Education and the “Knowability” Problem

There was a wonderful PBS Nature episode in 2006 called “The Queen of Trees” [full video, YouTube] which went into details about the survival strategy and rhythms and interactions with the environment of one tree in Africa and all the complexities this involves:

This Nature episode explores the evolution of a fig tree in Africa and its only pollinator, the fig wasp. This film takes us through a journey of intertwining relationships. It shows how the fig (queen) tree is life sustaining for an entire range of species, from plants, to insects, to other animals and even mammals. These other species are in turn life-sustaining to the fig tree itself. It could not survive without the interaction of all these different creatures and the various functions they perform. This is one of the single greatest documented (on video) examples of the wonders of our natural world; the intricacies involved for survival and ensuring the perpetual existence of species.

It shows us how fragile the balance is between survival and extinction.

One can begin to see that the tree/animal/bacteria/season/roots/climate interaction is highly complex and not quite fully understood to this day.

The fact that one tree yields new information every time we probe into it gives you a “meta” (i.e., meta-intelligent) clue that final theories of the cosmos and fully unified theories of physics will be elusive at best and unreachable at worst. If one can hardly pin down the workings of a single tree, does it sound plausible that “everything that is” from the electron to galaxy clusters to multiverses will be captured by an equation? The objective answer has to be: not particularly.

Think of the quest of the great unifiers like the great philosopherphysicist Hermann Weyl (died in 1955, like Einstein):

Since the 19th century, some physicists, notably Albert Einstein, have attempted to develop a single theoretical framework that can account for all the fundamental forces of nature–a unified field theory. Classical unified field theories are attempts to create a unified field theory based on classical physics. In particular, unification of gravitation and electromagnetism was actively pursued by several physicists and mathematicians in the years between the two World Wars. This work spurred the purely mathematical development of differential geometry.

Hermann Klaus Hugo Weyl (9 November, 1885 – 8 December, 1955) was a German mathematician, theoretical physicist and philosopher. Although much of his working life was spent in Zürich, Switzerland and then Princeton, New Jersey, he is associated with the University of Göttingen tradition of mathematics, represented by David Hilbert and Hermann Minkowski.

His research has had major significance for theoretical physics as well as purely mathematical disciplines including number theory. He was one of the most influential mathematicians of the twentieth century, and an important member of the Institute for Advanced Study during its early years.

Weyl published technical and some general works on space, time, matter, philosophy, logic, symmetry and the history of mathematics. He was one of the first to conceive of combining general relativity with the laws of electromagnetism. While no mathematician of his generation aspired to the “universalism” of Henri Poincaré or Hilbert, Weyl came as close as anyone.

Weyl is quoted as saying:

“I am bold enough to believe that the whole of physical phenomena may be derived from one single universal world-law of the greatest mathematical simplicity.”

(The Trouble with Physics, Lee Smolin, Houghton Mifflin Co., 2006, page 46)

This reminds one of Stephen Hawking’s credo that he repeated often and without wavering, that the rational human mind would soon understand “the mind of God.”

This WeylHawkingEinstein program of “knowing the mind of God” via a world-equation seems both extremely charming and beautiful, as a human quest, but potentially mono-maniacal à la Captain Ahab in Moby-Dick. The reason that only Ishmael survives the sinking of the ship, the Pequod, is that he has become non-monomaniacal and accepts the variegatedness of the world and thus achieves a more moderate view of human existence and its limits. “The Whiteness of the Whale” chapter in the novel gives you Melville’s sense (from 1851) of the unknowability of some final world-reality or world-theory or world-equation.


New Articles in PLOS Pathogens

Insertive Condom-Protected and Condomless Vaginal Sex Both Have a Profound Impact on the Penile Immune Correlates of HIV Susceptibility

by Avid Mohammadi, Sareh Bagherichimeh, Yoojin Choi, Azadeh Fazel, Elizabeth Tevlin, Sanja Huibner, Zhongtian Shao, David Zuanazzi, Jessica L. Prodger, Sara V. Good, Wangari Tharao & Rupert Kaul

Summary: In heterosexual men, the penis is the primary site of Human Immunodeficiency Virus (HIV) acquisition. Levels of inflammatory cytokines in the coronal sulcus are associated with an increased HIV risk, and we hypothesized that these may be altered after insertive penile sex. Therefore, we designed the Sex, Couples and Science Study (SECS study) to define the impact of penilevaginal sex on the penile immune correlates of HIV susceptibility. We found that multiple coronal sulcus cytokines increased dramatically and rapidly after sex, regardless of condom use, with a return to baseline levels by 72 hours. The changes observed after condomless sex were strongly predicted by cytokine concentrations in the vaginal secretions of the female partner, and were similar in circumcised and uncircumcised men. We believe that these findings have important implications for understanding the immunopathogenesis of penile HIV acquisition; in addition, they have important implications for the design of clinical studies of penile HIV acquisition and prevention.

