Here is some insight into the first ever blockchain advert

All the details on Uber's biggest announcements as well as updates on the controversial company's trials and tribulations

A group of technologists has led crowdsourcing efforts to create a single repository of information for specialists fighting the Coronavirus outbreak. Techworld speaks with founder Edward Saperia to hear more about how collaboration tools can help the efforts

Karin Melnick of the University of Maryland, College Park, has been awarded the AMS Joan and Joseph Birman Fellowship for Women Scholars for the 2020–2021 academic year.

Melnick’s research is on differential-geometric aspects of rigidity. This work comprises global and local results relating the automorphisms of a differential-geometric structure with the geometric and topological properties of the space. Melnick also works in smooth dynamics, in which an invariant differential-geometric structure plays an important role in the proof of rigidity theorems. Melnick is a leader in research on the Lorentzian Lichnerowicz conjecture, a statement about conformal transformations of compact Lorentzian manifolds. Together with collaborators, she has developed new techniques in the setting of Cartan connections that have facilitated progress on this problem, as well as many results for other differential-geometric structures and general parabolic Cartan geometries.  

Brief Biography of Karin Melnick:

Melnick received her PhD at the University of Chicago in 2006 under the direction of Benson Farb. With an NSF Postdoctoral Research Fellowship, she went to Yale University as a Gibbs Assistant Professor. She received a Junior Research Fellowship from the Erwin Schrödinger Institute in the spring of 2009 and that fall began at the University of Maryland, where she is now an associate professor. Previously, Melnick has been awarded an AMS Centennial Fellowship and an NSF CAREER grant. She divides her time between the U.S. and Germany with her partner and their young child, and is very grateful for the flexibility provided by the Birman Fellowship and the opportunities it provides to advance her research and career goals.  

About the Fellowship:

Established in 2017, the AMS Joan and Joseph Birman Fellowship for Women Scholars seeks to give exceptionally talented women extra research support during their mid-career years. The primary selection criterion for the Birman Fellowship, which carries a stipend of US$50,000, is the excellence of the candidate’s research. Read an interview with Joan Birman about her decision to create the Fellowship with the goal of "helping more women mathematicians to develop their creative voices." See more information about the Fellowship.

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The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

Below, Mac Hyman, Tulane University, talks about types of mathematical models--their strengths and weaknesses--the data that we currently have and what we really need, and what models can tell us about a possible second wave.

At the beginning of the video, he thanks the mathematics community for its work, and near the end says, "Our mathematical community is really playing a central role in helping to predict the spread, and help mitigate this epidemic, and prioritize our efforts. …Do not underestimate the power that mathematics can have in helping to mitigate this epidemic—-we have a role to play."

See the full set of videos on modeling COVID-19 and see media coverage of mathematics' role in modeling the pandemic.

The AMS is pleased to announce that Scott Hershberger has been chosen as the 2020 AMS Mass Media Fellow. Scott studied mathematics and physics at Washington University in St. Louis and will graduate in May 2020. He will be working at Scientific American this summer.

The Mass Media Science and Engineering Fellows program is organized by the American Association for the Advancement of Science (AAAS). This program is designed to improve public understanding of science and technology by placing advanced undergraduate, graduate and postgraduate science, mathematics and engineering students in media outlets nationwide. The fellows work for ten weeks over the summer as reporters, researchers, and production assistants alongside media professionals to sharpen their communication skills and increase their understanding of the editorial process by which events and ideas become news.

Now in its 45th year, this fellowship program has placed more than 700 fellows in media organizations nationwide as they research, write, and report today’s headlines. The program is designed to report science-related issues in the media in easy-to-understand ways so as to improve public understanding and appreciation for science and technology.

For more information on the AMS Mass Media Fellowship, visit the website.

(Fundação de Amparo à Pesquisa do Estado de São Paulo) Thanks to its magnetic properties, the material -- zinc-doped manganese chromite -- can be used in a range of products, from gas sensors to data storage devices.

(College of Engineering, Carnegie Mellon University) Carnegie Mellon University's Maarten de Boer and Gianluca Piazza are developing reliable, mechanical switches the size of a DNA molecule, thanks to a $2M LEAP-HI grant from the National Science Foundation.

