bluuebunny/crossref_metadata_2025 huggingface dataset:
The Plantation's Outsides: The Work of Settlement in Kalimpong, India
Authors: Besky Sarah
Published: March 2021

While the colonial and contemporary economy of Bengal's Himalayan foothills is most often associated with the tea plantations of Darjeeling and the Dooars, the small farms of nearby Kalimpong were also a key space in which colonial agents and missionaries worked to “settle” the mountainous terrain. Focused on Kalimpong, this article traces the trajectory of one technology of settlement, agricultural extension, from the late 1880s to the early 1940s. It highlights agricultural extension's racialized and gendered politics, as well as its implication in a long-term project that merged material (i.e., food) provision with social reproduction (i.e., childrearing, kin-making). Agricultural extension created a patchwork of relatively biodiverse small farms that historical and contemporary accounts describe as a “green belt”: a socio-ecological outside to the plantation monocultures that dominate the hills. British governors attempted to use non-plantation space for multiple ends. In this sense, their work might be termed “biopolitical,” in that it was geared toward supporting and amplifying the life chances of certain human bodies and certain botanical species. Through a series of experiments, colonial agents made calculated choices about which of these forms of life should be made to flourish, and which might be allowed to perish. Importantly, settlement, as a set of intertwined projects, did not unfold in a coherent or deliberately sequential manner. Settlement was, and continues to be, a sedimentary process.
Of Fistulas, Sutures, and Silences
Authors: Baron Beth
Published: March 2021

Upon arrival at the Qasr al-ʿAyni Hospital in Cairo in 1908, a woman from a village in Qena province in Upper Egypt related her harrowing medical saga. It began when she developed a urinary fistula (nāsur bawlī) due to prolonged labor (a urinary fistula causes urine to leak from the bladder into the vagina, resulting in deep discomfort and social ostracism of those afflicted). She had gone to a hospital in the city of Qena, capital of the province with the same name, but medical officers there sent her to Asyut. There, in the government hospital, she underwent three operations without success, whereupon doctors instructed her to go to Qasr al-ʿAyni Hospital in Cairo to see Dr. Nagib Mahfuz (1882–1974), who had developed a reputation for his surgical prowess in treating fistulas. The woman from Qena traveled by foot, begging along the way, until, exhausted, she reached the city of Minya, halfway between Asyut and Bani Suwayf. There she was sent once again to the government hospital, examined, and once again told to go to Qasr al-ʿAyni.
A new record of a cryptogenic Dipolydora species (Annelida: Spionidae) in South Africa
Authors: David Andrew A. , Williams Jason D. , Simon Carol A.
Published: March 2021

In this study we report a new record of a cryptogenic polychaete from southern Africa. The species was found inhabiting sand tubes in intertidal sand flats in the Knysna Estuary on the southern coast of South Africa. Morphological comparisons using light and scanning electron microscopy showed extensive taxonomic similarities with Dipolydora socialis described from other localities and from museum vouchers. In addition, 18S rRNA and COI barcodes were generated for the species. Genetic analysis of the assembled polydorid dataset corroborated the morphological data in delineating the species as a taxonomic unit with >99% genetic similarity to available sequences of D. socialis in the GenBank database. Dipolydora socialis has been reported as having a widespread distribution, and since it can reside within tubes associated with fouling communities or as a shell borer, several vectors may have been responsible for its global spread and introduction to southern Africa. Finally, considering the many cryptic complexes that are currently being uncovered within polychaetes, including spionids, future taxonomic studies should incorporate additional genetic data from other regions of the world to determine whether D. socialis may also be part of a larger species complex.
Vitamin D sufficiency attenuates the effect of early social adversity on child antisocial behavior
Authors: Choy Olivia , Raine Adrian
Published: March 2021

Background

Vitamin D insufficiency and child antisocial behavior are public health concerns. It is unknown whether vitamin D plays a role in antisocial outcomes. This study examines whether higher levels of vitamin D can act as a protective factor against antisocial behavior for children who are exposed to early social adversity.

Methods

In a community sample of 300 children aged 11–12 years (151 females, 149 males), serum concentrations of 25-hydroxyvitamin D [25(OH)D] were assessed alongside early social adversity, and both parent and child-reported antisocial behavior.

Results

Vitamin D moderated the association between early social adversity and multiple antisocial outcomes. Higher social adversity was associated with greater antisocial behavior among vitamin D-insufficient [25(OH)D < 30 ng/mL], but not vitamin D-sufficient children [25(OH)D ⩾ 30 ng/mL], after adjusting for other variables. Results from child reports of antisocial behavior were replicated with parent reports, providing support for the robustness of the findings. At serum 25(OH)D concentrations above 27.16–30.69 ng/mL (close to 30 ng/mL, the recommended optimal vitamin D level for pediatric populations), the effect of social adversity on antisocial behavior outcomes was nullified.