[Archived PDF]

Engineering, Decoding and Systems-Level Characterization of Chimpanzee Cytomegalovirus

by Quang Vinh Phan, Boris Bogdanow, Emanuel Wyler, Markus Landthaler, Fan Liu, Christian Hagemeier & Lüder Wiebusch

Summary: Human cytomegalovirus (HCMV) infection is associated with systemic disease in immunocompromised individuals and congenitally infected neonates. Animal CMVs and their bacterial artificial chromosome (BAC) clones have been utilized as models for CMV infection and thereby contributed immensely to the understanding of pathogenesis, host immune response and underlying molecular mechanism of CMV infections. As the closest relative to HCMV, the chimpanzee CMV (CCMV) holds a great potential as a model system for HCMV infection but its application was limited due to the lack of tools and data for functional genomic analyses. Here, the cloning of the CCMV as a BAC vector made its viral genome available to gene targeting techniques that allow the efficient application of reverse genetic strategies. Furthermore, the multi-omic datasets created in this study provide an in-depth view of the viral gene repertoire and the host cell responses to infection, confirming the close phylogenetic relationship between HCMV and CCMV on a system level. Taken together, the newly established CCMVBAC system presents a framework for HCMV modeling and comparative studies to address key questions in evolutionary processes and infection mechanisms.

[Archived PDF]

RplI Interacts with 5′ UTR of exsA to Repress Its Translation and Type III Secretion System in Pseudomonas aeruginosa

by Dan Wang, Xinxin Zhang, Liwen Yin, Qi Liu, Zhaoli Yu, Congjuan Xu, Zhenzhen Ma, Yushan Xia, Jing Shi, Yuehua Gong, Fang Bai, Zhihui Cheng, Weihui Wu, Jinzhong Lin & Yongxin Jin

Summary: Ribosomes provide all living organisms the capacity to synthesize proteins. The production of many ribosomal proteins is often controlled by an autoregulatory feedback mechanism. Paeruginosa is an opportunistic human pathogen and its type III secretion system (T3SS) is a critical virulence determinant in host infections. In this study, by screening a Tn5 mutant library, we identified rplI, encoding ribosomal large subunit protein L9, as a novel repressor for the T3SS. Further exploring the regulatory mechanism, we found that the RplI protein interacts with the 5’ UTR (5’ untranslated region) of exsA, a gene coding for transcriptional activator of the T3SS. Such an interaction likely blocks ribosome loading on the exsA 5’ UTR, inhibiting the initiation of exsA translation. The significance of this work is in the identification of a novel repressor for the T3SS and elucidation of its molecular mechanism. Furthermore, this work provides evidence for individual ribosomal protein regulating mRNA translation beyond its autogenous feedback control.

[Archived PDF]

Structure of a Bacterial Rhs Effector Exported by the Type VI Secretion System

by Patrick Günther, Dennis Quentin, Shehryar Ahmad, Kartik Sachar, Christos Gatsogiannis, John C. Whitney & Stefan Raunser

Summary: Bacteria have developed a variety of strategies to compete for nutrients and limited resources. One system widely used by Gram-negative bacteria is the T6 secretion system which delivers a plethora of effectors into competing bacterial cells. Known functions of effectors are degradation of the cell wall, the depletion of essential metabolites such as NAD+ or the cleavage of DNA. RhsA is an effector from the widespread plant-protecting bacteria Pseudomonas protegens. We found that RhsA forms a closed cocoon similar to that found in bacterial Tc toxins and metazoan teneurin proteins. The effector cleaves its polypeptide chain by itself in three pieces, namely the N-terminal domain including a seal, the cocoon and the actual toxic component which potentially cleaves DNA. The toxic component is encapsulated in the large cocoon, so that the effector producing bacterium is protected from the toxin. In order for the toxin to exit the cocoon, we propose that the seal, which closes the cocoon at one end, is removed by mechanical forces during injection of the effector by the T6 secretion system. We further hypothesize about different scenarios for the delivery of the toxin into the cytoplasm of the host cell. Together, our findings expand the knowledge of the mechanism of action of the T6 secretion system and its essential role in interbacterial competition.

