Shammas Masood A. , Munshi Nikhil C.
Published: May 2022

Genomic instability contributes to cancer progression and is at least partly due to dysregulated homologous recombination. Here, we show that an elevated level of ABL1 kinase overactivates the HR pathway and causes genomic instability in multiple myeloma (MM) cells. Inhibiting ABL1 with either shRNA or a pharmacological inhibitor (nilotinib) inhibits HR activity, reduces genomic instability, and slows MM cell growth. Moreover, inhibiting ABL1 rescues the HR dysregulation and genomic instability caused by melphalan, a chemotherapeutic agent used in MM treatment, and increases melphalan’s efficacy and cytotoxicity in vivo in a subcutaneous tumor model. In these tumors, nilotinib inhibits endogenous as well as melphalan-induced HR activity. These data demonstrate that inhibiting ABL1 using the clinically approved drug nilotinib reduces MM cell growth, promotes genome stability, increases the cytotoxicity of melphalan (and similar chemotherapeutic agents), and can potentially prevent or delay progression in MM patients.
Blockade of TGF-β signaling reactivates HIV-1/SIV reservoirs and immune responsesin vivo
Authors: Samer S , Thomas Y , Araínga M , Carter CM , Shirreff LM , Arif MS , Avita JM , Frank I , McRaven M , Thuruthiyil CT , Heybeli V , Anderson MR , Owen B , Gaisin A , Bose D , Simons LM , Hultquist JF , Arthos J , Cicala C , Sereti I , Santangelo P , Lorenzo-Redondo R , Hope TJ , Villinger FJ , Martinelli E
Published: May 2022

Elevated levels of TGF-β, a potent immunosuppressive factor, are present in HIV-1 infected individuals even after years of antiretroviral therapy (ART). TGF-β plays a critical role in maintaining immune cells in a resting state by inhibiting cell activation and proliferation. Resting HIV-1 target cells represent one of the main cellular reservoirs after long term ART and the low inducibility of the latent provirus constitutes one of the major obstacles to “kick and kill” cure strategies. We hypothesized that releasing cells from TGF-β-driven signaling would promote latency reversal. To test our hypothesis, we comparedex vivomodels of HIV-1 latency reactivation with and without TGF-β and a TGF-β type 1 receptor (TGFBR1) inhibitor, galunisertib. We also tested the effect of galunisertib in SIV infected, ART treated macaques by monitoring SIV envelope (env) protein expression via PET/CT using the Cu64-anti gp120 Fab (7D3) probe, along with plasma and tissue viral loads (VL). Exogenous TGF-1β reduced HIV-1 reactivation in U1 and ACH2 latency models. Galunisertib increased HIV-1 latency reversal both inex vivomodels and in PBMC from HIV-1 infected, cART treated aviremic donors.In vivo, oral galunisertib promoted increased SIV env protein total standardized uptake values (SUVtot) in PET/CT images of tissues (gut and lymph nodes) of 5 out of 7 aviremic, long-term ART-treated, SIV-infected, macaques. This increase correlated with an increase in SIV RNA in gut tissue. Two out of 7 animals also exhibited increases in plasma viral load. Higher anti-SIV T cell responses and anti-SIV env antibody titers were detected after galunisertib treatment in most animals. In summary, our data suggest that blocking TGF-β signaling simultaneously increases retroviral reactivation events and enhances anti-SIV immune responses.
Predicting the HER2 status in esophageal cancer from tissue microarrays using convolutional neural networks
Authors: Pisula Juan I. , Datta Rabi R. , Börner Valdez Leandra , Avemarg Jan-Robert , Jung Jin-On , Plum Patrick , Löser Heike , Lohneis Philipp , Meuschke Monique , dos Santos Daniel Pinto , Gebauer Florian , Quaas Alexander , Bruns Christiane J. , Walch Axel , Lawonn Kai , Popp Felix C. , Bozek Katarzyna
Published: May 2022

Background

Fast and accurate diagnostics are key for personalized medicine. Particularly in cancer, precise diagnosis is a prerequisite for targeted therapies which can prolong lives. In this work we focus on the automatic identification of gastroesophageal adenocarcinoma (GEA) patients that qualify for a personalized therapy targeting epidermal growth factor receptor 2 (HER2). We present a deep learning method for scoring microscopy images of GEA for the presence of HER2 overexpression.

Methods

Our method is based on convolutional neural networks (CNNs) trained on a rich dataset of 1,602 patient samples and tested on an independent set of 307 patient samples. We incorporated an attention mechanism in the CNN architecture to identify the tissue regions in these patient cases which the network has detected as important for the prediction outcome. Our solution allows for direct automated detection of HER2 in immunohistochemistry-stained tissue slides without the need for manual assessment and additional costly in situ hybridization (ISH) tests.