(University of South Florida (USF Health)) A new preclinical study by researchers at the University of South Florida Health (USF Health) Morsani College of Medicine and Johns Hopkins University School of Medicine offers promise of a specific treatment for NEC, a rare inflammatory bowel disease that is a leading cause of death in premature infants. The team found that inhibiting the inflammatory and blood-clotting molecule thrombin with targeted nanotherapy can protect against NEC-like injury in newborn mice.

(University of Jyväskylä - Jyväskylän yliopisto) Researchers at the universities of Jyvaskyla and Xiamen discovered a novel way to make functional macroscopic crystalline materials out of nanometer-size 34-atom silver-gold intermetallic clusters. The cluster material has a highly anisotropic electrical conductivity, being a semiconductor in one direction and an electrical insulator in other directions. The research was published in Nature Communications on May 6, 2020.

(University of Illinois Grainger College of Engineering) Three Nick Holonyak Jr., Micro and Nanotechnology Lab (HMNTL) faculty members received NSF Rapid Response Research (RAPID) program grants, all of which aim to shorten the amount of time it takes to process a COVID-19 test with less false negatives. Current tests can take as long as five days for results to be.

(Georgia Institute of Technology) The science behind sticky gecko's feet lets gecko adhesion materials pick up about anything. But cost-effective mass production of the materials was out of reach until now. A new method of making them could usher the spread of gecko-inspired grabbers to assembly lines and homes.

(Johannes Gutenberg Universitaet Mainz) Scientists at Johannes Gutenberg University Mainz (JGU) and the Helmholtz Institute Mainz (HIM) in Germany have presented a non-contact method for detecting the state of charge and any defects in lithium-ion batteries.

Claus Sorensen
Represent. Theory 24 (2020), 151-177.
Abstract, references and article information

The Government will distribute free reusable face masks to all Hong Kong citizens, the Innovation & Technology Bureau announced today.

The CuMask, made with six layers and special ergonomic features, was developed by the Hong Kong Research Institute of Textiles & Apparel.

Two of its layers contain copper which is capable of immobilising bacteria, common viruses and other harmful substances.

The mask complies with the American Society for Testing & Materials F2100 Level 1 Standard in terms of particle and bacterial filtration efficiency, resistance to penetration by synthetic blood, and flammability and pressure resistance.

It is also reusable for up to 60 washes.

The bureau said, except for babies and infants, all holders of valid Hong Kong identity cards are eligible to obtain a mask.

Citizens can register online from 7am tomorrow till June 6. Each registration can cater for a maximum of six persons.

Upon successful registration, the mask will be delivered to the door by Hongkong Post within two weeks.

Primary and kindergarten students will each be given two masks, which will be delivered directly to children's schools. Parents do not have to register.

The Government has also arranged to deliver over 140,000 of the masks to residential homes and social welfare institutions for their distribution to those including elderly and the homeless.

Click here for registration details.

Subsidies to local primary producers and wholesale traders operating in fresh food wholesale markets are being disbursed from today, the Agriculture, Fisheries & Conservation Department announced.

The department said 2,847 applications for the subsidy scheme of $10,000 to each local primary producer under the second round of the Anti-epidemic Fund have been received, with 1,294 approved involving a total of $12,940,000.

A total of 346 applications to the scheme to provide a subsidy of $40,000 to each eligible wholesale trader operating in fresh food wholesale markets were also received with 148 approved involving a total of $5,920,000.

The application periods of the two schemes will end on June 1.

Additionally, 57 borrowers have participated in the arrangement of a one-off interest-free deferral of loan repayment for one year under the Fisheries Development Loan Fund, it said.

"In his new book--The Math of Life & Death: 7 Mathematical Principles that Shape Our Lives--mathematician Kit Yates makes complex mathematical concepts easily accessible to anyone, and which can improve decision making in an increasingly quantitative society. In this Q&A, Yates discusses why math is relevant to everyday life." See "Mathematician Kit Yates on Anti Vaxxer Movement, Air Travel Germs and Samoa's Measles Outbreak," by Meredith Wold Schizer, Newsweek, December 23, 2019.