[Archived PDF]

Non-Neutralizing Antibodies Targeting the Immunogenic Regions of HIV-1 Envelope Reduce Mucosal Infection and Virus Burden in Humanized Mice

by Catarina E. Hioe, Guangming Li, Xiaomei Liu, Ourania Tsahouridis, Xiuting He, Masaya Funaki, Jéromine Klingler, Alex F. Tang, Roya Feyznezhad, Daniel W. Heindel, Xiao-Hong Wang, David A. Spencer, Guangnan Hu, Namita Satija, Jérémie Prévost, Andrés Finzi, Ann J. Hessell, Shixia Wang, Shan Lu, Benjamin K. Chen, Susan Zolla-Pazner, Chitra Upadhyay, Raymond Alvarez & Lishan Su

Summary: In the past decade, HIV-1 has infected an estimated 1.5 to 2 million people every year, but vaccines needed to control this pandemic are unavailable. Among vaccines tested in the human efficacy trials, the RV144 vaccine regimen showed a modest efficacy and revealed non-neutralizing antibodies against the virus envelope glycoproteins as a correlate of reduced virus acquisition. To design more efficacious HIV-1 vaccines, a better understanding about antiviral mechanisms of these antibodies is needed. Here non-neutralizing monoclonal antibodies against two immunogenic sites on the virus envelope were evaluated for passive administration to humanized mice that were subsequently challenged with HIV-1. The antibodies did not block mucosal HIV-1 infection but reduced virus burden. The level of virus reduction correlated with the antibody binding potency and the effector functions mediated through their Fc fragments, which included antibody-dependent phagocytosis and complement activation, but not the commonly studied antibody-dependent cellular cytotoxicity. The importance of the Fc functions was further demonstrated by reduced virus control when mutations were introduced to decrease Fc activities. This study provides new evidence for the important contribution of multiple Fc-dependent antibody functions in immune control against HIV-1.

[Archived PDF]

Variability in an Effector Gene Promoter of a Necrotrophic Fungal Pathogen Dictates Epistasis and Effector-Triggered Susceptibility in Wheat

by Evan John, Silke Jacques, Huyen T. T. Phan, Lifang Liu, Danilo Pereira, Daniel Croll, Karam B. Singh, Richard P. Oliver & Kar-Chun Tan

Summary: Breeding for durable resistance to fungal diseases in crops is a continual challenge for crop breeders. Fungal pathogens evolve ways to overcome host resistance by masking themselves through effector evolution and evasion of broad-spectrum defense responses. Association studies on mapping populations infected by isolate mixtures are often used by researchers to seek out novel sources of genetic resistance. Disease resistance quantitative trait loci (QTL) are often minor or inconsistent across environments. This is a particular problem with septoria diseases of cereals such as septoria nodorum blotch (SNB) of wheat caused by Parastagonospora nodorum. The fungus uses a suite of necrotrophic effectors (NEs) to cause SNB. We characterized a genetic element, called PE401, in the promoter of the major NE gene Tox1, which is present in some Pnodorum isolates. PE401 functions as a transcriptional repressor of Tox1 and exerts epistatic control on another major SNB resistance QTL in the host. In the context of crop protection, constant surveillance of the pathogen population for the frequency of PE401 in conjunction with NE diversity will enable agronomists to provide the best advice to growers on which wheat varieties can be tailored to provide optimal SNB resistance to regional pathogen population genotypes.

[Archived PDF]

Mutational Analysis of Aedes aegypti Dicer 2 Provides Insights into the Biogenesis of Antiviral Exogenous Small Interfering RNAs

by Rommel J. Gestuveo, Rhys Parry, Laura B. Dickson, Sebastian Lequime, Vattipally B. Sreenu, Matthew J. Arnold, Alexander A. Khromykh, Esther Schnettler, Louis Lambrechts, Margus Varjak & Alain Kohl

Summary: Aedes aegypti mosquitoes that transmit human-pathogenic viruses rely on the exogenous small interfering RNA (exo-siRNA) pathway as part of antiviral responses. This pathway is triggered by virus-derived double-stranded RNA (dsRNA) produced during viral replication that is then cleaved by Dicer 2 (Dcr2) into virus-derived small interfering RNAs (vsiRNAs). These vsiRNAs target viral RNA, leading to suppression of viral replication. The importance of Dcr2 in this pathway has been intensely studied in the Drosophila melanogaster model but is largely lacking in mosquitoes. Here, we have identified conserved and functionally relevant amino acids in the helicase and RNase III domains of Aeaegypti Dcr2 that are important in its silencing activity and antiviral responses against Semliki Forest virus (SFV). Small RNA sequencing of SFV-infected mosquito cells with functional or mutated Dcr2 gave new insights into the nature and origin of vsiRNAs. The findings of this study, together with the different molecular tools we have previously developed to investigate the exo-siRNA pathway of mosquito cells, have started to uncover important properties of Dcr2 that could be valuable in understanding mosquito-arbovirus interactions and potentially in developing or assisting vector control strategies.