Results

We show accuracy of 0.94, precision of 0.97, and recall of 0.95. Importantly, our approach offers accurate predictions in cases that pathologists cannot resolve, requiring additional ISH testing. We confirmed our findings in an independent dataset collected in a different clinical center.

Conclusions

We demonstrate that our approach not only automates an important diagnostic process for GEA patients but also paves the way for the discovery of new morphological features that were previously unknown for GEA pathology.
Modelling human and non-human animal network data in R using STRAND
Authors: Ross Cody T. , McElreath Richard , Redhead Daniel
Published: May 2022

There have been recent calls for wider application of generative modelling approaches in applied social network analysis. These calls have been motivated by the limitations of contemporary empirical frameworks, which have generally relied on post hoc permutation methods that do not actively account for interdependence in network data. At present, however, it remains difficult for typical end-users—e.g., field researchers—to apply generative network models, as there is a dearth of openly available software packages that make application of such methods as simple as other, permutation-based methods.

Here, we outline the STRAND R package, which provides a suite of generative models for Bayesian analysis of human and non-human animal social network data that can be implemented using simple, base R syntax.

To facilitate ease-of-use, we provide a tutorial demonstrating how STRAND can be used to model binary, count, or proportion data using stochastic blockmodels, social relations models, or a combination of the two modelling frameworks.
Borrelia burgdorferiengages mammalian type I interferon responses via the cGAS-STING pathway
Authors: Farris Lauren C. , Torres-Odio Sylvia , Adams L. Garry , West A. Phillip , Hyde Jenny A.
Published: May 2022

Borrelia burgdorferi, the etiologic agent of Lyme disease, is a spirochete that modulates numerous host pathways to cause a chronic, multi-system inflammatory disease in humans.B. burgdorferiinfection can lead to Lyme carditis, neurologic complications, and arthritis, due to the ability of specific borrelial strains to disseminate, invade, and drive inflammation.B. burgdorferielicits type I interferon (IFN-I) responses in mammalian cells and tissues that are associated with the development of severe arthritis or other Lyme-related complications. However, the innate immune sensors and signaling pathways controlling IFN-I induction remain unclear. In this study, we examined whether intracellular nucleic acid sensing is required for the induction of IFN-I toB. burgdorferi. Using fluorescence microscopy, we show thatB. burgdorferiassociates with mouse and human cells in culture and we document that internalized spirochetes co-localize with the pattern recognition receptor cyclic GMP-AMP synthase (cGAS). Moreover, we report that IFN-I responses in mouse macrophages and murine embryonic fibroblasts are significantly attenuated in the absence cGAS or its adaptor Stimulator of Interferon Genes (STING), which function to sense and respond to intracellular DNA. Longitudinal in vivo tracking of bioluminescentB. burgdorferirevealed similar dissemination kinetics and borrelial load in C57BL/6J wild-type, cGAS-deficient, or STING-deficient mice. However, infection-associated tibiotarsal joint pathology and inflammation were modestly reduced in cGAS-deficient compared to wild-type mice. Collectively, these results indicate that the cGAS-STING pathway is a critical mediator of mammalian IFN-I signaling and innate immune responses toB. burgdorferi.

KEY POINTS

B. burgdorferitriggers type I interferon responses in macrophages and fibroblasts

Coiled spirochetes are observed in the cytosol and co-localize with cGAS

cGAS and STING mediateB. burgdorferi-induced type I interferon responses
An atrial fibrillation-associated regulatory region modulates cardiac Tbx5 levels and arrhythmia susceptibility
Authors: Bosada Fernanda M. , van Duijvenboden Karel , Rivaud Mathilde R. , Uhm Jae-Sun , Verkerk Arie O. , Boukens Bastiaan J. , Christoffels Vincent M.
Published: May 2022