Students in a math class at Columbine High School in Colorado used geometry to work with Habitat for Humanity to build homes for those in need. See the video segment at "Students Build Houses For Families In Need...In Math Class," by Shaun Boyd, CBS4 Denver TV, December 23, 2019.

"Artist uses snow as canvas for massive geometrical designs," by Thomas Peipert, AP, January 16, 2020.

The 2020 Mathematical Art Exhibition Awards were made at the Joint Mathematics Meetings last week "for aesthetically pleasing works that combine mathematics and art." The chosen works were selected from the exhibition of juried works in various media by over 90 mathematicians and artists from around the world.

"Suspended Helical Stair," by Mark Donohue (California College of the Arts, San Francisco, CA), was awarded Best textile, sculpture, or other medium. "A unique cable system to suspend a stair was developed in collaboration with a leading structural engineer. The suspended cables form a double helicoid nested within an ascending spiral hyperboloid to create the necessary points of support for the gravity loads and lateral bracing for the seismic loads. Each concrete stair tread was designed as an independent element that is strung together with the stairs above and below it to form a single spiral stair when the steel cables that run through them are post tensioned. The entire stair tread and suspension cable system can be understood as a play of ruled surfaces with each part related to the other through their shared geometric lineage." The work is string and plywood,45 x 23 x 23 cm, 2018.

2018

"A Unit Domino," by Douglas McKenna (Mathemaesthetics, Inc., Boulder, CO), was awarded Best photograph, painting, or print. "This piece is based upon an artist-discovered "half-domino" space-filling curve. The drawing comprises some half-million connected line segments, arranged in two perfectly recursive levels of double-spiral pairs, slowly changing color, in a single, over-one-mile-long self-avoiding path from lower left to lower right (the lower right square that sticks out is an integral part of its self-negative structure). The limiting curve covers a self-similar gasket tile with an infinitely long, almost-everywhere linear border. With an upside-down copy of itself, two such gaskets of unit area exactly cover a 1x2 domino, without overlap. The artist's app/eBook "Hilbert Curves" for iPad/iPhone explains how he discovered these beautiful constructions." The work is a glicée print,106 x 66 cm, 2015.

"Computational Wings," by David Bachman (Pitzer College, Claremont, CA), received Honorable Mention. "The body of this dragonfly is taken from a photograph, while the wings were computationally generated. A variety of algorithms were used to create them. First, a set of points were randomly populated across each wing and moved by a circle packing algorithm, where the radius of each circle was inversely proportional to the distance from the body. Next, those points were used to create a Voronoi diagram. Main veins were located by a shortest walk algorithm through the edges of this diagram, and those veins were given a variable thickness according to the distance travelled as you traverse them outward from the body." The work is laser etched acrylic, 23 x 35 x 3 cm, 2019.

(Click on the thumbnails to see larger versions of the images.)

The Mathematical Art Exhibition Award "for aesthetically pleasing works that combine mathematics and art" was established in 2008 through an endowment provided to the American Mathematical Society by an anonymous donor who wishes to acknowledge those whose works demonstrate the beauty and elegance of mathematics expressed in a visual art form. The awards are $400 for Best photograph, painting, or print; $400 for Best textile, sculpture, or other medium; and $200 for Honorable Mention. The Mathematical Art Exhibition of juried works in various media is held at the annual Joint Mathematics Meetings of the American Mathematical Society (AMS) and Mathematical Association of America (MAA). a gallery of works in the 2020 exhibition will be on AMS Mathematical Imagery.

Find out more about the Mathematical Art Exhibition Award and see past recipients.

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The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.