Conclusions

To our knowledge, this study is the first to document that a nutritional factor, vitamin D, can potentially confer resilience to antisocial behavior. Our findings in a pediatric population suggest a possible role of vitamin D supplementation in interventions to reduce antisocial behavior, which may be further investigated in future randomized controlled trials.
Effect of sex and dyad composition on speech and gesture development of singleton and twin children
Authors: OZTURK Sumeyra , PINAR Ebru , KETREZ F. Nihan , ÖZÇALIŞKAN Şeyda
Published: March 2021

Children's early vocabulary shows sex differences – with boys having smaller vocabularies than age-comparable girls – a pattern that becomes evident in both singletons and twins. Twins also use fewer words than their singleton peers. However, we know relatively less about sex differences in early gesturing in singletons or twins, and also how singletons and twins might differ in their early gesture use. We examine the patterns of speech and gesture production of singleton and twin children, ages 0;10-to-3;4, during structured parent-child play. Boys and girls – singleton or twin – were similar in speech and gesture production, but singletons used a greater amount and diversity of speech and gestures than twins. There was no effect of twin dyad type (boy-boy, girl-girl, boy-girl) on either speech or gesture production. These results confirm earlier research showing close integration between gesture and speech in singletons in early language development, and further extend these patterns to twin children.
Heartbeats, Burdens, and Biofixtures
Authors: GIPE KELSEY
Published: March 2021

This paper addresses a dichotomy in the attitudes of some clinicians and bioethicists regarding whether there is a moral difference between deactivating a cardiac pacemaker in a highly dependent patient at the end of life, as opposed to standard cases of withdrawal of treatment. Although many clinicians hold that there is a difference, some bioethicists maintain that the two sorts of cases are morally equivalent. The author explores one potential morally significant point of difference between pacemakers and certain other life-sustaining treatments: specifically, that the former are biofixtures, which become part of the patient in a way that the latter do not. The concept of the pacemaker as biofixture grants pacemakers a unique moral status that gives reason to treat a pacemaker the same as other parts of the patient that are necessary to sustain life. The author employs this biofixture analysis to affirm the intuition that deactivating a pacemaker in a highly dependent patient at the end of life is, in moral terms, more analogous to active euthanasia than it is to standard cases of withdrawal of treatment. The paper concludes with consideration of potential implications for further implantable medical technologies, such as ventricular assist devices and total artificial hearts.
A Future for Migrants with Acute Heart Problems Seeking Asylum?
Authors: HERMERÉN GÖRAN
Published: March 2021

This paper discusses the future of migrants with acute heart problems and without permanent permission to remain in the country where they are seeking asylum. What does the country they have traveled to owe them? Specifically, what healthcare services are they entitled to? This may seem a niche problem, but numbers of migrants with acute heart problems could increase in the future. Besides, similar problems could be raised by, for instance, traumatized migrants with acute needs for healthcare services for other serious conditions. The paper identifies the issues and some positions on them. Arguments for and against these positions are explored. This particular set of problems in healthcare ethics creates several challenges, at both national and international levels, concerning access to transplantation, public willingness to donate organs, optimal use of organs, justice and fairness, and potential conflicts of law, politics and ethics, as well as issues revolving around interaction and communication (or lack of it) between agencies and professions.
School food offer at lunchtime: assessing the validity and reliability of a web-based questionnaire
Authors: Morin Pascale , Boulanger Amélie , Landry Myriam , Lebel Alexandre , Gagnon Pierre
Published: March 2021

Objectives:

To develop and validate a web-based self-diagnostic questionnaire on school food service offer aimed at food service managers (FSM) by: (i) identifying relevant indicators of school food offer, developing a questionnaire and validating the concept using an expert panel; (ii) validating the questions by comparing the FSM’s responses with observations by dietitians and (iii) undergoing a qualitative evaluation of the tool through direct observation and short interviews.

Design:

Mixed methods.

Setting:

Quebec, Canada.

Participants:

Nine experts validated the theoretical constructs and indicators on which the questionnaire was based. Inter-rater reliability tests were conducted with thirty-nine FSM, who then participated in interviews about platform functionality satisfaction. Twenty school stakeholders participated in the survey pertaining to their use of the personalised report.

Results:

The questionnaire focused on the main school food service’s lunchtime offer and comprised twenty-six questions. The overall strength of agreement was good, and all questions’ strengths of agreement were fair to excellent except for one question. Qualitative data reached saturation and showed that navigation through the questionnaire was fluid. Improvements were suggested to increase user-friendliness and simplicity of both the platform and questionnaire. Results from the survey showed that all respondents were either satisfied or very satisfied with their personalised report.

Conclusions:

We successfully developed and validated a web-based self-diagnostic questionnaire. The final version facilitates knowledge mobilisation with school stakeholders and offers a new opportunity for the assessment and surveillance of school food offer.
Strengthening health system building blocks: configuring post-COVID-19 scenario in Pakistan
Authors: Shaikh Babar Tasneem
Published: March 2021

Aim:

To gauge the level of preparedness of health system of Pakistan in the wake of Corona Virus Disease 2019 (COVID-19) pandemic.