Heart development and rhythm control are highly Tbx5 dosage-sensitive. TBX5 haploinsufficiency causes congenital conduction disorders, whereas increased expression levels of TBX5 in human heart samples has been associated with atrial fibrillation. We deleted the conserved mouse orthologues of two independent AF-associated genomic regions in the Tbx5 locus, one intronic (RE(int)-/-) and one downstream of Tbx5 (RE(down)-/-). In both lines we observed a modest (30%) increase of Tbx5 in the postnatal atria. To gain insight into the effects of slight dosage increase in vivo, we investigated the atrial transcriptional, epigenetic and electrophysiological properties of both lines. We observed induction of genes involved in development, ion transport and conduction, increased action potential duration and increased susceptibility to atrial arrhythmias. We identified an AF-associated variant in the human intronic regulatory region that increases transcriptional activity. Expression of the AF-associated transcription factor Prrx1 was induced in RE(int)-/- cardiomyocytes. We found that some of the transcriptional and functional changes in the atria caused by increased Tbx5 expression were normalized when reducing cardiac Prrx1 expression in RE(int)-/- mice, indicating an interaction between these two AF genes. We conclude that modest increases in expression of dose-dependent transcription factors, caused by common regulatory variants, significantly impact on the cardiac gene regulatory network and disease susceptibility.
KDM4A promotes the progression of neuroendocrine prostate cancer
Authors: Mak Celia Sze Ling , Zhu Ming , Liang Xin , Wang Feng , Yuan Fei , Hoang Anh G , Song Xingzhi , Shepherd Peter , Liang Derek , Suh Jessica , Pradhan Bijeta , Park Jiwon , Zhang Miao , Metzger Eric , Schüle Roland , Jain Abhinav K. , Karasik Ellen , Foster Barbara A. , Lee Min Gyu , Corn Paul , Logothetis Christopher J. , Aparicio Ana , Navone Nora , Troncoso Patricia , Tan Zhi , Zhang Jianhua , Lin Sue-Hwa , Wang Guocan
Published: May 2022

Neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of prostate cancer (PCa) and lacks life-prolonging treatment. The incidence of NEPC is increased due to the widespread use of AR pathway inhibitors (ARPIs) in the treatment of non-metastatic CRPC and hormone-sensitive metastatic tumors. Here, we identified histone lysine demethylase KDM4A as a key player in NEPC progression and an effective therapeutic target. We found that KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Knockdown (KD) or knockout (KO) ofKDM4Ain NEPC cell lines suppressed cancer cell growthin vitroandin vivo. Mechanistically, we found that KDM4A promotes NEPC progression, in part, through direct transcriptional regulation ofMYC. We showed thatMYCis hyper-activated in human and mouse NEPC.KDM4AKD led to suppression of MYC signaling.MYCKD or inhibition profoundly suppressed NEPC cell proliferation. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduced NEPC cell growthin vitroandin vivo. Taken together, we demonstrated that KDM4A is an important regulator of NEPC progression and targeting KDM4A may potentially be an effective therapeutic strategy for NEPC.

Significance

Neuroendocrine prostate cancer (NEPC) is a highly aggressive prostate cancer subtype that is resistant to potent androgen receptor pathway inhibitors (ARPIs) and currently lacks effective therapeutic options. Histone lysine demethylase KDM4A is an important epigenetic regulator of gene expression in development and cancer. In this study, we show that KDM4A is highly expressed in NEPC and is required for NEPC proliferation, anchorage-independent growth, andin vivogrowth, which is in part mediated through the regulation of MYC expression. Importantly, we demonstrate that inhibition of KDM4A significantly impairs NEPC growth in preclinical models. Thus, our findings provide valuable insights into the molecular mechanisms underlying NEPC progression and offer a rationale for clinical trials with KDM4 inhibitor in NEPC patients.
Human Surfactant Protein D Facilitates SARS-CoV-2 Pseudotype Binding and Entry in DC-SIGN Expressing Cells, and Downregulates Spike protein Induced Inflammation
Authors: Beirag Nazar , Kumar Chandan , Madan Taruna , Shamji Mohamed H. , Bulla Roberta , Mitchell Daniel , Murugaiah Valarmathy , Neto Martin Mayora , Temperton Nigel , Idicula-Thomas Susan , Varghese Praveen M , Kishore Uday
Published: May 2022