Extracytoplasmic sugar decoration of glycopolymer components of the bacterial cell wall contributes to their structural diversity. Typically, the molecular mechanism that underpins such a decoration process involves a three-component glycosylation system (TGS) represented by an undecaprenyl-phosphate (Und-P) sugar-activating glycosyltransferase (Und-P GT), a flippase, and a polytopic glycosyltransferase (PolM GT) dedicated to attaching sugar residues to a specific glycopolymer. Here, using bioinformatic analyses, CRISPR-assisted recombineering, structural analysis of cell wall–associated polysaccharides (CWPS) through MALDI-TOF MS and methylation analysis, we report on three such systems in the bacterium Lactococcus lactis. On the basis of sequence similarities, we first identified three gene pairs, csdAB, csdCD, and csdEF, each encoding an Und-P GT and a PolM GT, as potential TGS component candidates. Our experimental results show that csdAB and csdCD are involved in Glc side-chain addition on the CWPS components rhamnan and polysaccharide pellicle (PSP), respectively, whereas csdEF plays a role in galactosylation of lipoteichoic acid (LTA). We also identified a potential flippase encoded in the L. lactis genome (llnz_02975, cflA) and confirmed that it participates in the glycosylation of the three cell wall glycopolymers rhamnan, PSP, and LTA, thus indicating that its function is shared by the three TGSs. Finally, we observed that glucosylation of both rhamnan and PSP can increase resistance to bacteriophage predation and that LTA galactosylation alters L. lactis resistance to bacteriocin.

Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

Previous studies have shown that sphingosine kinase interacting protein (SKIP) inhibits sphingosine kinase (SK) function in fibroblasts. SK phosphorylates sphingosine producing the potent signaling molecule sphingosine-1-phosphate (S1P). SKIP gene (SPHKAP) expression is silenced by hypermethylation of its promoter in acute myeloid leukemia (AML). However, why SKIP activity is silenced in primary AML cells is unclear. Here, we investigated the consequences of SKIP down-regulation in AML primary cells and the effects of SKIP re-expression in leukemic cell lines. Using targeted ultra-HPLC-tandem MS (UPLC-MS/MS), we measured sphingolipids (including S1P and ceramides) in AML and control cells. Primary AML cells had significantly lower SK activity and intracellular S1P concentrations than control cells, and SKIP-transfected leukemia cell lines exhibited increased SK activity. These findings show that SKIP re-expression enhances SK activity in leukemia cells. Furthermore, other bioactive sphingolipids such as ceramide were also down-regulated in primary AML cells. Of note, SKIP re-expression in leukemia cells increased ceramide levels 2-fold, inactivated the key signaling protein extracellular signal-regulated kinase, and increased apoptosis following serum deprivation or chemotherapy. These results indicate that SKIP down-regulation in AML reduces SK activity and ceramide levels, an effect that ultimately inhibits apoptosis in leukemia cells. The findings of our study contrast with previous results indicating that SKIP inhibits SK function in fibroblasts and therefore challenge the notion that SKIP always inhibits SK activity.

The transcription factor forkhead box P3 (FOXP3) is a biomarker for regulatory T cells and can also be expressed in cancer cells, but its function in cancer appears to be divergent. The role of hepatocyte-expressed FOXP3 in hepatocellular carcinoma (HCC) is unknown. Here, we collected tumor samples and clinical information from 115 HCC patients and used five human cancer cell lines. We examined FOXP3 mRNA sequences for mutations, used a luciferase assay to assess promoter activities of FOXP3's target genes, and employed mouse tumor models to confirm in vitro results. We detected mutations in the FKH domain of FOXP3 mRNAs in 33% of the HCC tumor tissues, but in none of the adjacent nontumor tissues. None of the mutations occurred at high frequency, indicating that they occurred randomly. Notably, the mutations were not detected in the corresponding regions of FOXP3 genomic DNA, and many of them resulted in amino acid substitutions in the FKH region, altering FOXP3's subcellular localization. FOXP3 delocalization from the nucleus to the cytoplasm caused loss of transcriptional regulation of its target genes, inactivated its tumor-inhibitory capability, and changed cellular responses to histone deacetylase (HDAC) inhibitors. More complex FKH mutations appeared to be associated with worse prognosis in HCC patients. We conclude that mutations in the FKH domain of FOXP3 mRNA frequently occur in HCC and that these mutations are caused by errors in transcription and are not derived from genomic DNA mutations. Our results suggest that transcriptional mutagenesis of FOXP3 plays a role in HCC.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Telomeres are specific nucleoprotein structures that are located at the ends of linear eukaryotic chromosomes and play crucial roles in genomic stability. Telomere DNA consists of simple repeats of a short G-rich sequence: TTAGGG in mammals and TTTAGGG in most plants. In recent years, the mammalian telomeric G-rich repeats have been shown to form G-quadruplex (G4) structures, which are crucial for modulating telomere functions. Surprisingly, even though plant telomeres are essential for plant growth, development, and environmental adaptions, only few reports exist on plant telomeric G4 DNA (pTG4). Here, using bulk and single-molecule assays, including CD spectroscopy, and single-molecule FRET approaches, we comprehensively characterized the structure and dynamics of a typical plant telomeric sequence, d[GGG(TTTAGGG)3]. We found that this sequence can fold into mixed G4s in potassium, including parallel and antiparallel structures. We also directly detected intermediate dynamic transitions, including G-hairpin, parallel G-triplex, and antiparallel G-triplex structures. Moreover, we observed that pTG4 is unfolded by the AtRecQ2 helicase but not by AtRecQ3. The results of our work shed light on our understanding about the existence, topological structures, stability, intermediates, unwinding, and functions of pTG4.