Background:

The global COVID-19 outbreak and its subsequent repercussions and implications, after being declared as a pandemic by the World Health Organization (WHO), exposed all the inherent, lingering, and acute shortcomings of the health systems in many developing countries and Pakistan was no exception.

Methods:

A detailed literature review was done which included peer-reviewed articles on COVID-19 and health system, published in local and international journals, WHO and World Bank’s publications, and the documents and official reports of the government. Focus was to glean and cite strategies adopted by the developing countries in response to COVID-19 and to see the applicability of those which are feasible for Pakistan.

Findings:

Level of preparedness was minimal and the response to manage the outbreak was weak. Based on toll of the cases and number of deaths, this public health threat turned out to be a catastrophe beyond the controlling authority and capacity of the health system, and hence other sectors and agencies had to be engaged for devising a concerted and integrated response to deal with the emergency. Governance was disorderly, financing was inadequate, human resources were not trained, supplies and logistic were not stocked, information system was patchy, and research capacity was limited, and most of all the service delivery was in a biggest chaos of times. COVID-19 demanded to re-configure the health system of Pakistan.

Conclusion:

Improving the emergency preparedness of the hospitals is the foremost and an urgent need. A strong national public health system in Pakistan is needed to rapidly investigate and analyze the reports, assess the magnitude of the public health risk, share real-time information, and implement public health control measures in a concerted and systematic demeanor.
Active Faults' Geometry in the Gulf of Aqaba, Southern Dead Sea Fault, Illuminated by Multibeam Bathymetric Data
Authors: Ribot Matthieu , Klinger Yann , Jónsson Sigurjón , Avsar Ulas , Pons‐Branchu Edwige , Matrau Rémi , Mallon Francis L.
Published: March 2021

Detailed knowledge of fault geometry is important for accurate seismic hazard assessment. The Gulf of Aqaba, which corresponds to the southern termination of the 1200‐km‐long Dead Sea fault system, remains one of the least known parts of this plate boundary fault, in large part due to its location offshore. Classically, the Gulf of Aqaba has been described as a succession of three pull‐apart basins. Here, building on a new multibeam bathymetric survey of the Gulf of Aqaba, we provide details about the geometry of the faults at the bottom of the gulf that controls its morphology. In particular, we identify a 50‐km‐long fault section that shows evidence of recent activation. We associate this fault section (Aragonese fault) with the main fault section that ruptured during the 1995 magnitude Mw7.3 Nuweiba earthquake. In the southern part of the gulf, bathymetry emphasizes the strike‐slip nature of the Arnona fault, while dip‐slip motion seems to be accommodated mostly by faults located along the eastern edge of the gulf. Considering the simple linear geometry of the Arnona fault and the absence of any large earthquake for several centuries, despite an average slip‐rate of ∼5 mm/yr, this fault should be considered as a significant candidate for an earthquake rupture of magnitude 7 or above in the near future.
Neddylation is required for presynaptic clustering of mGlu7 and maturation of presynaptic terminals
Authors: Kang Minji , Lee DoEun , Song Jae-man , Park Sunha , Park Da-ha , Lee Sanghyeon , Suh Young Ho
Published: March 2021

Neddylation is a posttranslational modification in which NEDD8 is conjugated to a target substrate by cellular processes similar to those involved in ubiquitination. Recent studies have identified PSD-95 and cofilin as substrates for neddylation in the brain and have shown that neddylation modulates the maturation and stability of dendritic spines in developing neurons. However, the precise substrates and functional consequences of neddylation at presynaptic terminals remain elusive. Here, we provide evidence that the mGlu7 receptor is a target of neddylation in heterologous cells and rat primary cultured neurons. We found that mGlu7 neddylation is reduced by agonist treatment and is required for the clustering of mGlu7 in the presynaptic active zone. In addition, we observed that neddylation is not required for the endocytosis of mGlu7, but it facilitates the ubiquitination of mGlu7 and stabilizes mGlu7 protein expression. Finally, we demonstrate that neddylation is necessary for the maturation of excitatory presynaptic terminals, providing a key role for neddylation in synaptic function.
The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development
Authors: Macrae Trisha A. , Ramalho-Santos Miguel
Published: March 2021

Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of this global redistribution of H3K27me3 is poorly understood. Here we report a post-translational mechanism that destabilizes PRC2 to constrict H3K27me3 during lineage commitment. Using an auxin-inducible degron system, we show that the deubiquitinase Usp9x is required for mouse embryonic stem (ES) cell self-renewal. Usp9x-high ES cells have high PRC2 levels and bear a chromatin and transcriptional signature of the pre-implantation embryo, whereas Usp9x-low ES cells resemble the post-implantation, gastrulating epiblast. We show that Usp9x interacts with, deubiquitinates and stabilizes PRC2. Deletion of Usp9x in post-implantation embryos results in the derepression of genes that normally gain H3K27me3 after gastrulation, followed by the appearance of morphological abnormalities at E9.5, pointing to a recurrent link between Usp9x and PRC2 during development. Usp9x is a marker of “stemness” and is mutated in various neurological disorders and cancers. Our results unveil a Usp9x-PRC2 regulatory axis that is critical at peri-implantation and may be redeployed in other stem cell fate transitions and disease states.
Apico-basal cell compression regulates Lamin A/C levels in epithelial tissues
Authors: Iyer K. Venkatesan , Taubenberger Anna , Zeidan Salma Ahmed , Dye Natalie A. , Eaton Suzanne , Jülicher Frank
Published: March 2021

The levels of nuclear protein Lamin A/C are crucial for nuclear mechanotransduction. Lamin A/C levels are known to scale with tissue stiffness and extracellular matrix levels in mesenchymal tissues. But in epithelial tissues, where cells lack a strong interaction with the extracellular matrix, it is unclear how Lamin A/C is regulated. Here, we show in epithelial tissues that Lamin A/C levels scale with apico-basal cell compression, independent of tissue stiffness. Using genetic perturbations in Drosophila epithelial tissues, we show that apico-basal cell compression regulates the levels of Lamin A/C by deforming the nucleus. Further, in mammalian epithelial cells, we show that nuclear deformation regulates Lamin A/C levels by modulating the levels of phosphorylation of Lamin A/C at Serine 22, a target for Lamin A/C degradation. Taken together, our results reveal a mechanism of Lamin A/C regulation which could provide key insights for understanding nuclear mechanotransduction in epithelial tissues.
The box C/D snoRNP assembly factor Bcd1 interacts with the histone chaperone Rtt106 and controls its transcription dependent activity
Authors: Bragantini Benoît , Charron Christophe , Bourguet Maxime , Paul Arnaud , Tiotiu Decebal , Rothé Benjamin , Marty Hélène , Terral Guillaume , Hessmann Steve , Decourty Laurence , Chagot Marie-Eve , Strub Jean-Marc , Massenet Séverine , Bertrand Edouard , Quinternet Marc , Saveanu Cosmin , Cianférani Sarah , Labialle Stéphane , Manival Xavier , Charpentier Bruno
Published: March 2021

Biogenesis of eukaryotic box C/D small nucleolar ribonucleoproteins initiates co-transcriptionally and requires the action of the assembly machinery including the Hsp90/R2TP complex, the Rsa1p:Hit1p heterodimer and the Bcd1 protein. We present genetic interactions between the Rsa1p-encoding gene and genes involved in chromatin organization includingRTT106that codes for the H3-H4 histone chaperone Rtt106p controlling H3K56ac deposition. We show that Bcd1p binds Rtt106p and controls its transcription-dependent recruitment by reducing its association with RNA polymerase II, modulating H3K56ac levels at gene body. We reveal the 3D structures of the free and Rtt106p-bound forms of Bcd1p using nuclear magnetic resonance and X-ray crystallography. The interaction is also studied by a combination of biophysical and proteomic techniques. Bcd1p interacts with a region that is distinct from the interaction interface between the histone chaperone and histone H3. Our results are evidence for a protein interaction interface for Rtt106p that controls its transcription-associated activity.
Qualitative similarities and differences in visual object representations between brains and deep networks
Authors: Jacob Georgin , Pramod R. T. , Katti Harish , Arun S. P.
Published: March 2021

Deep neural networks have revolutionized computer vision, and their object representations across layers match coarsely with visual cortical areas in the brain. However, whether these representations exhibit qualitative patterns seen in human perception or brain representations remains unresolved. Here, we recast well-known perceptual and neural phenomena in terms of distance comparisons, and ask whether they are present in feedforward deep neural networks trained for object recognition. Some phenomena were present in randomly initialized networks, such as the global advantage effect, sparseness, and relative size. Many others were present after object recognition training, such as the Thatcher effect, mirror confusion, Weber’s law, relative size, multiple object normalization and correlated sparseness. Yet other phenomena were absent in trained networks, such as 3D shape processing, surface invariance, occlusion, natural parts and the global advantage. These findings indicate sufficient conditions for the emergence of these phenomena in brains and deep networks, and offer clues to the properties that could be incorporated to improve deep networks.
Hinge-shift mechanism as a protein design principle for the evolution of β-lactamases from substrate promiscuity to specificity
Authors: Modi Tushar , Risso Valeria A. , Martinez-Rodriguez Sergio , Gavira Jose A. , Mebrat Mubark D. , Van Horn Wade D. , Sanchez-Ruiz Jose M. , Banu Ozkan S.
Published: March 2021