[Archived PDF]

Probing the Structure and Function of the Protease Domain of Botulinum Neurotoxins Using Single-Domain Antibodies

by Kwok-ho Lam, Jacqueline M. Tremblay, Kay Perry, Konstantin Ichtchenko, Charles B. Shoemaker & Rongsheng Jin

Summary: Botulinum neurotoxins (BoNTs) are extremely toxic to humans by causing flaccid paralysis of botulism. The catalytic light chain (LC) of BoNTs is the warhead of the toxin, which is mainly responsible for BoNT’s neurotoxic effects. As an endopeptidase, LC is delivered by the toxin to inside neurons where it specifically cleaves neuronal SNARE proteins and causes muscle paralysis. While the currently available equine and human antitoxin sera can prevent further intoxication, they do not promote recovery from paralysis that has already occurred. We strike to develop single-domain variable heavy-chain (VHH) antibodies targeting the LC of BoNT/A (LC/A) and BoNT/B (LC/B) as antidotes to inhibit or eliminate the intraneuronal LC protease. Here, we report the identification and characterization of large panels of new and unique VHHs that bind to LC/A or LC/B. Using a combination of X-ray crystallography and biochemical assays, we reveal that VHHs exploit diverse mechanisms to interact with LC/A and LC/B and inhibit their protease activity, and such knowledge can be harnessed to predict their specificity towards different toxin subtypes within each serotype. We anticipate that the new VHHs and their characterization reported here will contribute to the development of improved botulism therapeutics having high potencies and broad specificities.

[Archived PDF]

B Cell Overexpression of FCRL5 and PD-1 Is Associated with Low Antibody Titers in HCV Infection

by Clinton O. Ogega, Nicole E. Skinner, Andrew I. Flyak, Kaitlyn E. Clark, Nathan L. Board, Pamela J. Bjorkman, James E. Crowe Jr., Andrea L. Cox, Stuart C. Ray & Justin R. Bailey

Summary: Antiviral immunity relies on production of protective immunoglobulin G (IgG) by B cells, but many hepatitis C virus (HCV)-infected individuals have very low levels of HCV-specific IgG in their serum. Elucidating mechanisms underlying this suboptimal IgG expression remains paramount in guiding therapeutic and vaccine strategies. In this study, we developed a highly specific method to capture HCV-specific B cells and characterized their surface protein expression. Two proteins analyzed were Fc receptor-like protein 5 (FCRL5), a cell surface receptor for IgG, and programmed cell death protein-1 (PD-1), a marker of lymphocyte activation and exhaustion. We measured serum levels of anti-HCV IgG in these subjects and demonstrated that overexpression of FCRL5 and PD-1 on memory B cells was associated with reduced anti-E2 IgG levels. This study uses HCV as a viral model, but the findings may be applicable to many viral infections, and they offer new potential targets to enhance antiviral IgG production.

[Archived PDF]

Education and Causality Changes

Scientific classification
Species:H. naledi
Binomial name:Homo naledi
Berger et al., 2015

The box above shows you, if you reflect for a moment, how involved and hierarchical taxonomy can be. The box refers to the tremendous fossil finds around 2013 outside Johannesburg, South Africa by Professor Lee Berger of Witwatersrand University and his team and associates in caves nearby.

The fossil finds are determined to be “homo” and not “australo” as you see in the table above (to the right of the word genus).

The PBS NOVA program “Dawn of Humanity” (2015), is about the story of these fossil finds and the interpretations of the finds which are deeply instructive for all knowledge-seekers, students, etc. because they leave behind any idea of a linear clearly branching “tree of life” in favor of the “bushiness” of evolution (no clear tree structure) and the whole process finally seen as a “braided stream.” This refers to a geological concept of the multiple pathways and reticulations of glacial ice and snow melt going down a mountain valley to a lake. The rivulets, channels, are crisscrossing in a “fluvial” flow pattern that is so complex one doesn’t know exactly which “exact” water went into the lake. If you say the lake is “homo sapiens” (humanity) and the swirling bushy tangled flow is the evolutionary raw material, some final causality is elusive.
When a “braided stream” (this kind of glacial water flow) metaphor gets fused with a “bushiness” one, then one sees that the random factors and endless crisscrossing obscures linear mono-causal explanations as we always imagined.

If you imagine a time when these concepts are applied to history, economy, and society you can begin to sense many “causality revolutions” in front of us where today’s textbooks will seem charmingly naive.

Every student, enrolled or not, should ponder the concepts of “braided streamtaxonomy (shown in the initial table above) and “bushiness” as opposed to tree structure. The student might also “walk around” these metaphors and ask what they imply for the “fractal geometry of nature” (a twig is like a little tree or branch on a bigger tree or branch and so on).