Prevention of aberrant cutaneous wound repair and appropriate regeneration of an intact and functional integument require the coordinated timing of fibroblast and keratinocyte migration. Here, we identified a mechanism whereby opposing cell-specific motogenic functions of a multifunctional intracellular and extracellular protein, the receptor for hyaluronan-mediated motility (RHAMM), coordinates fibroblast and keratinocyte migration speed and ensures appropriate timing of excisional wound closure. We found that, unlike in WT mice, in Rhamm-null mice, keratinocyte migration initiates prematurely in the excisional wounds, resulting in wounds that have re-surfaced before the formation of normal granulation tissue, leading to a defective epidermal architecture. We also noted aberrant keratinocyte and fibroblast migration in the Rhamm-null mice, indicating that RHAMM suppresses keratinocyte motility but increases fibroblast motility. This cell context–dependent effect resulted from cell-specific regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) activation and expression of a RHAMM target gene encoding matrix metalloprotease 9 (MMP-9). In fibroblasts, RHAMM promoted ERK1/2 activation and MMP-9 expression, whereas in keratinocytes, RHAMM suppressed these activities. In keratinocytes, loss of RHAMM function or expression promoted epidermal growth factor receptor–regulated MMP-9 expression via ERK1/2, which resulted in cleavage of the ectodomain of the RHAMM partner protein CD44 and thereby increased keratinocyte motility. These results identify RHAMM as a key factor that integrates the timing of wound repair by controlling cell migration.

Hypersecretion of glucagon from pancreatic α-cells strongly contributes to diabetic hyperglycemia. Moreover, failure of α-cells to increase glucagon secretion in response to falling blood glucose concentrations compromises the defense against hypoglycemia, a common complication in diabetes therapy. However, the mechanisms underlying glucose regulation of glucagon secretion are poorly understood and likely involve both α-cell–intrinsic and intraislet paracrine signaling. Among paracrine factors, glucose-stimulated release of the GABA metabolite γ-hydroxybutyric acid (GHB) from pancreatic β-cells might mediate glucose suppression of glucagon release via GHB receptors on α-cells. However, the direct effects of GHB on α-cell signaling and glucagon release have not been investigated. Here, we found that GHB (4–10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells. Glucagon secretion from perifused mouse islets was also unaffected by GHB at both 1 and 7 mm glucose. The GHB receptor agonist 3-chloropropanoic acid and the antagonist NCS-382 had no effects on glucagon secretion and did not affect stimulation of secretion induced by a drop in glucose from 7 to 1 mm. Inhibition of endogenous GHB formation with the GABA transaminase inhibitor vigabatrin also failed to influence glucagon secretion at 1 mm glucose and did not prevent the suppressive effect of 7 mm glucose. In human islets, GHB tended to stimulate glucagon secretion at 1 mm glucose, an effect mimicked by 3-chloropropanoic acid. We conclude that GHB does not mediate the inhibitory effect of glucose on glucagon secretion.

Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.