TEM-1 β-lactamase degrades β-lactam antibiotics with a strong preference for penicillins. Sequence reconstruction studies indicate that it evolved from ancestral enzymes that degraded a variety of β-lactam antibiotics with moderate efficiency. This generalist to specialist conversion involved more than 100 mutational changes, but conserved fold and catalytic residues, suggesting a role for dynamics in enzyme evolution. Here, we develop a conformational dynamics computational approach to rationally mold a protein flexibility profile on the basis of a hinge-shift mechanism. By deliberately weighting and altering the conformational dynamics of a putative Precambrian β-lactamase, we engineer enzyme specificity that mimics the modern TEM-1 β-lactamase with only 21 amino acid replacements. Our conformational dynamics design thus re-enacts the evolutionary process and provides a rational allosteric approach for manipulating function while conserving the enzyme active site.
Dynamic lattice distortions driven by surface trapping in semiconductor nanocrystals
Authors: Guzelturk Burak , Cotts Benjamin L. , Jasrasaria Dipti , Philbin John P. , Hanifi David A. , Koscher Brent A. , Balan Arunima D. , Curling Ethan , Zajac Marc , Park Suji , Yazdani Nuri , Nyby Clara , Kamysbayev Vladislav , Fischer Stefan , Nett Zach , Shen Xiaozhe , Kozina Michael E. , Lin Ming-Fu , Reid Alexander H. , Weathersby Stephen P. , Schaller Richard D. , Wood Vanessa , Wang Xijie , Dionne Jennifer A. , Talapin Dmitri V. , Alivisatos A. Paul , Salleo Alberto , Rabani Eran , Lindenberg Aaron M.
Published: March 2021

Nonradiative processes limit optoelectronic functionality of nanocrystals and curb their device performance. Nevertheless, the dynamic structural origins of nonradiative relaxations in such materials are not understood. Here, femtosecond electron diffraction measurements corroborated by atomistic simulations uncover transient lattice deformations accompanying radiationless electronic processes in colloidal semiconductor nanocrystals. Investigation of the excitation energy dependence in a core/shell system shows that hot carriers created by a photon energy considerably larger than the bandgap induce structural distortions at nanocrystal surfaces on few picosecond timescales associated with the localization of trapped holes. On the other hand, carriers created by a photon energy close to the bandgap of the core in the same system result in transient lattice heating that occurs on a much longer 200 picosecond timescale, dominated by an Auger heating mechanism. Elucidation of the structural deformations associated with the surface trapping of hot holes provides atomic-scale insights into the mechanisms deteriorating optoelectronic performance and a pathway towards minimizing these losses in nanocrystal devices.
Quantitative characterization of extracellular vesicle uptake and content delivery within mammalian cells
Authors: Bonsergent Emeline , Grisard Eleonora , Buchrieser Julian , Schwartz Olivier , Théry Clotilde , Lavieu Grégory
Published: March 2021

Extracellular vesicles (EVs), including exosomes, are thought to mediate intercellular communication through the transfer of cargoes from donor to acceptor cells. Occurrence of EV-content delivery within acceptor cells has not been unambiguously demonstrated, let alone quantified, and remains debated. Here, we developed a cell-based assay in which EVs containing luciferase- or fluorescent-protein tagged cytosolic cargoes are loaded on unlabeled acceptor cells. Results from dose-responses, kinetics, and temperature-block experiments suggest that EV uptake is a low yield process (~1% spontaneous rate at 1 h). Further characterization of this limited EV uptake, through fractionation of membranes and cytosol, revealed cytosolic release (~30% of the uptaken EVs) in acceptor cells. This release is inhibited by bafilomycin A1 and overexpression of IFITM proteins, which prevent virus entry and fusion. Our results show that EV content release requires endosomal acidification and suggest the involvement of membrane fusion.
Scaffolding proteins guide the evolution of algal light harvesting antennas
Authors: Rathbone Harry W. , Michie Katharine A. , Landsberg Michael J. , Green Beverley R. , Curmi Paul M. G.
Published: March 2021

Photosynthetic organisms have developed diverse antennas composed of chromophorylated proteins to increase photon capture. Cryptophyte algae acquired their photosynthetic organelles (plastids) from a red alga by secondary endosymbiosis. Cryptophytes lost the primary red algal antenna, the red algal phycobilisome, replacing it with a unique antenna composed of αβ protomers, where the β subunit originates from the red algal phycobilisome. The origin of the cryptophyte antenna, particularly the unique α subunit, is unknown. Here we show that the cryptophyte antenna evolved from a complex between a red algal scaffolding protein and phycoerythrin β. Published cryo-EM maps for two red algal phycobilisomes contain clusters of unmodelled density homologous to the cryptophyte-αβ protomer. We modelled these densities, identifying a new family of scaffolding proteins related to red algal phycobilisome linker proteins that possess multiple copies of a cryptophyte-α-like domain. These domains bind to, and stabilise, a conserved hydrophobic surface on phycoerythrin β, which is the same binding site for its primary partner in the red algal phycobilisome, phycoerythrin α. We propose that after endosymbiosis these scaffolding proteins outcompeted the primary binding partner of phycoerythrin β, resulting in the demise of the red algal phycobilisome and emergence of the cryptophyte antenna.
Discovery of a weak topological insulating state and van Hove singularity in triclinic RhBi2
Authors: Lee Kyungchan , Lange Gunnar F. , Wang Lin-Lin , Kuthanazhi Brinda , Trevisan Thaís V. , Jo Na Hyun , Schrunk Benjamin , Orth Peter P. , Slager Robert-Jan , Canfield Paul C. , Kaminski Adam
Published: March 2021