Pattern recognition receptors are crucial for innate anti-viral immunity, including C-type lectin receptors. Two such examples are Lung surfactant protein D (SP-D) and Dendritic cell-specific intercellular adhesion molecules-3 grabbing non-integrin (DC-SIGN) which are soluble and membrane-bound C-type lectin receptors, respectively. SP-D has a crucial immune function in detecting and clearing pulmonary pathogens; DC-SIGN is involved in facilitating dendritic cell interaction as an antigen-presenting cell with naïve T cells to mount an anti-viral immune response. Both SP-D and DC-SIGN have been shown to interact with various viruses, including HIV-1, Influenza A virus and SARS-CoV-2. SARS-CoV-2 is an enveloped RNA virus that causes COVID-19. A recombinant fragment of human SP-D (rfhSP-D) comprising of α-helical neck region, carbohydrate recognition domain, and eight N-terminal Gly-X-Y repeats has been shown to bind SARS-CoV-2 Spike protein and inhibit SARS-CoV-2 replication by preventing viral entry in Vero cells and HEK293T cells expressing ACE2. DC-SIGN has also been shown to act as a cell surface receptor for SARS-CoV-2 independent of ACE2. Since rfhSP-D is known to interact with SARS-CoV-2 Spike protein and DC-SIGN, this study was aimed at investigating the potential of rfhSP-D in modulating SARS-CoV-2 infection. Coincubation of rfhSP-D with Spike protein improved the Spike Protein: DC-SIGN interaction. Molecular dynamic studies revealed that rfhSP-D stabilised the interaction between DC-SIGN and Spike protein. Cell binding analysis with DC-SIGN expressing HEK 293T and THP-1 cells and rfhSP-D treated SARS-CoV-2 Spike pseudotypes confirmed the increased binding. Furthermore, infection assays using the pseudotypes revealed their increased uptake by DC-SIGN expressing cells. The immunomodulatory effect of rfhSP-D on the DC-SIGN: Spike protein interaction on DC-SIGN expressing epithelial and macrophage-like cell lines was also assessed by measuring the mRNA expression of cytokines and chemokines. The RT-qPCR analysis showed that rfhSP-D treatment downregulated the mRNA expression levels of pro-inflammatory cytokines and chemokines such as TNF-α, IFN-α, IL-1β, IL-6, IL-8, and RANTES (as well as NF-κB) in DC-SIGN expressing cells challenged by Spike protein. Furthermore, rfhSP-D treatment was found to downregulate the mRNA levels of MHC class II in DC expressing THP-1 when compared to the untreated controls. We conclude that rfhSP-D helps stabilise the interaction of SARS-CoV-2 Spike protein and DC-SIGN and increases viral uptake by macrophages via DC-SIGN, suggesting an additional role for rfhSP-D in SARS-CoV-2 infection.
Sensorimotor decisions rely on the entanglement of evidence and motor accumulation processes
Authors: Verdonck Stijn , Loossens Tim , Philiastides Marios G.
Published: May 2022

Most contemporary theories of sensorimotor decision-making formalize the process leading up to a decision as a gradual accumulation of noisy stimulus information over time. The resulting evidence signal is thought to be continuously tested against an internal criterion representing the amount of evidence required to make the decision. In the currently prevailing view, the amount of accumulated evidence required for a decision is independent of the amount of sensory evidence presented by the stimulus, and once that level is reached, a choice is categorically communicated to the motor system to execute an overt response. Recent experimental research casts doubts on both of these assumptions. Using a Leaky Integrating Threshold model, we relax these assumptions specifying both an evidence accumulation and a motor accumulation process. The evidence accumulation signal feeds into a leaky motor accumulator, and it is on the level of the motor accumulation that the final decision criterion is set. This adaptation results in a markedly better description of choice-RT data, especially when it comes to urgency manipulations. We show that this alternative theory, which proposes that sensory evidence is doubly integrated before final evaluation, does not only describe the behavioral data better, but its neural correlates can also be readily derived from EEG signatures involving systems of both evidence and motor accumulation.
Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy
Authors: Bhatia Vipul , Kamat Nikhil V. , Pariva Tiffany E. , Wu Li-Ting , Tsao Annabelle , Sasaki Koichi , Wiest Lauren T. , Zhang Ailin , Rudoy Dmytro , Gulati Roman , Patel Radhika A. , Roudier Martine P. , True Lawrence D. , Haffner Michael C. , Nelson Peter S. , Priceman Saul J. , Ishihara Jun , Lee John K.
Published: May 2022

Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. We identified broad expression of STEAP1 (87% positive) in lethal metastatic prostate cancer, even more so than prostate-specific membrane antigen (PSMA, 60% positive) which is a clinically established diagnostic and therapeutic target. Second-generation chimeric antigen receptor (CAR) T cells were engineered for reactivity against STEAP1 and demonstrated substantial antitumor activity in metastatic human prostate cancer models in immunodeficient mice. Adoptive transfer of STEAP1 CAR T cells was associated with prolonged peripheral persistence and either disease eradication or substantial tumor growth inhibition with progressive disease demonstrating antigen loss. As STEAP1 CAR T cells were also highly active in antigen density conditions as low as ∼1,500 molecules/cell, we generated a human STEAP1 (hSTEAP1) knock-in (KI) mouse to evaluate the potential for on-target off-tumor toxicities. hSTEAP1-KI mice demonstrated a pattern of systemic hSTEAP1 expression akin to that observed in humans with the greatest expression found in the prostate gland. Mouse-in-mouse studies of STEAP1 CAR T cell therapy in immunocompetent hSTEAP1-KI mice engrafted with disseminated mouse prostate cancer showed preliminary safety without evidence of gross toxicity, cytokine storm, or architectural disruption and increased T cell infiltration at sites of systemic hSTEAP1 expression. Tumor responses and extension of survival were appreciated but antigen loss was identified in recurrent and progressive disease. In summary, we report the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, the generation of a STEAP1 CAR T cell therapy with promising potency and safety in preclinical studies of advanced prostate cancer, and antigen escape as a mechanism of resistance to effective STEAP1 CAR T cell therapy.