Time reversal symmetric (TRS) invariant topological insulators (TIs) fullfil a paradigmatic role in the field of topological materials, standing at the origin of its development. Apart from TRS protected strong TIs, it was realized early on that more confounding weak topological insulators (WTI) exist. WTIs depend on translational symmetry and exhibit topological surface states only in certain directions making it significantly more difficult to match the experimental success of strong TIs. We here report on the discovery of a WTI state in RhBi2 that belongs to the optimal space group P$$\bar{1}$$

1

¯

, which is the only space group where symmetry indicated eigenvalues enumerate all possible invariants due to absence of additional constraining crystalline symmetries. Our ARPES, DFT calculations, and effective model reveal topological surface states with saddle points that are located in the vicinity of a Dirac point resulting in a van Hove singularity (VHS) along the (100) direction close to the Fermi energy (EF). Due to the combination of exotic features, this material offers great potential as a material platform for novel quantum effects.
Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities
Authors: Oben Bénedith , Froyen Guy , Maclachlan Kylee H. , Leongamornlert Daniel , Abascal Federico , Zheng-Lin Binbin , Yellapantula Venkata , Derkach Andriy , Geerdens Ellen , Diamond Benjamin T. , Arijs Ingrid , Maes Brigitte , Vanhees Kimberly , Hultcrantz Malin , Manasanch Elisabet E. , Kazandjian Dickran , Lesokhin Alexander , Dogan Ahmet , Zhang Yanming , Mikulasova Aneta , Walker Brian , Morgan Gareth , Campbell Peter J. , Landgren Ola , Rummens Jean-Luc , Bolli Niccolò , Maura Francesco
Published: March 2021

Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n = 15) are characterized by later initiation in the patient’s life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.
An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability
Authors: Nagy Zsuzsanna , Seneviratne Janith A. , Kanikevich Maxwell , Chang William , Mayoh Chelsea , Venkat Pooja , Du Yanhua , Jiang Cizhong , Salib Alice , Koach Jessica , Carter Daniel R. , Mittra Rituparna , Liu Tao , Parker Michael W. , Cheung Belamy B. , Marshall Glenn M.
Published: March 2021

To achieve the very high oncoprotein levels required to drive the malignant state cancer cells utilise the ubiquitin proteasome system to upregulate transcription factor levels. Here our analyses identify ALYREF, expressed from the most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between ALYREF and MYCN from transgenic models of neuroblastoma in vitro and in vivo. The two proteins form a nuclear coactivator complex which stimulates transcription of the ubiquitin specific peptidase 3, USP3. We show that increased USP3 levels reduce K-48- and K-63-linked ubiquitination of MYCN, thus driving up MYCN protein stability. In the MYCN-ALYREF-USP3 signal, ALYREF is required for MYCN effects on the malignant phenotype and that of USP3 on MYCN stability. This data defines a MYCN oncoprotein dependency state which provides a rationale for future pharmacological studies.
Pili allow dominant marine cyanobacteria to avoid sinking and evade predation
Authors: Aguilo-Ferretjans Maria del Mar , Bosch Rafael , Puxty Richard J. , Latva Mira , Zadjelovic Vinko , Chhun Audam , Sousoni Despoina , Polin Marco , Scanlan David J. , Christie-Oleza Joseph A.
Published: March 2021

How oligotrophic marine cyanobacteria position themselves in the water column is currently unknown. The current paradigm is that these organisms avoid sinking due to their reduced size and passive drift within currents. Here, we show that one in four picocyanobacteria encode a type IV pilus which allows these organisms to increase drag and remain suspended at optimal positions in the water column, as well as evade predation by grazers. The evolution of this sophisticated floatation mechanism in these purely planktonic streamlined microorganisms has important implications for our current understanding of microbial distribution in the oceans and predator–prey interactions which ultimately will need incorporating into future models of marine carbon flux dynamics.
SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition
Authors: Mullen Peter J. , Garcia Gustavo , Purkayastha Arunima , Matulionis Nedas , Schmid Ernst W. , Momcilovic Milica , Sen Chandani , Langerman Justin , Ramaiah Arunachalam , Shackelford David B. , Damoiseaux Robert , French Samuel W. , Plath Kathrin , Gomperts Brigitte N. , Arumugaswami Vaithilingaraja , Christofk Heather R.
Published: March 2021

Viruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.
Natural product fragment combination to performance-diverse pseudo-natural products
Authors: Grigalunas Michael , Burhop Annina , Zinken Sarah , Pahl Axel , Gally José-Manuel , Wild Niklas , Mantel Yannik , Sievers Sonja , Foley Daniel J. , Scheel Rebecca , Strohmann Carsten , Antonchick Andrey P. , Waldmann Herbert
Published: March 2021

Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.
Coagulase-negative staphylococci release a purine analog that inhibits Staphylococcus aureus virulence
Authors: Chin Denny , Goncheva Mariya I. , Flannagan Ronald S. , Deecker Shayna R. , Guariglia-Oropeza Veronica , Ensminger Alexander W. , Heinrichs David E.
Published: March 2021

Coagulase-negative staphylococci and Staphylococcus aureus colonize similar niches in mammals and conceivably compete for space and nutrients. Here, we report that a coagulase-negative staphylococcus, Staphylococcus chromogenes ATCC43764, synthesizes and secretes 6-thioguanine (6-TG), a purine analog that suppresses S. aureus growth by inhibiting de novo purine biosynthesis. We identify a 6-TG biosynthetic gene cluster in S. chromogenes and other coagulase-negative staphylococci including S. epidermidis, S. pseudintermedius and S. capitis. Recombinant S. aureus strains harbouring this operon produce 6-TG and, when used in subcutaneous co-infections in mice with virulent S. aureus USA300, protect the host from necrotic lesion formation. Used prophylactically, 6-TG reduces necrotic skin lesions in mice infected with USA300, and this effect is mediated by abrogation of toxin production. RNAseq analyses reveal that 6-TG downregulates expression of genes coding for purine biosynthesis, the accessory gene regulator (agr) and ribosomal proteins in S. aureus, providing an explanation for its effect on toxin production.
Dissection of two routes to naïve pluripotency using different kinase inhibitors
Authors: Martinez-Val Ana , Lynch Cian J. , Calvo Isabel , Ximénez-Embún Pilar , Garcia Fernando , Zarzuela Eduardo , Serrano Manuel , Munoz Javier
Published: March 2021

Embryonic stem cells (ESCs) can be maintained in the naïve state through inhibition of Mek1/2 and Gsk3 (2i). A relevant effect of 2i is the inhibition of Cdk8/19, which are negative regulators of the Mediator complex, responsible for the activity of enhancers. Inhibition of Cdk8/19 (Cdk8/19i) stimulates enhancers and, similar to 2i, stabilizes ESCs in the naïve state. Here, we use mass spectrometry to describe the molecular events (phosphoproteome, proteome, and metabolome) triggered by 2i and Cdk8/19i on ESCs. Our data reveal widespread commonalities between these two treatments, suggesting overlapping processes. We find that post-transcriptional de-repression by both 2i and Cdk8/19i might support the mitochondrial capacity of naive cells. However, proteome reprogramming in each treatment is achieved by different mechanisms. Cdk8/19i acts directly on the transcriptional machinery, activating key identity genes to promote the naïve program. In contrast, 2i stabilizes the naïve circuitry through, in part, de-phosphorylation of downstream transcriptional effectors.
Predicting treatment response from longitudinal images using multi-task deep learning
Authors: Jin Cheng , Yu Heng , Ke Jia , Ding Peirong , Yi Yongju , Jiang Xiaofeng , Duan Xin , Tang Jinghua , Chang Daniel T. , Wu Xiaojian , Gao Feng , Li Ruijiang
Published: March 2021

Radiographic imaging is routinely used to evaluate treatment response in solid tumors. Current imaging response metrics do not reliably predict the underlying biological response. Here, we present a multi-task deep learning approach that allows simultaneous tumor segmentation and response prediction. We design two Siamese subnetworks that are joined at multiple layers, which enables integration of multi-scale feature representations and in-depth comparison of pre-treatment and post-treatment images. The network is trained using 2568 magnetic resonance imaging scans of 321 rectal cancer patients for predicting pathologic complete response after neoadjuvant chemoradiotherapy. In multi-institution validation, the imaging-based model achieves AUC of 0.95 (95% confidence interval: 0.91–0.98) and 0.92 (0.87–0.96) in two independent cohorts of 160 and 141 patients, respectively. When combined with blood-based tumor markers, the integrated model further improves prediction accuracy with AUC 0.97 (0.93–0.99). Our approach to capturing dynamic information in longitudinal images may be broadly used for screening, treatment response evaluation, disease monitoring, and surveillance.
A rationally engineered decoder of transient intracellular signals
Authors: Lormeau Claude , Rudolf Fabian , Stelling Jörg
Published: March 2021

Cells can encode information about their environment by modulating signaling dynamics and responding accordingly. Yet, the mechanisms cells use to decode these dynamics remain unknown when cells respond exclusively to transient signals. Here, we approach design principles underlying such decoding by rationally engineering a synthetic short-pulse decoder in budding yeast. A computational method for rapid prototyping, TopoDesign, allowed us to explore 4122 possible circuit architectures, design targeted experiments, and then rationally select a single circuit for implementation. This circuit demonstrates short-pulse decoding through incoherent feedforward and positive feedback. We predict incoherent feedforward to be essential for decoding transient signals, thereby complementing proposed design principles of temporal filtering, the ability to respond to sustained signals, but not to transient signals. More generally, we anticipate TopoDesign to help designing other synthetic circuits with non-intuitive dynamics, simply by assembling available biological components.
Association of CYP2D6 genotype and tamoxifen metabolites with breast cancer recurrence in a low-dose trial
Authors: DeCensi Andrea , Johansson Harriet , Helland Thomas , Puntoni Matteo , Macis Debora , Aristarco Valentina , Caviglia Silvia , Webber Tania Buttiron , Briata Irene Maria , D’Amico Mauro , Serrano Davide , Guerrieri-Gonzaga Aliana , Bifulco Ersilia , Hustad Steinar , Søiland Håvard , Boni Luca , Bonanni Bernardo , Mellgren Gunnar
Published: March 2021

Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p < 0.05), and a CRP increase after 3 years was associated with higher risk of recurrence (HR = 4.37, 95% CI, 1.14–16.73, P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.
Thermodynamics of order and randomness in dopant distributions inferred from atomically resolved imaging
Authors: Vlcek Lukas , Yang Shize , Gong Yongji , Ajayan Pulickel , Zhou Wu , Chisholm Matthew F. , Ziatdinov Maxim , Vasudevan Rama K. , Kalinin Sergei V.
Published: March 2021

Exploration of structure-property relationships as a function of dopant concentration is commonly based on mean field theories for solid solutions. However, such theories that work well for semiconductors tend to fail in materials with strong correlations, either in electronic behavior or chemical segregation. In these cases, the details of atomic arrangements are generally not explored and analyzed. The knowledge of the generative physics and chemistry of the material can obviate this problem, since defect configuration libraries as stochastic representation of atomic level structures can be generated, or parameters of mesoscopic thermodynamic models can be derived. To obtain such information for improved predictions, we use data from atomically resolved microscopic images that visualize complex structural correlations within the system and translate them into statistical mechanical models of structure formation. Given the significant uncertainties about the microscopic aspects of the material’s processing history along with the limited number of available images, we combine model optimization techniques with the principles of statistical hypothesis testing. We demonstrate the approach on data from a series of atomically-resolved scanning transmission electron microscopy images of MoxRe1-xS2 at varying ratios of Mo/Re stoichiometries, for which we propose an effective interaction model that is then used to generate atomic configurations and make testable predictions at a range of concentrations and formation temperatures.
Comparison of the diagnostic yield of aCGH and genome-wide sequencing across different neurodevelopmental disorders
Authors: Martinez-Granero Francisco , Blanco-Kelly Fiona , Sanchez-Jimeno Carolina , Avila-Fernandez Almudena , Arteche Ana , Bustamante-Aragones Ana , Rodilla Cristina , Rodríguez-Pinilla Elvira , Riveiro-Alvarez Rosa , Tahsin-Swafiri Saoud , Trujillo-Tiebas Maria Jose , Ayuso Carmen , Rodríguez de Alba Marta , Lorda-Sanchez Isabel , Almoguera Berta
Published: March 2021

Most consensus recommendations for the genetic diagnosis of neurodevelopmental disorders (NDDs) do not include the use of next generation sequencing (NGS) and are still based on chromosomal microarrays, such as comparative genomic hybridization array (aCGH). This study compares the diagnostic yield obtained by aCGH and clinical exome sequencing in NDD globally and its spectrum of disorders. To that end, 1412 patients clinically diagnosed with NDDs and studied with aCGH were classified into phenotype categories: global developmental delay/intellectual disability (GDD/ID); autism spectrum disorder (ASD); and other NDDs. These categories were further subclassified based on the most frequent accompanying signs and symptoms into isolated forms, forms with epilepsy; forms with micro/macrocephaly and syndromic forms. Two hundred and forty-five patients of the 1412 were subjected to clinical exome sequencing. Diagnostic yield of aCGH and clinical exome sequencing, expressed as the number of solved cases, was compared for each phenotype category and subcategory. Clinical exome sequencing was superior than aCGH for all cases except for isolated ASD, with no additional cases solved by NGS. Globally, clinical exome sequencing solved 20% of cases (versus 5.7% by aCGH) and the diagnostic yield was highest for all forms of GDD/ID and lowest for Other NDDs (7.1% versus 1.4% by aCGH) and ASD (6.1% versus 3% by aCGH). In the majority of cases, diagnostic yield was higher in the phenotype subcategories than in the mother category. These results suggest that NGS could be used as a first-tier test in the diagnostic algorithm of all NDDs followed by aCGH when necessary.